Achalia, R. and C. Andrade (2014).

"Reversible abnormality of the splenium in a

bipolar patient with neuroleptic malignant syndrome." Bipolar Disord 16(7): 773-
775.
OBJECTIVE: To report reversible abnormality of the splenium in a bipolar
patient with neuroleptic malignant syndrome (NMS). METHODS: We studied a 23-year-
old male who received oral and parenteral neuroleptics, atypical antipsychotic
agents, and mood stabilizers, as well as a course of six electroconvulsive therapy
treatments, for an episode of mania. He improved. Five days after discharge on
maintenance atypical antipsychotic agents and mood stabilizers, he returned with
symptoms suggestive of NMS. Laboratory investigations revealed leucopenia,
thrombocytopenia, and elevated creatine phosphokinase levels. Brain magnetic
resonance imaging showed swelling of the splenium with centrally restricted
diffusion; there was no other abnormality. He was defensively treated with
antimicrobials, methylprednisolone, and bromocriptine. RESULTS: Clinical recovery
was complete after nine days, and the splenium lesion resolved after four further
days; there were no neuropsychiatric sequelae. Nine months later, the patient
remains well on maintenance lithium therapy. CONCLUSIONS: This is the first report
of an isolated splenial lesion reversing within days of resolution of NMS. The
outcome supports the recent literature which suggests that an isolated splenial
lesion does not need investigation, and that prognosis depends on the underlying
disorder, and not on the presence or absence of the splenial lesion.

Adida, M., et al. (2010). "[Affective disorders, antipsychotics and mood

stabilizers: Therapeutic innovations]." Encephale 36 Suppl 6: S188-196.
Management of bipolar disorder has undergone many revisions in recent years
as new agents and treatments have been developed and studied with variable success.
In conjunction with the advent of novel therapies and indications, there has been
an increase in the understanding of the phenomenology and neurobiology of bipolar
disorder that has made the classification and management of the illness necessarily
more sophisticated. However, there remains a significant delay of 8 years in
detecting and diagnosing bipolar disorder, and a further need to improve
treatments. However, this paper has emphasized the need to be aware of recent
advances and the emerging uses of new pharmacological treatments in the management
of bipolar disorder. It has also highlighted the need for tailoring management to
the individual. In particular, the successful treatment of bipolar disorder
requires achieving prophylaxis and preventing relapse. In this regard, maintenance
therapy is of paramount importance, and thus the tolerability of agents needs to be
considered throughout treatment and should be factored into all management
decisions. At the centre is the individual with bipolar disorder and the need to
maintain a healthy therapeutic relationship. However, it is important to note that
the evidence synthesized in this paper serves only as a guide to the management of
bipolar disorder and that, in clinical practice, all treatment recommendations
require contextual interpretation, the consideration of local factors and the
consultation of additional resources.

Al Jurdi, R. K., et al. (2010). "Role of extended release quetiapine in the

management of bipolar disorders." Neuropsychiatr Dis Treat 6: 29-35.
Atypical antipsychotics have become a widely utilized component of the
bipolar disorder treatment armamentarium, with approximately 45% of bipolar
patients prescribed atypicals. Over the last decade all atypical drugs except for
clozapine have received a Food and Drug Administration (FDA) bipolar indication. In
October 2008, the FDA approved quetiapine XR monotherapy for the treatment of acute
depressive episodes of bipolar disorder and acute manic or mixed episodes in
bipolar I disorder based on two placebo-control trials. Quetiapine was also
approved as adjunct therapy with lithium and divalproex for the treatment of acute
manic or mixed episodes as well as maintenance of bipolar I disorder. In contrast
to immediate release quetiapine which may require a twice-daily regimen, the XR
formulation is intended for once-daily administration. This drug profile of
quetiapine XR will address chemistry, pharmacodynamics, pharmacokinetics,
metabolism, safety and tolerability and clinical trials in bipolar disorder.

Albert, U., et al. (2013). "Lithium-associated hyperparathyroidism and

hypercalcaemia: a case-control cross-sectional study." J Affect Disord 151(2): 786-
790.
BACKGROUND: Lithium is recommended as a first-line treatment for Bipolar
Disorder (BD). Thyroid and renal alterations are well known lithium side-effects,
while effects on parathyroids are less studied. The aim of this case-control cross-
sectional study is to compare parathyroid hormone (PTH) and calcium levels in
lithium-exposed bipolar patients and in subjects who had never been exposed to
lithium. METHODS: 112 BD patients were enrolled, 58 on lithium since at least 1
month (mean exposure 60.8 +/- 74.8 months) and 54 in the control group. Blood exams
included complete blood count, PTH, total and ionized calcium, TSH, T3 and T4,
creatinine, urea, sodium and potassium, and lithium serum levels. The Student's t-
test and the Pearson's Chi-square test were used for bivariate analyses. A linear
regression model was used to analyze the relationship between the duration of
exposure to lithium and PTH and calcium levels. RESULTS: PTH and ionized calcium
levels were significantly higher in lithium-exposed patients; the proportions of
subjects with hyperparathyroidism (8.6%) and hypercalcaemia (24.1%) were
significantly greater in lithium-exposed patients. The linear regression analyses
showed a significant effect of exposure to lithium in months on ionized calcium
levels but not on PTH levels. LIMITATIONS: Given the cross-sectional design of the
study we could not identify the exact time of occurrence of hyperparathyroidism.
CONCLUSIONS: Our results indicate that lithium-associated stimulation of
parathyroid function is more common than assumed to date. Among parameters to be
evaluated prior to lithium implementation and during long-term lithium maintenance,
calcium (and eventually PTH) should be added.

Albert, U., et al. (2015). "Effects of maintenance lithium treatment on serum

parathyroid hormone and calcium levels: a retrospective longitudinal naturalistic
study." Neuropsychiatr Dis Treat 11: 1785-1791.
OBJECTIVE: The aim of this retrospective longitudinal naturalistic study was
to evaluate the effects of maintenance lithium treatment on parathyroid hormone
(PTH) and calcium levels. METHODS: A retrospective longitudinal naturalistic study
design was used. Data were collected from the database of a tertiary psychiatric
center covering the years 2010-2014. Included were bipolar patients who had never
been exposed to lithium and had lithium started, and who had PTH, and total and
ionized calcium levels available before and during lithium treatment. Paired t-
tests were used to analyze changes in PTH and calcium levels. Linear regressions
were performed, with mean lithium level and duration of lithium exposure as
independent variables and change in PTH levels as dependent variable. RESULTS: A
total 31 patients were included. The mean duration of lithium treatment was 18.6+/-
11.4 months. PTH levels significantly increased during lithium treatment (+13.55+/-
14.20 pg/mL); the rate of hyperparathyroidism was 12.9%. Neither total nor ionized
calcium increased from baseline to follow-up; none of our patients developed
hypercalcemia. Linear regressions analyses did not show an effect of duration of
lithium exposure or mean lithium level on PTH levels. CONCLUSION: Lithium-
associated stimulation of parathyroid function is more common than assumed to date.
Among parameters to be evaluated prior to lithium implementation, calcium and PTH
should be added.

Albert, U., et al. (2014). "[Lithium treatment and potential long-term side
effects: a systematic review of the literature]." Riv Psichiatr 49(1): 12-21.
INTRODUCTION AND AIM: Lithium is recommended by all treatment guidelines for
bipolar disorder (BD) as a first-line maintenance treatment. However, the potential
side effects and risks associated with long-term lithium use may at times make the
implementation of these recommendations in daily practice challenging. The aim of
the study is to review available literature on potential long-term side effects of
lithium. MATERIALS AND METHODS: A PubMed/Medline search was performed on papers
dealing with long-term treatment with lithium and side effects. Articles published
from January 1980 to February 2013 were selected. RESULTS: Long-term lithium
treatment is associated with a reduced urinary concentrating ability, with
subsequent polyuria and polidypsia and nephrogenic diabetes insipidus (in 10-40% of
patients). Lithium also reduces glomerular filtration rate, and increases risk of
renal failure, although the absolute risk is small (0.5% of patients). Lithium
treatment is associated with significant higher TSH levels, with a 6-fold greater
risk of hypothyroidism in lithium-treated than in control subjects. Less known is
the increase of PTH and calcium levels induced by lithium. An exacerbation of
psoriasis is also frequently associated with lithium treatment. CONCLUSIONS:
Lithium remains a fundamental tool for the treatment of BD. Clinicians should know
potential side effects (renal, endocrine and dermatological) associated with long-
term treatment with lithium, for a correct management of the patient. A specialist
referral is often necessary; the question is how to deal with long-term side
effects more than whether or not withdrawing lithium. This decision should remain a
psychiatrist's competence.

Al-Ghoul, K. J., et al. (2010). "A novel terminal web-like structure in cortical
lens fibers: architecture and functional assessment." Anat Rec (Hoboken) 293(11):
1805-1815.
This study describes a novel cytoskeletal array in fiber cells of the ocular
lens of the rat and shows its relationship to the classical terminal web of other
epithelial tissues. Naive adult Sprague-Dawley rats (n = 28) were utilized. F-
actin, fodrin, myosin IIA, and CP49 distribution was assessed in anterior and
posterior polar sections. For functional analysis, lenses were cultured with or
without cytochalasin-D for 3 hr, then processed for confocal microscopy or assessed
by laser scan analysis along sutures. Phalloidin labeling demonstrated a dense mesh
of F-actin adjacent to posterior sutural domains to a subcapsular depth of 400 mum.
Anterior polar sections revealed a comparable actin structure adjacent to anterior
suture branches however, it was not developed in superficial fibers. Fodrin and
myosin were localized within the web-like actin apparatus. The data was used to
construct a model showing that the cytoskeletal array is located within the blunt,
variable-width fiber ends that abut at sutures such that the "terminal web" flanks
the suture on either side. Treatment with cytochalasin-D resulted in partial
disassembly of the "terminal web" and perturbed cellular organization. Laser scan
analysis revealed that cytochalasin-D treated lenses had significantly greater
focal variability than control lenses (P = 0.020). We conclude that cortical fibers
of rat lenses contain a bipolar structure that is structurally and compositionally
analogous to classical terminal webs. The results indicate that the lens "terminal
web" functions to stabilize lens fiber ends at sutures thus minimizing structural
disorder, which in turn, promotes the establishment and maintenance of lens
transparency.

Alphs, L., et al. (2016). "Paliperidone for the treatment of schizoaffective

disorder." Expert Opin Pharmacother 17(6): 871-883.
INTRODUCTION: Schizoaffective disorder (SCA) is a complex mental illness
characterized by psychosis and affective symptoms. Treatment usually involves
concomitant therapy with antipsychotics, mood stabilizers, and/or antidepressants.
Effective treatment must address acute symptoms, maintain long-term stability,
promote recovery, and improve patient functioning. AREAS COVERED: Data from 3
pivotal studies evaluating the acute and maintenance treatment of SCA with
paliperidone are reviewed. Two formulations of paliperidone have been studied for
these indications: an extended-release oral formulation (NCT00397033, NCT00412373)
and long-acting injectable once-monthly paliperidone palmitate (NCT01193153). The
reported effects of these formulations on psychotic, depressive, and manic symptoms
are discussed. EXPERT OPINION: Both formulations were found to be safe and
effective for the acute and maintenance treatment of SCA. Of critical importance
for this treatment population is that rapid improvement was seen in all major
symptoms of SCA, including psychosis, depression, and mania. Mediation analyses
suggest that the known antipsychotic effects of paliperidone occur independently of
its antidepressant effects. Both formulations of the drug are effective when used
as monotherapy or adjunctively with antidepressants or mood stabilizers. Beyond
symptom control, both formulations improved patient functioning and increased
patient satisfaction.

Amino, K., et al. (2011). "Successful treatment with maintenance electroconvulsive

therapy for a patient with medication-resistant rapid cycling bipolar disorder."
Psychiatry Clin Neurosci 65(3): 299-300.

Anderson, S. L. and J. P. Vande Griend (2014). "Quetiapine for insomnia: A review

of the literature." Am J Health Syst Pharm 71(5): 394-402.
PURPOSE: The safety and efficacy of quetiapine for the treatment of insomnia
in adults are reviewed. SUMMARY: Quetiapine was developed for the treatment of
psychiatric disorders, but its antagonism of histamine H1- and serotonin type 2A
receptors has the added effect of causing sedation. As such, quetiapine is widely
used off-label as a treatment for insomnia. Due to quetiapine's potential adverse
effects, guidelines for the treatment of insomnia have recommended the drug's use
only in patients with specific comorbid psychiatric disorders. The use of
quetiapine for the treatment of insomnia in the absence of comorbid conditions has
been evaluated in only two clinical trials of 31 patients in total, and very few
studies have evaluated quetiapine use in patients with insomnia and other
comorbidities. No trials have been conducted comparing quetiapine with an active
control (e.g., zolpidem); the data that exist compare quetiapine to a placebo or
there is no comparison and all patients are treated with quetiapine. Very few
studies have evaluated quetiapine's efficacy in the treatment of insomnia using
sleep objective testing, another limitation of the available data on quetiapine.
CONCLUSION: Robust studies evaluating the safety and efficacy of quetiapine for the
treatment of insomnia are lacking. Given its limited efficacy data, its adverse-
effect profile, and the availability of agents approved by the Food and Drug
Administration for the treatment of insomnia, quetiapine's benefit in the treatment
of insomnia has not been proven to outweigh potential risks, even in patients with
a comorbid labeled indication for quetiapine.

Andrade, C. (2015). "Examination of participant flow in the CONSORT diagram can

improve the understanding of the generalizability of study results." J Clin
Psychiatry 76(11): e1469-1471.
A fundamental principle in research is that the findings of a study can only
be generalized to the population from which the sample of the study was drawn. What
this population was can be discerned from an examination of the study selection
criteria. Additional insights can sometimes be gleaned from the study flowchart or
CONSORT diagram, which may show sample attenuation between subject screening and
final recruitment. Such sample attenuation, if present, implies further limitation
to the generalizability of the study outcomes. Two large, 2-year, randomized
controlled maintenance therapy trials are described to illustrate sample
attenuation that limits study generalizability, one in the context of mindfulness-
based cognitive therapy versus antidepressant drugs for recurrent major depressive
disorder and the other in the context of quetiapine versus placebo for bipolar
disorder. Readers therefore need to examine both study selection criteria and the
CONSORT diagram in order to better understand the extent to which study results
apply to the patients whom they see.

Angst, J., et al. (2010). "Subjective distress predicts treatment seeking for
depression, bipolar, anxiety, panic, neurasthenia and insomnia severity spectra."
Acta Psychiatr Scand 122(6): 488-498.
OBJECTIVE: To examine correlates of mental health treatment seeking such as
gender, diagnosis, impairment, distress and mastery. METHOD: Longitudinal
epidemiological data from the Zurich Study of common psychiatric syndromes,
including unipolar and bipolar depression, panic, anxiety, neurasthenia and
insomnia, were utilized. In longitudinal Generalized Estimating Equations,
treatment seeking was regressed on measures of subjective distress and impairment,
childhood family problems, mastery and number of comorbid diagnoses. RESULTS:
Approximately half of all treated participants across all six syndromes suffered
from subthreshold disorders. Meeting full or subthreshold diagnostic criteria was
associated with treatment seeking for insomnia. Being female was associated with
treatment seeking for depression. The only variable highly and consistently
associated with treatment seeking, across all syndromes, was subjective distress.
Treated participants reported high levels of distress, work and social impairment
in both diagnostic and subthreshold groups. CONCLUSION: Subjective distress may be
a better indicator of treatment seeking than symptom count.

Applebaum, A. J., et al. (2010). "Rates of mood and anxiety disorders and
contributors to continued heroin use in methadone maintenance patients: A
comparison by HIV status." Neurobehav HIV Med 2010(2): 49-57.
The frequency of mood and anxiety disorders is elevated among individuals
with a history of intravenous drug abuse and among those with human
immunodeficiency virus (HIV), and these disorders are associated with continued
substance use despite treatment. The present study examined rates of mood and
anxiety disorders, and recent heroin use, among HIV-infected and HIV-noninfected
patients receiving methadone maintenance therapy. Participants were 160 (80 HIV-
infected, 80 HIV-noninfected) methadone patients. Clinician-administered,
semistructured interviews were used to identify unipolar and bipolar depression,
and four major anxiety disorders (panic disorder with agoraphobia [PDA],
generalized anxiety disorder [GAD], post-traumatic stress disorder [PTSD], and
social anxiety disorder [SAD]). Toxicology screens and self-reporting were used to
assess heroin, cocaine, marijuana, and alcohol use over the past month. The entire
sample met criteria for at least one psychiatric disorder other than substance
dependence. Substantial proportions of participants met criteria for major
depressive disorder (55.6%), bipolar I, bipolar II, or cyclothymia (6.4%), PDA
(34.4%), GAD (22.5%), SAD (16.9%), and PTSD (34.4%). A greater proportion of HIV-
infected participants met criteria for SAD (chi2 = 5.03), and a greater proportion
of HIV-noninfected participants met criteria for GAD (chi2 = 5.39, P < 0.01). About
14% of participants continued to use heroin over the past month, a significantly
greater proportion of whom were HIV-infected. In adjusted analyses, none of the
mood or anxiety disorders emerged as significant predictors of recent heroin use,
but being HIV-infected did. This study highlights the high rate of psychopathology
and continued heroin use despite substance abuse treatment, and underscores the
need for interventions that help mitigate these problems among methadone patients.

Arora, M. and S. K. Praharaj (2014). "Olanzapine discontinuation emergent

recurrence in bipolar disorder." Indian J Psychol Med 36(2): 170-173.
OBJECTIVE: The efficacy of atypical antipsychotics including olanzapine in
acute treatment of manic episode has been established, whereas its role in
maintenance treatment is not clear. MATERIALS AND METHODS: Thirteen patients of
bipolar disorder who were on regular treatment with mood stabilizer and
subsequently relapsed into mania or depressive episode after discontinuation of
olanzapine were studied for various socio-demographic and clinical factors using
retrospective chart review. RESULTS: There was no correlation found between the
period of tapering olanzapine, time to recurrence of episode after discontinuation,
and the dosage of olanzapine at the time of discontinuation. The predominant early
signs of relapse after discontinuation of olanzapine included sleep disturbance
(72.7%), lack of insight for change in behavior (72.7%), irritability (54.5%), and
elevated mood (45.5%). CONCLUSION: Mood stabilizer alone as a maintenance therapy
of bipolar disorder may be inadequate for long-term management. A low dose of
olanzapine along with mood stabilizers might be useful for prevention of recurrence
in bipolar disorder.

Arvilommi, P., et al. (2010). "Maintenance treatment received by patients with

bipolar I and II disorders--a naturalistic prospective study." J Affect Disord
121(1-2): 116-126.
BACKGROUND: We investigated the adequacy of maintenance phase pharmacotherapy
received by psychiatric in- and outpatients with bipolar I or II disorder,
including patients both with and without a clinical diagnosis of bipolar disorder
(BD). METHODS: In the Jorvi Bipolar Study (JoBS), a naturalistic prospective 18-
month study representing psychiatric in- and outpatients with DSM-IV BD I and II in
three Finnish cities, we studied the adequacy of pharmacological treatment received
by 154 patients during the first maintenance phase after index episode. Information
on treatments prescribed during the follow-up was gathered in interviews and from
psychiatric records. RESULTS: Of the patients with a maintenance phase in follow-
up, adequate maintenance treatment was received by 75.3% for some time, but by only
61.0% throughout the maintenance phase and for 69.3% of the time (783/1129 patient
months) indicated. Uninterrupted adequate maintenance treatment received was most
strongly independently associated with having a clinical diagnosis of BD; other
associations included inpatient treatment, rapid cycling and not having a
personality disorder. LIMITATIONS: Adequacy of dosage, duration or serum
concentrations were not estimated. Findings represent an upper limit for adequate
treatment within the cohort. CONCLUSIONS: Provision or continuity of maintenance
treatment was found to be compromised in more than one-third of BD patients during
their first follow-up maintenance phase. As expected, clinical diagnosis of BD has
a decisive role in determining adequacy of maintenance treatments. However, also
rapid cycling may facilitate provision of adequate maintenance treatment, whereas
outpatients and those with comorbid personality disorders may be disadvantaged
subgroups.

Atigari, O. V. and D. Healy (2013). "Sustained antidepressant response to

ketamine." BMJ Case Rep 2013.
Case series outlining the treatment of three patients with ketamine, in which
two of the patients had a sustained antidepressant effect to ketamine without the
need for maintenance on antidepressants. These two responders have an established
diagnosis of bipolar affective disorder with a history of response to
electroconvulsive therapy and lithium, both of which have an influence on the
seizure threshold as has ketamine. The mechanism of action of ketamine is yet
unclear and although the current focus is on the N-methyl-d-aspartate and alpha-
amino-3-4-hydroxy-5methyl-4-isoxazoleproprionic acid receptors, we additionally
recommend that its impact on the seizure threshold should be explored with a view
to fully elucidating the mechanism of action.

Awaluddin, A., et al. (2015). "Roles of primary care physicians in managing bipolar
disorders in adults." Malays Fam Physician 10(3): 27-31.
Management of bipolar disorder (BD) is challenging due to its multiple and
complex facets of presentations as well as various levels of interventions. There
is also limitation of treatment accessibility especially at the primary care level.
Local evidence-based clinical practice guidelines address the importance of
integrated care of BD at various levels. Primary care physicians hold pertinent
role in maintaining remission and preventing relapse by providing systematic
monitoring of people with BD. Pharmacological treatment in particular mood
stabilisers remain the most effective management with psychosocial interventions as
adjunct. This paper highlights the role of primary care physicians in the
management of BD.

Azab, A. N., et al. (2015). "Lithium nephrotoxicity." Int J Bipolar Disord 3(1):
28.
Reports of toxic effects on the kidney of lithium treatment emerged very soon
after lithium therapy was introduced. Lithium-induced nephrogenic diabetes
insipidus is usually self-limiting or not clinically dangerous. Some reports of
irreversible chronic kidney disease and renal failure were difficult to attribute
to lithium treatment since chronic kidney disease and renal failure exist in the
population at large. In recent years, large-scale epidemiological studies have
convincingly shown that lithium treatment elevates the risk of chronic kidney
disease and renal failure. Most patients do not experience renal side effects. The
most common side effect of polyuria only weakly predicts increasing creatinine or
reduced kidney function. Among those patients who do experience decrease in
creatinine clearance, some may require continuation of lithium treatment even as
their creatinine increases. Other patients may be able to switch to a different
mood stabilizer medication, but kidney function may continue to deteriorate even
after lithium cessation. Most, but not all, evidence today recommends using a lower
lithium plasma level target for long-term maintenance and thereby reducing risks of
severe nephrotoxicity.

Azorin, J. M., et al. (2010). "[Management of patients with acute manic or mixed
episodes and outcome at three months]." Encephale 36(3): 226-235.
METHODS: EMBLEM is a prospective, multicenter observational study on the
management of patients with a manic or mixed episode in routine clinical practice
(total of 3566 subjects included in 14 European countries). The study consisted of
a 12-week acute phase and a 24-month maintenance phase. Subjects were included if
they initiated or changed oral medication, according to the decision of the
treating psychiatrist, with antipsychotics, anticonvulsants and / or lithium, for
the treatment of a manic or mixed episode. The present report describes the acute
phase outcomes of the French subgroup. RESULTS: Between December 2002 and June
2004, 126 investigators included a total of 795 subjects as in- or outpatients (450
women, 320 men, mean age: 45.6 years). The episode was most often recurrent (74.7
%) and patients were suffering from either a manic (65.8 %) or a mixed episode
(34.2 % vs. EMBLEM Europe, 24 %). The intensity of manic symptoms was elevated
(YMRS mean total score: 26.6) and functional impairment of the individuals was
high, with 41.9 % experiencing moderate to severe work impairment and 23.6 % being
unable to work. The prevalence of suicide attempts was 35.8 % (lifelong), close to
the prevalence in the other French cohort EPIMAN (32 %). Abuse / dependence on
alcohol and cannabis were present in 10.2 % and 11.1 % of subjects, respectively.
At entry, 37.4 % were receiving monotherapy while 27.3 % received a combined
therapy. All patients received treatment for their manic / mixed episode, either in
combination (59.2 %) or in monotherapy (40.8 %). Atypical antipsychotics were more
often prescribed in association (34.0 % of subjects) than in monotherapy (21.1 %).
In patients treated in monotherapy, atypical antipsychotics were the most often
prescribed drug (51.9 %). Results showed an improvement within both monotherapy and
combination therapy in effectiveness measures at week 12. After 12 weeks, 31.3 %
were considered recovered and 67.9 % did not relapse. These results confirm current
data on co-morbidities and give information on treatment for bipolar patients at
three months of follow-up. The long-term evaluation of the French EMBLEM cohort -
12, 24 months and up to five years - is presently ongoing.

Baandrup, L., et al. (2016). "Objective and subjective sleep quality: Melatonin
versus placebo add-on treatment in patients with schizophrenia or bipolar disorder
withdrawing from long-term benzodiazepine use." Psychiatry Res 240: 163-169.
Benzodiazepines are frequently long-term prescribed for the treatment of
patients with severe mental illness. This prescribing practice is problematic
because of well-described side effects including risk of dependence. We examined
the efficacy of prolonged-release melatonin on objective and subjective sleep
quality during benzodiazepine discontinuation and whether sleep variables were
associated with benzodiazepine withdrawal. Eligible patients included adults with a
diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder and long-
term use of benzodiazepines in combination with antipsychotics. All participants
gradually tapered the use of benzodiazepines after randomization to add-on
treatment with melatonin versus placebo. Here we report a subsample of 23 patients
undergoing sleep recordings (one-night polysomnography) and 55 patients
participating in subjective sleep quality ratings. Melatonin had no effect on
objective sleep efficiency, but significantly improved self-reported sleep quality.
Reduced benzodiazepine dosage at the 24-week follow-up was associated with a
significantly decreased proportion of stage 2 sleep. These results indicate that
prolonged-release melatonin has some efficacy for self-reported sleep quality after
gradual benzodiazepine dose reduction, and that benzodiazepine discontinuation is
not associated with rebound insomnia in medicated patients with severe mental
illness. However, these findings were limited by a small sample size and a low
retention rate.

Baek, J. H., et al. (2015). "Anxiety symptoms are linked to new-onset suicidal
ideation after six months of follow-up in outpatients with major depressive
disorder." J Affect Disord 187: 183-187.
BACKGROUND: Suicide risk evaluation is one of the most challenging
assessments of patients with major depressive disorder (MDD). Initial risk
evaluation might be insufficient in predicting emergence of suicidal ideation
during the maintenance period. We aimed to elucidate factors associated with
emergence or persistence of suicidal ideation 6 months after initiation of
outpatient treatment in patients with MDD. METHODS: A total of 300 participants
with MDD defined by DSM-IV-TR criteria underwent face-to-face interview at baseline
and follow-up phone interview at 6 months later. Severity of depression, suicidal
ideation, and anxiety were evaluated. RESULTS: Among participants who did not
report any suicidal idea at baseline, 10.9% reported suicidal ideation during the
6-month phone interview, while 28.4% of participants who reported suicidal ideation
at baseline reported suicidal ideation during the phone interview. No significant
difference in remission rate of depression was observed between the groups, but
subjects without suicidal ideation at baseline had a higher rate of symptom
improvement at the 6-month phone interview. After controlling for age, sex,
baseline severity of suicide risk and depression and lifetime history of suicide
attempts, emergence of suicidal ideation was significantly associated with anxiety
level at baseline (t=2.127, p=0.039) and severity of depression symptoms at 6 month
(t=-3.028, p=0.004); persistence of suicidal ideation was associated with severity
of depression symptoms at 6 month (t=-4.962, p<0.001). LIMITATION: Follow-up
evaluation was done by phone interview. CONCLUSION: Anxiety at baseline needs to be
carefully evaluated in assessing suicide risk of patients with MDD.

Baek, J. H., et al. (2014). "Clinical applications of herbal medicines for anxiety
and insomnia; targeting patients with bipolar disorder." Aust N Z J Psychiatry
48(8): 705-715.
OBJECTIVES: Patients with bipolar disorder frequently continue to experience
residual anxiety and insomnia between mood episodes. In real-world practice,
patients increasingly self-prescribe alternative medicines. METHODS: We reviewed
case reports, open-label, and placebo-controlled trials investigating the use of
herbal medicines to treat anxiety and insomnia, and discussed their potential
applications for bipolar disorder. RESULTS: Eleven herbal medicines that have been
studied in human subjects are included in this review. Mechanisms of action,
efficacy, side effects, and drug-drug interactions are discussed. Based on
currently available evidence, valerian seems to be the most promising candidate for
insomnia and anxiety in bipolar disorder. CONCLUSIONS: Adjunctive herbal medicines
may have the potential to alleviate these symptoms and improve the outcomes of
standard treatment, despite limited evidence. Physicians need to have a more in-
depth understanding of the evidence of benefits, risks, and drug interactions of
alternative treatments.

Bailly, D. (2016). "[Pharmacological treatment of bipolar disorder in children and

adolescents]." Encephale.
OBJECTIVE: To review the options for acute and maintenance pharmacological
treatment of bipolar disorder in children and adolescents. METHODS: A comprehensive
literature review of randomized clinical trials and open-label studies was
conducted. RESULTS: Published data from randomized controlled trials show that
antipsychotics are significantly more effective than mood stabilizers in the
treatment of manic or mixed episodes. Few data are available related to the
treatment of depressive episodes. No trials of selective serotonin reuptake
inhibitors have been conducted. Only open trials suggest that lithium and
lamotrigine may be effective, whereas quetiapine did not demonstrate efficacy
relative to placebo in two studies. Studies regarding the effectiveness of
antipsychotics and mood stabilizers for the comorbid disorders are also few and
inconclusive. Although long-term treatment is a core aspect of the management of
children and adolescents with bipolar disorder, there is a lack of consistent
efficacy data. If non-controlled trials suggest that lithium, lamotrigine,
quetiapine, ziprazidone, and the combination of risperidone and divalproex or
lithium may be useful in some conditions, only aripiprazole has shown efficacy
relative to placebo for long-term symptom reduction and relapse prevention. Safety
data show that the most frequently reported adverse events in children and
adolescents treated with mood stabilizers are gastrointestinal and neurological,
whereas use of antipsychotics is mainly related to weight gain and sedation.
Lastly, while results from studies having evaluated the impact of pharmacological
treatment on neuropsychological functioning are inconsistent, some of them
nevertheless suggest that treatment with mood stabilizers may be associated with
specific impairments. CONCLUSION: Despite recent developments in identifying
effective pharmacological interventions, numerous critical gaps remain.

Bajoghli, H., et al. (2014). ""I love you more than I can stand!" - romantic love,
symptoms of depression and anxiety, and sleep complaints are related among young
adults." Int J Psychiatry Clin Pract 18(3): 169-174.
BACKGROUND: Falling in love is a universal human behavior. Studies indicate
that both adolescents and adults experience romantic love (RL) and emotional states
of joy and happiness. However, there is evidence that among adolescents RL is also
associated with symptoms of depression and anxiety, but no data on these
associations are available for adults. The aim of the present study was therefore
to explore the associations between RL, symptoms of depression, anxiety, hypomania,
and sleep among a sample of Iranian adults. METHODS: One hundred adults (mean age:
26 years; 53% males) took part in the study. They completed a series of
questionnaires related to RL, symptoms of depression, anxiety, hypomania, and
sleep. RESULTS: An increased state of RL was associated with the bright side of
hypomania, stronger symptoms of depression and state anxiety, and better sleep
quality. There was no relation to sleep duration. CONCLUSIONS: Unlike
psychobiological studies assessing highly selected samples of adults happily in
love, the present pattern of results shows that in adults, RL is not entirely a
joyful and happy period of life. Rather, data suggest that for young adults,
falling in love might be a critical life event also associated with uncertainty and
unpleasant feelings.

Ban, H. J., et al. (2011). "Genetic and metabolic characterization of insomnia."

PLoS One 6(4): e18455.
Insomnia is reported to chronically affect 10 approximately 15% of the adult
population. However, very little is known about the genetics and metabolism of
insomnia. Here we surveyed 10,038 Korean subjects whose genotypes have been
previously profiled on a genome-wide scale. About 16.5% reported insomnia and
displayed distinct metabolic changes reflecting an increase in insulin secretion, a
higher risk of diabetes, and disrupted calcium signaling. Insomnia-associated
genotypic differences were highly concentrated within genes involved in neural
function. The most significant SNPs resided in ROR1 and PLCB1, genes known to be
involved in bipolar disorder and schizophrenia, respectively. Putative enhancers,
as indicated by the histone mark H3K4me1, were discovered within both genes near
the significant SNPs. In neuronal cells, the enhancers were bound by PAX6, a neural
transcription factor that is essential for central nervous system development. Open
chromatin signatures were found on the enhancers in human pancreas, a tissue where
PAX6 is known to play a role in insulin secretion. In PLCB1, CTCF was found to bind
downstream of the enhancer and interact with PAX6, suggesting that it can probably
inhibit gene activation by PAX6. PLCB4, a circadian gene that is closely located
downstream of PLCB1, was identified as a candidate target gene. Hence,
dysregulation of ROR1, PLCB1, or PLCB4 by PAX6 and CTCF may be one mechanism that
links neural and pancreatic dysfunction not only in insomnia but also in the
relevant psychiatric disorders that are accompanied with circadian rhythm
disruption and metabolic syndrome.

Barbui, C., et al. (2013). "Treatment choices in women with bipolar disorder
seeking pregnancy: a clinical case illustration." Case Rep Psychiatry 2013: 630732.
After ten years of successful maintenance treatment with lithium and
olanzapine, a 40-year-old woman with bipolar disorder expressed concerns about
continuing the use of medicines, as she was planning a pregnancy. In the past, she
had suffered from five severe manic episodes with hospital admissions. After
consultations with the treating psychiatrist, gynaecologist, and family doctor,
olanzapine was stopped and lithium was gradually withdrawn. After few months, the
patient, still in treatment with lithium 300 mg/die, experienced a new manic
episode with hospital admission. Treatment with lithium and olanzapine was
restored, and she progressively recovered. This case suggests that the risk of
manic recurrence after ten years of maintenance treatment may be as high as the
well-known risk of recurrence after few years of maintenance treatment, a
consideration that doctors may find useful in the light of a complete absence of
evidence on treatment choices after five years of successful maintenance treatment.

Barnat, M., et al. (2017). "Huntingtin-Mediated Multipolar-Bipolar Transition of

Newborn Cortical Neurons Is Critical for Their Postnatal Neuronal Morphology."
Neuron 93(1): 99-114.
In the developing cortex, projection neurons undergo multipolar-bipolar
transition, radial-directed migration, and maturation. The contribution of these
developmental steps to the structure of the adult cortex is not completely
understood. Here, we report that huntingtin (HTT), the protein mutated in
Huntington's disease, is enriched in polarizing projection neurons. The depletion
of HTT in postmitotic projection neurons leads to the mislocalization of layer-
specific neuronal populations in the mouse neocortex. HTT is required for the
multipolar-bipolar transition of projection neurons and for the maintenance of
their bipolar shape during their radial migration. HTT mediates these effects in
vivo through the regulation of RAB11-dependent N-Cadherin trafficking. Importantly,
HD pathological HTT alters RAB11-dependent neuronal migration. Finally, we show
that the cortical defects resulting from the postmitotic loss of HTT specifically
during embryonic development affect neuronal morphology at adulthood. Our data
reveal a new HTT-RAB11-N-Cadherin pathway regulating multipolar-bipolar transition
with direct implications for mature brain. VIDEO ABSTRACT.

Bartels, S. J., et al. (2015). "Pragmatic replication trial of health promotion

coaching for obesity in serious mental illness and maintenance of outcomes." Am J
Psychiatry 172(4): 344-352.
OBJECTIVE: Few studies targeting obesity in serious mental illness have
reported clinically significant risk reduction, and none have been replicated in
community settings or demonstrated sustained outcomes after intervention
withdrawal. The authors sought to replicate positive health outcomes demonstrated
in a previous randomized effectiveness study of the In SHAPE program across urban
community mental health organizations serving an ethnically diverse population.
METHOD: Persons with serious mental illness and a body mass index (BMI) >25
receiving services in three community mental health organizations were recruited
and randomly assigned either to the 12-month In SHAPE program, which included
membership in a public fitness club and weekly meetings with a health promotion
coach, or to fitness club membership alone. The primary outcome measures were
weight and cardiorespiratory fitness (as measured with the 6-minute walk test),
assessed at baseline and at 3, 6, 9, 12, and 18 months. RESULTS: Participants
(N=210) were ethnically diverse (46% were nonwhite), with a mean baseline BMI of
36.8 (SD=8.2). At 12 months, the In SHAPE group (N=104) had greater reduction in
weight and improved fitness compared with the fitness club membership only group
(N=106). Primary outcomes were maintained at 18 months. Approximately half of the
In SHAPE group (51% at 12 months and 46% at 18 months) achieved clinically
significant cardiovascular risk reduction (a weight loss >/=5% or an increase of
>50 meters on the 6-minute walk test). CONCLUSIONS: This is the first replication
study confirming the effectiveness of a health coaching intervention in achieving
and sustaining clinically significant reductions in cardiovascular risk for
overweight and obese persons with serious mental illness.

Bartels, S. J., et al. (2014). "Long-term outcomes of a randomized trial of

integrated skills training and preventive healthcare for older adults with serious
mental illness." Am J Geriatr Psychiatry 22(11): 1251-1261.
OBJECTIVE: This report describes 1-, 2-, and 3-year outcomes of a combined
psychosocial skills training and preventive healthcare intervention (Helping Older
People Experience Success [HOPES]) for older persons with serious mental illness.
METHODS: A randomized controlled trial compared HOPES with treatment as usual (TAU)
for 183 older adults (age >/= 50 years [mean age: 60.2]) with serious mental
illness (28% schizophrenia, 28% schizoaffective disorder, 20% bipolar disorder, 24%
major depression) from two community mental health centers in Boston,
Massachusetts, and one in Nashua, New Hampshire. HOPES comprised 12 months of
weekly skills training classes, twice-monthly community practice trips, and monthly
nurse preventive healthcare visits, followed by a 1-year maintenance phase of
monthly sessions. Blinded evaluations of functioning, symptoms, and service use
were conducted at baseline and at a 1-year (end of the intensive phase), 2-year
(end of the maintenance phase), and 3-year (12 months after the intervention)
follow-up. RESULTS: HOPES compared with TAU was associated with improved community
living skills and functioning, greater self-efficacy, lower overall psychiatric and
negative symptoms, greater acquisition of preventive healthcare (more frequent eye
exams, visual acuity, hearing tests, mammograms, and Pap smears), and nearly twice
the rate of completed advance directives. No differences were found for medical
severity, number of medical conditions, subjective health status, or acute service
use at the 3-year follow-up. CONCLUSION: Skills training and nurse facilitated
preventive healthcare for older adults with serious mental illness was associated
with sustained long-term improvement in functioning, symptoms, self-efficacy,
preventive healthcare screening, and advance care planning.

Bastiampillai, T. J., et al. (2010). "The long-term effectiveness of clozapine and

lamotrigine in a patient with treatment-resistant rapid-cycling bipolar disorder."
J Psychopharmacol 24(12): 1834-1836.
The challenges in the management of treatment-resistant rapid-cycling bipolar
disorder are multifaceted and represent a significant burden to the patient. There
is a need for more exploration into the potential utility of various combination
therapies in the setting of severe affective states. A 52-year-old woman with a
history of severe treatment-resistant rapid-cycling bipolar affective disorder
(BPAD) was hospitalized for the treatment of a severe mixed episode. The
introduction of lamotrigine and clozapine in combination proved remarkably
effective and well tolerated in both the acute management and in subsequent
maintenance. The patient has remained asymptomatic during the 5-year follow-up
without any further mood disturbance. Lamotrigine and clozapine are among the less-
prescribed agents for BPAD and there is as yet little research into their use in
combination. It is possible that these agents have complementary modes of action on
various facets of the affective pathology, resulting in superior mood stabilization
in this patient.

Bauer, M., et al. (2010). "Subsyndromal mood symptoms: a useful concept for
maintenance studies of bipolar disorder?" Psychopathology 43(1): 1-7.
OBJECTIVE: To explore the measurement of subsyndromal mood symptoms in
relation to studies of maintenance therapy for bipolar disorder. METHODS:
Literature review of the Medline database using the following selection criteria:
(1) 'bipolar disorder' plus 'inter-episode or interepisode or subsyndromal or
subclinical or residual or subthreshold' and (2) 'bipolar disorder' plus
'maintenance or prophylaxis or longitudinal'. Studies of children or adolescents
and non-English-language reports were excluded. RESULTS: Of the studies published
between 1987 and October 2007, 77 articles about subsyndromal mood symptoms and 257
studies of maintenance therapy agents were found. Only 11 of the 257 studies of
maintenance therapy agents discussed subsyndromal mood symptoms. Of the 77
articles, two thirds were published after 2000. Inconsistent definitions of
subsyndromal mood symptoms and different evaluation tools and methodologies were
used in the studies. CONCLUSIONS: There is a need to standardize definitions and
validate measuring approaches for subsyndromal mood symptoms. However, when
measured in both naturalistic studies and clinical trials, subsyndromal mood
symptoms were frequently reported by patients receiving maintenance therapy and
were associated with poor functioning. As with other chronic illnesses, knowledge
of the patient's perspective of daily morbidity is important for improving the
clinical outcome. Studies of maintenance therapy for bipolar disorder, regardless
of the approach, should measure subsyndromal mood symptoms as an additional
outcome.

Beby, F., et al. (2010). "Otx2 gene deletion in adult mouse retina induces rapid
RPE dystrophy and slow photoreceptor degeneration." PLoS One 5(7): e11673.
BACKGROUND: Many developmental genes are still active in specific tissues
after development is completed. This is the case for the homeobox gene Otx2, an
essential actor of forebrain and head development. In adult mouse, Otx2 is strongly
expressed in the retina. Mutations of this gene in humans have been linked to
severe ocular malformation and retinal diseases. It is, therefore, important to
explore its post-developmental functions. In the mature retina, Otx2 is expressed
in three cell types: bipolar and photoreceptor cells that belong to the neural
retina and retinal pigment epithelium (RPE), a neighbour structure that forms a
tightly interdependent functional unit together with photoreceptor cells.
METHODOLOGY/PRINCIPAL FINDINGS: Conditional self-knockout was used to address the
late functions of Otx2 gene in adult mice. This strategy is based on the
combination of a knock-in CreERT2 allele and a floxed allele at the Otx2 locus.
Time-controlled injection of tamoxifen activates the recombinase only in Otx2
expressing cells, resulting in selective ablation of the gene in its entire domain
of expression. In the adult retina, loss of Otx2 protein causes slow degeneration
of photoreceptor cells. By contrast, dramatic changes of RPE activity rapidly
occur, which may represent a primary cause of photoreceptor disease. CONCLUSIONS:
Our novel mouse model uncovers new Otx2 functions in adult retina. We show that
this transcription factor is necessary for long-term maintenance of photoreceptors,
likely through the control of specific activities of the RPE.

Beby, F. and T. Lamonerie (2013). "The homeobox gene Otx2 in development and
disease." Exp Eye Res 111: 9-16.
The Otx2 gene encodes a transcription factor essential for the normal
development of brain, cerebellum, pineal gland, and eye. In the retina, Otx2 has
essential functions from early embryogenesis to adulthood. As soon as the optic
vesicle is formed, the gene is required for retinal pigment epithelium
specification. Otx2 is also a key regulator of photoreceptor genesis and
differentiation, and is required after birth for bipolar cells terminal maturation.
Otx2 expression is maintained in the differentiated retina wherein the gene is
critical for the outer retina maintenance. In the visual cortex, the gene modulates
the neuronal plasticity through a paracrine mechanism. OTX2 heterozygous mutations
in humans have been linked to severe ocular malformations associated with brain
abnormalities and pituitary dysfunction. Recent studies have also established the
OTX2 gene as an oncogene for medulloblastoma, a malignant brain tumour originating
in the cerebellum.
Bellivier, F. (2012). "[Cognitions and functioning in euthymic bipolar patients:
screening and treatment]." Encephale 38 Suppl 4: S151-154.
Persistent cognitive deficits in euthymic bipolar patients are now well
documented. Indeed, several studies and meta-analyzes clearly establish the
existence of cognitive deficits in specific domains: attention (in particular
sustained attention), Memory (in particular verbal memory) and executive functions.
The impact of cognitive deficits on patient's functioning is also well documented
and their role appear to be more important than expected by comparison with the
impairment related to thymic residual symptoms. The development of specific
cognitive remediation strategies is therefore a major hope for improving the
quality of remission and functional outcome. The aetiology of these deficits
remains poorly understood. However, the implication of factors related to the
biological/genetic vulnerability to bipolar disorder is likely well as a
"neurotoxic" effects of major mood episodes, in particular acute manic episodes
that seems to play a important role in the worsening of these deficits over time.
This further stresses the importance maintenance strategies for long-term
functional outcome.

Benedetti, F., et al. (2015). "Effects of CLOCK gene variants and early stress on
hopelessness and suicide in bipolar depression." Chronobiol Int 32(8): 1156-1161.
BACKGROUND: Patients with mood disorders show a high dependence of behavior
on the molecular characteristics of the biological clock. CLOCK rs1801260 gene
polymorphism influences circadian behavior in bipolar disorder (BD), with *C
carriers showing a delayed sleep onset and worse insomnia. Sleep phase delay and
insomnia associate with suicide in the general population. METHODS: We investigated
the effects of rs1801260, and of exposure to stressful life events, on current
suicidal ideation and history of suicide attempts in 87 depressed patients with BD.
RESULTS: rs1801260*C carriers currently showed worse Hamilton Depression Rating
Scale scores for suicide and worse ratings for depressive cognitive distortions.
Previous history of attempted suicide associated with exposure to higher stressful
events in the early life, with rs1801260*C carriers showing a higher dependency of
the modeled probability of attempting suicide on the severity of exposure to early
stress. DISCUSSION: CLOCK rs1801260 modulated the relationship between early
stress, adult history of attempted suicide and current suicide ideation. Factors
affecting the biological clock can influence "non-clock" core psychopathological
features of mood disorders.

Benes, F. M. (2011). "Regulation of cell cycle and DNA repair in post-mitotic GABA
neurons in psychotic disorders." Neuropharmacology 60(7-8): 1232-1242.
Disturbances of cell cycle regulation and DNA repair in post-mitotic neurons
have been implicated in degenerative and malignant diseases of the human brain.
Recent work is now suggesting that abnormal regulation of these functions in GABA
cells of the adult hippocampus may also play a role in two neuropsychiatric
disorders. In schizophrenia and bipolar disorder, a network of genes involved in
the regulation of GAD(6)(7), a marker for the functional differentiation of GABA
cells, show pronounced changes in expression and include kainate receptor subunits,
TGFbeta and Wnt signaling pathways, epigenetic factors and transcription factors.
One of these genes, cyclin D2, is involved in the regulation of cell cycle and DNA
repair and appears to be a pivotal element in linking GAD(6)(7) expression with
these functional clusters of genes. Dysfunction of post-mitotic GABAergic neurons
in the adult hippocampus of patients with psychotic disorders is associated with
changes in the expression of genes that are involved in the maintenance of
functional and genomic integrity of GABA cells. The nature of these changes is
quite different in schizophrenia and bipolar disorder, suggesting that a common
cell phenotype (in this case, decreased GAD(6)(7) expression) may involve two
fundamentally different molecular endophenotypes and reflect unique susceptibility
genes involved in the respective disorders. This article is part of a Special Issue
entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Berghofer, A., et al. (2013). "Stability of lithium treatment in bipolar disorder -
long-term follow-up of 346 patients." Int J Bipolar Disord 1: 11.
BACKGROUND: The purpose of this study was to investigate the effectiveness
and stability of long-term lithium treatment in a prospective, international,
multicenter cohort of bipolar patients in a naturalistic setting. METHODS: Patients
were selected according to DSM IV criteria for bipolar disorder and required long-
term treatment. They were prospectively followed and documented in five centers
belonging to the International Group for the Study of Lithium-Treated Patients.
This was a prospective cohort study without a comparison group. Lithium treatment
was administered in a naturalistic and specialized outpatient setting. All patients
underwent a comprehensive psychiatric examination, which included the use of
standard rating scales, as well as an evaluation of clinical course based on the
morbidity index (MI). Wald tests were used to assess the significance of fixed
effects and covariates when analyzing the relationship between depressive, manic,
and total morbidity index and several characteristics of illness course. RESULTS
AND DISCUSSION: A total of 346 patients with bipolar disorder I or II were followed
for a mean period of 10.0 years (standard deviation (SD) 6.2, range 1 to 20). The
morbidity index remained stable over time: the mean MI was 0.125 (SD 0.299) in year
1 and 0.110 (SD 0.267) in year 20. The MI was not associated with the duration of
lithium treatment, the number or frequency of episodes prior to treatment, or
latency from the onset of bipolar disorder to the start of lithium treatment. The
drop-out rate was high over the study period. Our findings suggest that long-term
response to lithium maintenance treatment remains stable over time.

Bergink, V., et al. (2012). "Prevention of postpartum psychosis and mania in women
at high risk." Am J Psychiatry 169(6): 609-615.
OBJECTIVE: Women with a history of bipolar disorder or postpartum psychosis
are at extremely high risk of relapse postpartum. Although lithium prophylaxis has
demonstrated efficacy in reducing postpartum relapse, the timing of prophylaxis
remains controversial given the balance of risks and benefits for the mother and
fetus. The authors compared lithium use during pregnancy to its initiation
postpartum in women at high risk for postpartum psychosis. METHOD: Between 2003 and
2010, 70 pregnant women at high risk for postpartum psychosis were referred to the
authors' psychiatric outpatient clinic. Women who were initially medication free
were advised to start lithium prophylaxis immediately postpartum. Women already
taking maintenance lithium during pregnancy were advised to continue treatment.
RESULTS: All women with a history of psychosis limited to the postpartum period
(N=29) remained stable throughout pregnancy despite being medication free. Of the
women with bipolar disorder (N=41), 24.4% relapsed during pregnancy, despite
prophylaxis use by the majority throughout pregnancy. The postpartum relapse rate
was highest in women with bipolar disorder who experienced mood episodes during
pregnancy (60.0%). In contrast, none of the 20 women with a history of postpartum
psychosis only who used postpartum prophylaxis relapsed, compared to 44.4% of
patients with postpartum psychosis only who declined prophylaxis. CONCLUSIONS: The
authors recommend initiating prophylactic treatment immediately postpartum in women
with a history of psychosis limited to the postpartum period, to avoid in utero
fetal exposure to medication. Patients with bipolar disorder require continuous
prophylaxis throughout pregnancy and the postpartum period to reduce peripartum
relapse risk.

Bergink, V., et al. (2015). "Treatment of psychosis and mania in the postpartum
period." Am J Psychiatry 172(2): 115-123.
Postpartum psychosis is a severe disorder that warrants acute clinical
intervention. Little is known, however, about what interventions are most
effective. The authors present treatment response and remission outcomes at 9
months postpartum using a four-step algorithm in patients with first-onset
psychosis or mania in the postpartum period. Treatment involved the structured
sequential administration of benzodiazepines, antipsychotics, lithium, and ECT. The
outcome of clinical remission was examined in 64 women consecutively admitted for
postpartum psychosis. Remission was defined as the absence of psychotic, manic, and
severe depressive symptoms for at least 1 week. Women who remitted on antipsychotic
monotherapy were advised to continue this treatment as maintenance therapy, and
women who required both antipsychotics and lithium to achieve remission were
maintained on lithium monotherapy. Relapse was defined as the occurrence of any
mood or psychotic episode fulfilling DSM-IV-TR criteria. Using this treatment
algorithm, the authors observed that nearly all patients (98.4%) achieved complete
remission within the first three steps. None of the patients required ECT. At 9
months postpartum, sustained remission was observed in 79.7%. Patients treated with
lithium had a significantly lower rate of relapse compared with those treated with
antipsychotic monotherapy. Multiparity and nonaffective psychosis were identified
as risk factors for relapse. The authors conclude that a structured treatment
algorithm with the sequential addition of benzodiazepines, antipsychotics, and
lithium may result in high rates of remission in patients with first-onset
postpartum psychosis and that lithium maintenance may be most beneficial for
relapse prevention.

Bergink, V., et al. (2016). "Postpartum Psychosis: Madness, Mania, and Melancholia
in Motherhood." Am J Psychiatry 173(12): 1179-1188.
OBJECTIVE: Psychosis or mania after childbirth is a psychiatric emergency
with risk for suicide and infanticide. METHOD: The authors reviewed the
epidemiologic and genetic research and physiological postpartum triggers
(endocrine, immunological, circadian) of psychosis. They also summarized all
systematic reviews and synthesized the sparse clinical studies to provide
diagnostic recommendations, treatment options, and strategies for prevention.
RESULTS: The incidence of first-lifetime onset postpartum psychosis/mania from
population-based register studies of psychiatric admissions varies from 0.25 to 0.6
per 1,000 births. After an incipient episode, 20%-50% of women have isolated
postpartum psychosis. The remaining women have episodes outside the perinatal
period, usually within the bipolar spectrum. Presumably, the mechanism of onset is
related to physiological changes after birth (e.g., hormonal, immunological,
circadian), which precipitate disease in genetically vulnerable women. Some women
have treatable causes and comorbidities, such as autoimmune thyroiditis or
infections. N-methyl-d-aspartate-encephalitis or inborn errors of metabolism may
present after birth with psychosis. Fewer than 30 publications have focused on the
treatment of postpartum psychosis. The largest study (N=64) provided evidence that
lithium is highly efficacious for both acute and maintenance treatment. Another
report (N=34) described successful ECT treatment. Inpatient care is usually
required to ensure safety, complete the diagnostic evaluation, and initiate
treatment. The relapse risk after a subsequent pregnancy for women with isolated
postpartum psychoses is 31% (95% CI=22-42). Strategies for prevention of postpartum
psychosis include lithium prophylaxis immediately postpartum and proactive safety
monitoring. CONCLUSIONS: Postpartum psychosis offers an intriguing model to explore
etiologic contributions to the neurobiology of affective psychosis.

Berk, M., et al. (2011). "Does stage of illness impact treatment response in
bipolar disorder? Empirical treatment data and their implication for the staging
model and early intervention." Bipolar Disord 13(1): 87-98.
OBJECTIVE: The staging model suggests that early stages of bipolar disorder
respond better to treatments and have a more favourable prognosis. This study aims
to provide empirical support for the model, and the allied construct of early
intervention. METHODS: Pooled data from mania, depression, and maintenance studies
of olanzapine were analyzed. Individuals were categorized as having had 0, 1-5, 6-
10, or >10 prior episodes of illness, and data were analyzed across these groups.
RESULTS: Response rates for the mania and maintenance studies ranged from 52-69%
and 10-50%, respectively, for individuals with 1-5 previous episodes, and from 29-
59% and 11-40% for individuals with >5 previous episodes. These rates were
significantly higher for the 1-5 group on most measures of response with up to a
twofold increase in the chance of responding for those with fewer previous
episodes. For the depression studies, response rates were significantly higher for
the 1-5 group for two measures only. In the maintenance studies, the chance of
relapse to either mania or depression was reduced by 40-60% for those who had
experienced 1-5 episodes or 6-10 episodes compared to the >10 episode group,
respectively. This trend was statistically significant only for relapse into mania
for the 1-5 episode group (p=0.005). CONCLUSION: Those individuals at the earliest
stages of illness consistently had a more favourable response to treatment. This is
consistent with the staging model and underscores the need to support a policy of
early intervention.

Berk, M., et al. (2017). "Neuroprotection after a first episode of mania: a

randomized controlled maintenance trial comparing the effects of lithium and
quetiapine on grey and white matter volume." Transl Psychiatry 7(1): e1011.
Lithium and quetiapine are effective treatments for bipolar disorder, but
their potential neuroprotective effects in humans remain unclear. A single blinded
equivalence randomized controlled maintenance trial was conducted in a prospective
cohort of first-episode mania (FEM) patients (n=26) to longitudinally compare the
putative protective effects of lithium and quetapine on grey and white matter
volume. A healthy control sample was also collected (n=20). Using structural MRI
scans, voxel-wise grey and white matter volumes at baseline and changes over time
in response to treatment were investigated. Patients were assessed at three time
points (baseline, 3 and 12-month follow-up), whereas healthy controls were assessed
at two time points (baseline and 12-month follow-up). Patients were randomized to
lithium (serum level 0.6 mmol l-1, n=20) or quetiapine (flexibly dosed up to 800 mg
per day, n=19) monotherapy. At baseline, compared with healthy control subjects,
patients with FEM showed reduced grey matter in the orbitofrontal cortex, anterior
cingulate, inferior frontal gyrus and cerebellum. In addition, patients had reduced
internal capsule white matter volume bilaterally (t1,66>3.20, P<0.01).
Longitudinally, there was a significant treatment x time effect only in the white
matter of the left internal capsule (F2,112=8.54, P<0.01). Post hoc testing showed
that, compared with baseline, lithium was more effective than quetiapine in slowing
the progression of white matter volume reduction after 12 months (t1,24=3.76,
P<0.01). Our data support the role of lithium but not quetiapine therapy in
limiting white matter reduction early in the illness course after FEM.

Berk, M., et al. (2011). "The efficacy of N-acetylcysteine as an adjunctive

treatment in bipolar depression: an open label trial." J Affect Disord 135(1-3):
389-394.
BACKGROUND: Evidence is accumulating to support the presence of redox
dysregulation in a number of psychiatric disorders, including bipolar disorder.
This dysregulation may be amenable to therapeutic intervention. Glutathione is the
predominant non-enzymatic intracellular free radical scavenger in the brain, and
the most generic of all endogenous antioxidants in terms of action. N-
acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain
glutathione. Given the failure of almost all modern trials of antidepressants in
bipolar disorder to demonstrate efficacy, and the limited efficacy of mood
stabilisers in the depressive phase of the disorder, this is a major unmet need.
METHOD: This study reports data on the treatment of 149 individuals with moderate
depression during the 2 month open label phase of a randomised placebo controlled
clinical trial of the efficacy of 1g BID of NAC that examined the use of NAC as a
maintenance treatment for bipolar disorder. RESULTS: In this trial, the estimated
mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE=0.8), and
the mean BDRS score at the end of the 8 week open label treatment phase was 11.1
(SE=0.8). This reduction was statistically significant (p<0.001). Improvements in
functioning and quality of life were similarly evident. CONCLUSION: These open
label data demonstrate a robust decrement in depression scores with NAC treatment.
Large placebo controlled trials of acute bipolar depression are warranted.

Berk, M., et al. (2012). "Maintenance N-acetyl cysteine treatment for bipolar
disorder: a double-blind randomized placebo controlled trial." BMC Med 10: 91.
BACKGROUND: N-acetyl cysteine (NAC) is a glutathione precursor that has been
shown to have antidepressant efficacy in a placebo-controlled trial. The current
study aimed to investigate the maintenance effects of NAC following eight weeks of
open-label treatment for bipolar disorder. METHOD: The efficacy of a double blind
randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment
for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg
Depression Rating Score of >/=12 at trial entry and, after eight weeks of open-
label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to
treatment as usual. Participants (primarily outpatients) were recruited through
public and private services and through newspaper advertisements. Time to
intervention for a mood episode was the primary endpoint of the study, and changes
in mood symptoms, functionality and quality of life measures were secondary
outcomes. RESULTS: There was a substantial decrease in symptoms during the eight-
week open-label NAC treatment phase. During the subsequent double-blind phase,
there was minimal further change in outcome measures with scores remaining low.
Consequently, from this low plateau, between-group differences did not emerge on
recurrence, clinical functioning or quality of life measures. CONCLUSIONS: There
were no significant between-group differences in recurrence or symptomatic outcomes
during the maintenance phase of the trial; however, these findings may be
confounded by limitations. TRIAL REGISTRATION: The trial was registered with the
Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

Bersani, F. S., et al. (2013). "Deep transcranial magnetic stimulation for

treatment-resistant bipolar depression: a case report of acute and maintenance
efficacy." Neurocase 19(5): 451-457.
Deep Transcranial Magnetic Stimulation (dTMS) is currently being evaluated as
a possible treatment for several neuropsychiatric disorders and has been
demonstrated as a safe and effective procedure. This case presents a patient with
bipolar depression that has been treated with 20 daily consecutive dTMS sessions
and with one dTMS session every 2 weeks for the following 3 months. Depressive
symptoms improved rapidly and response was maintained during the next 6 months;
cognitive performances also improved. This report suggests that add-on dTMS may
help overcoming drug-resistance in bipolar depression and protect from subsequent
bipolar episodes of any polarity.

Bersani, G., et al. (2016). "Potential neuroprotective effect of lithium in bipolar

patients evaluated by neuropsychological assessment: preliminary results." Hum
Psychopharmacol 31(1): 19-28.
OBJECTIVE: Accumulating evidence is delineating a
neuroprotective/neurotrophic role for lithium. However, its primary effects on
cognition remain ambiguous. We sought to investigate the profile of cognitive
impairment in patients with bipolar disorder and to determine whether continued
treatment with lithium preserves cognitive functioning. METHODS: In this cross-
sectional study, we tested 15 euthymic patients with bipolar I disorder undergoing
long-term clinical maintenance treatment with lithium (for at least 12 months), 15
matched patients treated with other mood-stabilizing drugs and who had never
received lithium, and 15 matched healthy subjects on the Cambridge
Neuropsychological Test Automated Battery. Investigated cognitive domains were
visual memory, executive functions, attention, decision-making/impulsivity, and
response inhibition. We controlled for age, gender, intelligence, and residual
psychiatric symptomatology. RESULTS: Taken together, bipolar patients demonstrated
robust deficits in visual memory and executive functions. Once subdivided in
treatment subgroups, only non-lithium bipolar patients demonstrated impairments in
visual memory. Attention, decision-making, and response inhibition were preserved
in both groups. No correlation emerged between neuropsychological tests
performance, clinical, and psychological variables. CONCLUSIONS: This study is the
first to our knowledge to have demonstrated, by means of a highly sensitive test of
visual memory, a potential hippocampus neuroprotective effect of lithium in
patients with bipolar disorder. Besides, it confirms prior findings of cognitive
deficits in euthymic bipolar patients.

Berwaerts, J., et al. (2012). "A randomized, placebo- and active-controlled study
of paliperidone extended-release as maintenance treatment in patients with bipolar
I disorder after an acute manic or mixed episode." J Affect Disord 138(3): 247-258.
BACKGROUND: Paliperidone ER monotherapy was efficacious in treating acute
mania in two 3-week studies in patients with bipolar I disorder. We assessed its
efficacy in a study investigating maintenance treatment of clinically stable
patients with this disorder. METHODS: Patients (n=766), aged 18 to 65 years
inclusive, with current manic or mixed episodes were initially randomized (4:1) to
flexibly-dosed paliperidone ER (3-12 mg/day) or olanzapine (5-20 mg/day; 3-week
acute treatment phase); responders continued the same treatment (12-week
continuation phase). Patients on paliperidone ER who achieved remission during this
phase were randomized (1:1) to fixed-dose paliperidone ER (n=152) or placebo
(n=148); those on olanzapine continued to receive that at fixed dose (n=83)
(maintenance phase). RESULTS: Median time to recurrence of any mood symptoms
(primary endpoint) was: 558 days (paliperidone ER), 283 days (placebo) and not
observed with olanzapine (<50% of patients experienced recurrence). Time to
recurrence of any mood symptoms was significantly longer with paliperidone ER than
placebo (p=0.017; based on weighted Z-test at 0.0198 significance level; hazard
ratio [placebo: paliperidone ER; unweighted 95% confidence interval]: 1.43 [1.03;
1.98]); the difference was significant for preventing recurrence of manic, but not
depressive, symptoms. Treatment-emergent adverse events (maintenance phase)
occurred more often in olanzapine group (64%) than placebo (59%) or paliperidone ER
groups (55%). LIMITATIONS: Responder-enriched design prevents extrapolation of data
to patients not previously stabilized on paliperidone ER. CONCLUSIONS: Paliperidone
ER significantly delayed the time to recurrence of any mood symptoms, versus
placebo, in patients with bipolar I disorder. No new safety concerns emerged.

Bet, P. M., et al. (2013). "Could pramipexole induce acute mania? A case report."
Bipolar Disord 15(4): 446-448.
OBJECTIVE: In patients with bipolar disorder, olanzapine is commonly used to
prevent episodes of acute mania. The drug pramipexole can, in theory, undermine the
protective effect of olanzapine. Olanzapine is a dopamine D2 receptor antagonist
and pramipexole is a mixed dopamine D2 /D3 receptor agonist. These drugs may
therefore theoretically counteract their pharmacological effects. To date, there
are no known cases in the literature where this interaction has been described.
METHODS: We report on a case where a patient with bipolar disorder developed mania
after taking pramipexole in combination with olanzapine, and describe the
pharmacological background of this interaction. RESULTS: A patient with bipolar I
disorder was hospitalized with a manic episode characterized by agitation and
insomnia after taking pramipexole for restless leg syndrome (RLS) in combination
with olanzapine. Co-medication, i.e., lithium and mirtazapine, and other
circumstances are not likely to have contributed to this effect. CONCLUSION: There
is a probable interaction between pramipexole and olanzapine, where pramipexole
undermines the protective effect of olanzapine, provoking an episode of acute mania
and hospitalization. This interaction is of clinical importance since pramipexole
is the treatment of choice for RLS, a condition often seen in end-stage renal
disease, and has also been investigated as an antidepressant therapy in patients
with bipolar disorder.

Bicknell, L. T., et al. (2012). "Erythema multiforme vs. DRESS syndrome associated
with the combined use of lamotrigine and cyclobenzaprine: a case report." Int J
Psychiatry Med 44(4): 305-314.
Lamotrigine is FDA-approved as a maintenance treatment of bipolar disorder,
but its common off-label uses include bipolar depression and antidepressant
augmentation in patients with major depressive disorder. Among other adverse
effects, cutaneous reactions, particularly erythema multiforme, are cited as
concerns during treatment with this medication. In order to minimize the risk of
cutaneous side effect, efforts have been made to identify factors associated with a
higher rate of lamotrigine-induced rash. We report here a case of Drug Reaction
with Eosinophilia and Systemic Symptoms apparently precipitated by the associated
use of lamotrigine and cyclobenzaprine.

Bobo, W. V. and R. C. Shelton (2010). "Risperidone long-acting injectable

(Risperdal Consta(R)) for maintenance treatment in patients with bipolar disorder."
Expert Rev Neurother 10(11): 1637-1658.
Poor adherence to pharmacotherapy during maintenance-phase treatment of
bipolar disorder is a common occurrence, exposing patients to a high risk of
illness relapses, rehospitalization and other negative outcomes. In view of this,
there has been a reawakening of interest in the potential of long-acting injectable
antipsychotic medications to improve treatment outcome during bipolar maintenance
therapy. Indeed, long-acting injectable medications have practical advantages of
assuring delivery of medication at a prescribed dose, and perhaps also making it
easier to monitor adherence, at least to the long-acting drug. However, there are
important limitations to the long-term use of depot typical neuroleptics in
patients with bipolar disorder, including risk of extrapyramidal side effects and
tardive dyskinesia, which may exceed that of patients with schizophrenia, and the
potential for treatment-emergent exacerbation of depressive symptoms. Long-acting
injectable risperidone (RLAI) has recently been approved for maintenance treatment
in patients with bipolar I disorder. Evidence supporting the use of RLAI for this
indication consists of several nonrandomized, open-label studies; one randomized,
open-label trial; and two adequately powered randomized, double-blind trials. In
general, these studies have shown RLAI to be effective for the prevention of
relapse or hospitalization during bipolar maintenance treatment. In the double-
blind studies, RLAI was associated with reduced relapse rates, increased time to
relapse and greater control of clinical symptoms during maintenance treatment
following initial stabilization, compared with oral medication treatment or placebo
injection. RLAI appeared to be more effective for preventing manic/mixed episodes
than depressive episodes. RLAI showed good tolerability across studies; however,
dose-related extrapyramidal effects, sedation, weight gain and prolactin elevation
may occur during long-term treatment. Responder-enriched designs and exclusion of
important clinical subgroups in the double-blind trials may limit translation of
these results to routine care settings.

Bocchetta, A., et al. (2012). "Ammonemia in bipolar patients on maintenance

treatment with valproic acid." J Clin Psychopharmacol 32(1): 148-150.

Boland, E. M. and L. B. Alloy (2013). "Sleep disturbance and cognitive deficits in

bipolar disorder: toward an integrated examination of disorder maintenance and
functional impairment." Clin Psychol Rev 33(1): 33-44.
Bipolar disorder is frequently associated with a number of poor outcomes
including, but not limited to, a significant impairment in the ability to return to
premorbid levels of occupational and psychosocial functioning, often despite the
remission of mood symptoms. Sleep disturbance is an oft-reported residual symptom
of manic and depressive episodes that has likewise been associated with the onset
of manic episodes. Also present during affective episodes as well as the inter-
episode periods are reports of deficits in cognitive functioning, which many
reports have shown to play an important role in this persistent disability. Despite
the presence of deficits in these two domains of functioning during affective
episodes as well as the inter-episode phase, there has been no evaluation of the
degree to which these systems may interact to maintain such high rates of
functional disability. The aim of this review is to examine evidence for the study
of the relationship between sleep disturbance and cognitive impairments in bipolar
disorder as well as the ways in which deficits in these domains may work together
to maintain functional impairment.
Boland, E. M., et al. (2015). "Associations between sleep disturbance, cognitive
functioning and work disability in Bipolar Disorder." Psychiatry Res 230(2): 567-
574.
Bipolar Disorder (BD) is associated with impairment in a number of areas
including poor work functioning, often despite the remission of mood symptoms. The
present study aimed to examine the role of sleep disturbance and cognitive
functioning in occupational impairment in BD. Twenty-four euthymic BD participants
and 24 healthy control participants completed a week of prospective assessment of
sleep disruption via self-report and actigraphy, a battery of neuropsychological
tests of executive functioning, working memory, and verbal learning, and
assessments of work functioning. BD participants experienced significantly poorer
cognitive functioning as well as greater months of unemployment and greater
incidence of being fired than controls. Moderation analyses revealed that both poor
sleep and cognitive functioning were associated with poor work performance in BD
participants, but not control participants. Sleep and cognitive functioning may be
impaired in euthymic BD and are associated with poor work functioning in this
population. More research should be conducted to better understand how sleep and
cognitive functioning may interact in BD.

Bond, D. J., et al. (2010). "Weight gain, obesity, and metabolic indices following
a first manic episode: prospective 12-month data from the Systematic Treatment
Optimization Program for Early Mania (STOP-EM)." J Affect Disord 124(1-2): 108-117.
BACKGROUND: Numerous studies have demonstrated an association between bipolar
disorder (BD) and obesity. However, these reports are limited by retrospective or
cross-sectional designs, and the assessment of patients with lengthy illnesses.
Prospective data, and data on weight gain early in the course of BD, are lacking.
METHODS: We prospectively measured weight gain and laboratory metabolic indices
over 12 months in 47 patients with BD receiving maintenance treatment following
their first manic episode, and in 24 age- and gender-matched healthy subjects.
RESULTS: Although approximately two-thirds of patients had experienced previous
depressive or hypomanic episodes, there was no difference between patients and
healthy subjects in mean body mass index or rates of overweight or obesity at
recovery from the first mania. Mean weight gain over 12 months was 4.76kg in
patients and 1.50kg in healthy subjects (p=0.047). Combined rates of overweight and
obesity at 6 months and 12 months exceeded 50% in patients, and were almost double
those of healthy subjects. Logistic regression demonstrated that weight gain in the
first 6 months was significantly associated with male gender and prescription of
olanzapine or risperidone. Patients who were obese at 6 months and/or 12 months had
significantly greater mean serum triglyceride levels and fasting glucose levels
than non-obese patients. LIMITATIONS: This was a naturalistic study. CONCLUSIONS:
Even in patients with previous depressions and hypomanias, clinically significant
weight gain in BD begins following the first manic episode, suggesting that it is
primarily related to treatment with mood stabilizers and second-generation
antipsychotics. However, the very small number of patients in our sample who were
medication-free precludes a meaningful analysis of the degree to which weight gain
might be an inherent feature of post-manic BD.

Bond, D. J., et al. (2010). "Divalproex sodium versus placebo in the treatment of
acute bipolar depression: a systematic review and meta-analysis." J Affect Disord
124(3): 228-234.
BACKGROUND: Bipolar disorders (BDs) are defined by mania and hypomania, but
depressions occur more frequently, last longer, and lead to significant disability.
Divalproex is the most frequently prescribed anticonvulsant medication for BD.
While some evidence suggests that divalproex prevents depressive episodes during
maintenance treatment, it is not commonly used in the treatment of acute
depression, and there is a perception that there is little evidence to support its
efficacy. METHODS: We conducted a meta-analysis of randomized placebo-controlled
trials assessing the efficacy of divalproex in acute BD depression. We searched
MEDLINE and the Cochrane Database of Systematic Reviews using the search terms
"divalproex AND bipolar depression", "valproate AND bipolar depression", and
"valproic acid AND bipolar depression". We also accessed the databases of clinical
trial registries, including www.ClinicalTrials.gov, www.who.int/ictrp,
http://isrctn.org,
http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htm
l, and www.ClinicalStudyResults.org. All English-language, randomized, double-
blind, placebo-controlled trials assessing the efficacy of divalproex monotherapy
in the treatment of BD depression were included in the analysis. Data were
subjected to meta-analysis to determine the relative risks of response and
remission, and combined to estimate average response and remission rates. RESULTS:
We identified four trials, with a total sample size of 142 patients. The relative
risks of response (RR=2.10, p=0.02) and remission (RR=1.61, p=0.04) were
significantly greater for divalproex than placebo. Mean response rates were 39.3%
for divalproex and 17.5% for placebo, and mean remission rates were 40.6% and
24.3%, respectively. LIMITATIONS: The total sample size in the four trials was
small. CONCLUSIONS: These results provide preliminary evidence that divalproex is
efficacious in the treatment of BD depression.

Bottai, T., et al. (2010). "[Interpersonal and social rhythm therapy (IPSRT)]."
Encephale 36 Suppl 6: S206-217.
Bipolar disorder is common, recurrent, often severe and debiliting disorder.
All types of bipolar disorder have a common determinant: depressive episode. It is
justify to propose a psychotherapy which shown efficacy in depression. Howewer,
perturbations in circadian rhythms have been implicated in the genesis of each
episode of the illness. Biological circadian dysregulation can be encouraged by
alteration of time-givers (Zeitgebers) or occurrence of time-disturbers
(Zeitstorers). Addition of social rhythm therapy to interpersonal psychotherapy
leads to create a new psychotherapy adaptated to bipolar disorders: InterPersonal
and Social Rhythm Therapy (IPSRT). IPSRT, in combinaison with medication, has
demonstrated efficacy as a treatment for bipolar disorders. IPSRT combines
psychoeducation, behavioral strategy to regularize daily routines and interpersonal
psychotherapy which help patients cope better with the multiple psychosocial and
relationship problems associated with this chronic disorder. The main issues of
this psychotherapy are: to take the history of the patient's illness and review of
medication, to help patient for "grief for the lost healthy self" translated in the
french version in "acceptance of a long-term medical condition", to give the sick
role, to examinate the current relationships and changes proximal to the emergence
of mood symptoms in the four problem areas (unresolved grief, interpersonal
disputes, role transitions, role deficits), to examinate and increase daily
routines and social rhythms. French version of IPSRT called TIPARS (with few
differences), a time-limited psychotherapy, in 24 sessions during approximatively 6
months, is conducted in three phases. In the initial phase, the therapist takes a
thorough history of previous episodes and their interpersonal context and a review
of previous medication, provides psychoeducation, evaluates social rhythms,
introduces the Social Rhythm Metric, identifies the patient's main interpersonal
problem area, and contractualizes the therapy. In the second phase, the therapist
focuses work with patient toward regulating the patient's daily routines as well as
resolving the interpersonal problem areas relevant to episodes (mainly
interpersonal disputes and role transitions). In the third or terminaison phase,
the therapist evaluates efficacy of the therapy, enhances the patient's independent
functioning and develops strategies for relapse prevention. The further maintenance
phase suggests differents strategies as maintenance therapy or focused intensive
interventions on specific topics.

Bowden, C. L. (2010). "Diagnosis, treatment, and recovery maintenance in bipolar

depression." J Clin Psychiatry 71(1): e01.
Misdiagnosis of bipolar disorder and inappropriate pharmacotherapeutic
treatment is common. Clinicians should screen for manic/hypomanic symptoms during
depressive episodes to differentiate bipolar depression from other depressive
disorders. Depression is the dominant pole of bipolar disorder, and effective
maintenance therapy must prevent depressive episode recurrence. Few pharmacologic
treatments have evidence supporting both short- and long-term efficacy for bipolar
depression. Clinicians must consider the existing evidence on the long-term
efficacy of various pharmacologic and psychosocial interventions for preventing and
treating bipolar mood episodes.

Bowden, C. L. (2010). "Treatment strategies for bipolar depression." J Clin

Psychiatry 71(5): e10.
Resolving acute bipolar mood episodes is only one part of an overall strategy
for treating bipolar disorder. Successful prevention of mood episode relapse,
particularly bipolar depressive episodes, through effective continuation and
maintenance therapies can greatly improve patient functioning and outcomes. Little
evidence is available to guide decisions on the treatment of bipolar depression,
especially in the maintenance phase, and additional research into effective options
is urgently needed. General strategies for treating patients with bipolar disorder
include continuing the acute pharmacotherapeutic regimen into the maintenance phase
and considering tolerability.

Bowden, C. L. (2011). "The role of ziprasidone in adjunctive use with lithium or

valproate in maintenance treatment of bipolar disorder." Neuropsychiatr Dis Treat
7: 87-92.
OBJECTIVES: This article addresses the clinical role for ziprasidone used
adjunctively with a mood stabilizer in maintenance treatment of bipolar disorder.
This review also addresses the strengths and limitations of design features in
adjunctive studies of second-generation antipsychotic drugs added to mood
stabilizers. METHODS: The principal study relevant to this review enrolled subjects
who were >/=18 years of age, experiencing a recent or current manic or mixed
bipolar I episode, with at least moderately severe current manic symptoms. To meet
criteria for randomization to 6 months maintenance treatment, patients had to have
failed a short course of treatment with either lithium or valproate and achieved
benefit with added ziprasidone for 8 consecutive weeks. RESULTS: Time to
intervention for a new mood episode as well as time to discontinuation for any
reason was significantly longer with adjunctive ziprasidone treatment than with
monotherapy treatment with mood stabilizer. Three dosages of ziprasidone
augmentation were studied. Patients treated with 120 mg/day had better efficacy and
overall outcomes than did patients who received 80 or 160 mg/day of ziprasidone.
CONCLUSIONS: Good evidence exists that adjunctive ziprasidone will likely provide
greater overall efficacy coupled with good tolerability for at least a 6-month
period than a strategy of continued monotherapy with a mood stabilizer. Changes in
open phases of maintenance studies to reduce study enrichment, in study endpoints,
and in statistical approaches to analysis of data are warranted.

Bowden, C. L. (2015). "Providing assessable information on effectiveness of

maintenance treatments for bipolar disorder to psychiatrists and patients." Evid
Based Ment Health 18(2): 58.

Bowden, C. L., et al. (2013). "Characterizing relapse prevention in bipolar

disorder with adjunctive ziprasidone: clinical and methodological implications." J
Affect Disord 144(1-2): 171-175.
BACKGROUND: Ziprasidone, adjunctive to either lithium or valproate, has
previously been shown to be associated with a significantly lower risk of relapse
in bipolar disorder compared with lithium or valproate treatment alone. METHODS:
This placebo-controlled outpatient trial with ziprasidone adjunctive to lithium or
valproate or lithium and valproate alone, for subjects with a recent or current
manic or mixed episode of bipolar I disorder, comprised a 2.5- to 4-month, open-
label stabilization period, followed by a 6-month, double-blind maintenance period.
These post hoc analyses characterize the relapse outcomes by dose, relapse types
and timing as well as all-reason discontinuations during the maintenance period.
RESULTS: Time to relapse and all-reason discontinuation were both statistically
significant in favor of the ziprasidone 120mg/day group compared with placebo
(p=0.004 and 0.001, respectively) during the 6-month double-blind period. There was
no difference in time to relapse in the 80 and 160mg/day dose groups compared with
placebo (p=0.16 and 0.40, respectively) and, likewise, for time to all-reason
discontinuation (p=0.20 for both doses). The majority of relapses in each group
occurred prior to week 8, and most were depressive in nature. LIMITATIONS: The
primary study was not designed to compare relapse rates by dose groups.
CONCLUSIONS: These analyses confirm the effectiveness of ziprasidone (80-160mg/day)
in preventing relapses in subjects with bipolar disorder, with the 120mg/day dosage
appearing to have the highest relapse prevention rate.

Bowden, C. L., et al. (2016). "Multi-state outcome analysis of treatments (MOAT):

application of a new approach to evaluate outcomes in longitudinal studies of
bipolar disorder." Mol Psychiatry 21(2): 237-242.
Survival analyzes are usually based on a single point in time predefined
event. Dissatisfied with this approach to evaluating maintenance treatment
outcomes, we developed the Multi-state Outcome Analysis of Treatments (MOAT)
methodology using a combined database from two FDA registration studies of
lamotrigine, lithium and placebo. MOAT partitions total survival time into
clinically distinct periods operationally defined by cutpoints on rating scales.
For bipolar disorder (BD), the clinical states are remission, subsyndromal and
syndromal mania, mixed states or depression. MOAT results can be crossed with
information about tolerability and functioning to yield an outcome system
integrating efficacy and tolerability. As found in the original analysis, both
drugs were associated with longer time in study compared with the placebo. MOAT
supplements this by finding that both drugs increased the time remitted compared
with placebo. However, a substantial amount of time in all three treatments was
spent in subsyndromal depression. Time with manic symptoms was reduced with
lithium, but not lamotrigine. Patients on placebo neither benefitted nor had
adverse effects from the assignment but experienced more syndromal levels of
symptoms and were terminated from the study sooner than either drug treated group.
Lithium was associated with both benefit in time manic and worse tolerability
compared with placebo. In summary, lamotrigine was associated with limited
therapeutic benefit but not harm; lithium with both benefit and harm; and placebo
with neither. MOAT describes not only quantity but also quality of time spent in
longitudinal studies, providing a more clinically informative picture than Kaplan-
Meier survival analysis.

Bowden, C. L. and V. Singh (2012). "Lamotrigine (Lamictal IR) for the treatment of
bipolar disorder." Expert Opin Pharmacother 13(17): 2565-2571.
INTRODUCTION: Over the past decade the use of lamotrigine in bipolar disorder
has increased. However, the evidence base suggests a more limited role for
lamotrigine as part of an overall treatment regimen in bipolar disorder. AREAS
COVERED: We reviewed publications of randomized clinical trials of lamotrigine,
emphasizing studies in bipolar disorder. The low burden of adverse effects with
lamotrigine has been confirmed in these studies. Its lack of benefit in acute mania
is established. Despite modest benefits for a subset of depressive episodes in
bipolar disorder, it was not superior to placebo in well-designed studies. As
monotherapy, in randomized, blinded trials in rapid cycling bipolar disorder it was
not superior to placebo. Its role in maintenance treatment is relatively well
established as one component of combination therapy, with evidence for benefits
when combined with lithium or valproate. Combination regimens including lamotrigine
appear to be superior to monotherapy. Monotherapy utilization of lamotrigine for
maintenance treatment is not supported by these studies. EXPERT OPINION:
Lamotrigine has benefits in bipolar disorder management principally as a component
of combination treatment which includes a mood stabilizer. The utility of
lamotrigine in acute bipolar depression and major depressive disorder is modest.
Bowden, C. L., et al. (2012). "Lamotrigine vs. lamotrigine plus divalproex in
randomized, placebo-controlled maintenance treatment for bipolar depression." Acta
Psychiatr Scand 126(5): 342-350.
OBJECTIVE: To compare the maintenance efficacy of lamotrigine (Lam) to
combination therapy of Lam+divalproex ER (Div) in recently depressed patients with
bipolar disorder (BD). METHOD: We randomized 86 BD I or II patients in a major
depressive episode to 8 months of double-blind treatment with Lam+placebo or
Lam+Div. To be eligible for randomization, patients had to achieve control of both
depressive and manic symptoms during an open phase that included both Lam and Div.
RESULTS: Time to depressive episode did not differ significantly by Kaplan-Maier
survival analysis (chi2=1.82, df=1, P=0.18). However, several secondary outcomes
did show significant differences. The proportion of Lam+placebo patients who had at
least one Montgomery-Asberg Depression Rating Scale (MADRS) score>/=15 during the
maintenance phase was 67% (30/45) compared with 44% (18/41) for the Lam+Div group
(chi2=4.51, P=0.03). Among BD I patients assigned to Lam+placebo, 71.4% (25/35) had
at least one visit with MADRS score>/=15 compared with 36.7% (11/30) among Lam+Div
patients (chi2=7.89, df=1, P=0.005). CONCLUSION: Lam+Div generally provided greater
maintenance efficacy than Lam alone for depressive indices in recently depressed BD
patients.

Bowden, C. L., et al. (2010). "Ziprasidone plus a mood stabilizer in subjects with
bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial."
J Clin Psychiatry 71(2): 130-137.
OBJECTIVE: To evaluate the efficacy and safety of ziprasidone adjunctive to a
mood stabilizer for the maintenance treatment of bipolar mania. METHOD: Subjects
with DSM-IV bipolar I disorder with a Mania Rating Scale score > or = 14 were
enrolled. Subjects achieving > or = 8 consecutive weeks of stability with open-
label ziprasidone (80-160 mg/d) and lithium or valproate (period 1) were randomly
assigned in the 6-month, double-blind maintenance period (period 2) to ziprasidone
plus mood stabilizer or placebo plus mood stabilizer. The primary and key secondary
end points were the time to intervention for a mood episode and time to
discontinuation for any reason, respectively. Inferential analysis was performed
using a Kaplan-Meier product-limit estimator (log-rank test). The study was
conducted from December 2005 to May 2008. RESULTS: A total of 127 and 113 subjects
were randomly assigned to ziprasidone and placebo, respectively. Intervention for a
mood episode was required in 19.7% and 32.4% of ziprasidone and placebo subjects,
respectively. The time to intervention for a mood episode was significantly longer
for ziprasidone than placebo (P = .0104). The median time to intervention for a
mood episode among those requiring such an intervention (n = 61) was 43.0 days for
ziprasidone versus 26.5 days for placebo. The time to discontinuation for any
reason was significantly longer for ziprasidone (P = .0047). Adjunctive ziprasidone
treatment was well tolerated. Among treatment-emergent adverse events occurring in
> or = 5% of subjects in either treatment group during period 2, only tremor
occurred more frequently in the ziprasidone versus placebo group (6.3% vs 3.6%).
CONCLUSIONS: Ziprasidone is an effective, safe, and well-tolerated adjunctive
treatment with a mood stabilizer for long-term maintenance treatment of bipolar
mania. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00280566.

Boyden, P., et al. (2015). "A preliminary investigation into theory of mind and
attributional style in adults with grandiose delusions." Cogn Neuropsychiatry
20(2): 109-121.
INTRODUCTION: A preliminary cognitive model of grandiose delusions has been
put forward suggesting that persecutory and grandiose delusions shared distinct,
yet overlapping psychological processes. This study aims to test this model and
hypothesises that participants experiencing grandiose delusions may demonstrate a
theory of mind (ToM) impairment and differences in attributional style compared to
a control group. METHODS: A cross-sectional design compared the performance of 18
individuals with grandiose delusions to a control group of 14 participants with
depression. ToM was measured using a non-verbal joke appreciation task and a verbal
stories task. Attributional style was measured using the internal, personal and
situational attributions questionnaire. RESULTS: Participants experiencing
grandiose delusions performed significantly worse on both ToM tasks compared to
controls. Furthermore, these participants provided significantly more atypical
answers when explaining the joke behind the ToM cartoons. No differences for
subjective funniness ratings or attributional style were found. CONCLUSIONS: This
preliminary study indicated participants experiencing grandiose delusions have ToM
impairments which may contribute to the maintenance of this symptom.

Brand, S., et al. (2015). ""Tell me, how bright your hypomania is, and I tell you,
if you are happily in love!"--among young adults in love, bright side hypomania is
related to reduced depression and anxiety, and better sleep quality." Int J
Psychiatry Clin Pract 19(1): 24-31.
BACKGROUND: Studies on adolescents and adults show that romantic love (RL) is
associated with favorable emotional states. However, data on these associations are
scarce for adults. The aim of the present study was, therefore, to explore the
associations between RL, symptoms of depression, anxiety, hypomania (bright side
and dark side), and sleep in a sample of adults. METHOD: A total of 844
participants currently in love (M = 24.79 years, 75.8% females) took part in the
study. They completed a series of questionnaires related to RL, symptoms of
depression, anxiety, hypomania (bright side and dark side), and sleep. RESULTS: An
increased state of RL was associated both with the bright and the dark side of
hypomania (BRHYP and DAHYP). Relative to participants with BRHYP, participants with
DAHYP reported stronger symptoms of depression and state anxiety, and poor sleep
quality. CONCLUSIONS: The pattern of results adds to our knowledge that in adults
RL is not entirely a joyful and happy period of life. Rather, data suggest that for
young adults in love, bright versus dark side of hypomania was associated with a
different quality of psychological functioning and sleep. We conclude that
experiencing RL might be a critical life event associated with symptoms of
depression and anxiety, and poor sleep.

Brill, S., et al. (2011). "Sleep disturbances in euthymic bipolar patients." Ann
Clin Psychiatry 23(2): 113-116.
BACKGROUND: Sleep disturbance has been implicated in both prodromal and
syndromal phases of bipolar illness. METHODS: Charts of bipolar disorder (BD)
patients who had been euthymic for at least 2 months were reviewed for mood
symptoms, Clinical Global Impression scores, Global Assessment of Functioning
scores, and sleep. RESULTS: Among 116 patients, 10 never achieved a euthymic
interval of 2 months' duration. Among the remaining 106 euthymic patients, 59
(55.6%) had BD I, 23 (21.7%) had BD II, and 24 (22.8%) had BD not otherwise
specified (NOS). The mean age was 43.3+/-SD 14.6, and 35% were male. A total of 25
patients (23.6%) had a clinically significant ongoing sleep disturbance (27.1% of
those with BD I, 21.7% of those with BD II, and 16.6% of those with BD NOS). Of 16
patients for whom a sleep description was available, 25% had difficulty falling
asleep, 81.25% had middle insomnia (2 patients experienced both), and none had
early morning awakening. Eleven patients (10.4%) received sleep aids, and 33
(31.1%) received sedating antipsychotics (3 patients received both). CONCLUSIONS:
Sleeping aids and sedating antipsychotics can potentially disguise an underlying
sleep disturbance. Thus, it is possible that study patients taking these
medications (n = 58; 54.7%) suffer from a sleep disturbance that is being
adequately or inadequately treated.

Brown, J. D., et al. (2013). "Medication continuity among Medicaid beneficiaries

with schizophrenia and bipolar disorder." Psychiatr Serv 64(9): 878-885.
OBJECTIVE: This study was conducted to examine whether medication continuity
among Medicaid beneficiaries with schizophrenia and bipolar disorder was associated
with medication utilization management practices (prior authorization, copayment
amounts, and refill and pill quantity limits), managed care enrollment, and other
state and beneficiary characteristics. METHODS: With 2007 Medicaid Analytic Extract
claims data from 22 states, random-effects logistic regression modeled the odds of
high medication continuity, defined as receiving medications for at least 80% of
the days enrolled in Medicaid, among beneficiaries ages 18-64 with a diagnosis of
schizophrenia (N=91,451) or bipolar disorder (N=33,234). RESULTS: Sixty-four
percent of beneficiaries with schizophrenia and 54% of beneficiaries with bipolar
disorder had high medication continuity. Medication continuity was worse among
beneficiaries with schizophrenia in states that required prior authorization for
antipsychotics, $2-$3 copayments for generic medications, or $1 copayments for
branded medications (compared with no copayments). For beneficiaries with bipolar
disorder, medication continuity was worse among those in states with more prior-
authorization requirements for different classes of medications or $1 copayments
for branded medications. Medication continuity was worse among beneficiaries who
were African American, Hispanic, younger, or enrolled in a health maintenance
organization health plan or who had a comorbid substance use disorder or
cardiovascular disease. CONCLUSIONS: Prior-authorization requirements and
copayments for medications may present barriers to refilling medications for
Medicaid beneficiaries with schizophrenia or bipolar disorder. State Medicaid
programs should consider the unintended consequences of medication utilization
management practices for this population.

Brunelin, J., et al. (2010). "Successful switch to maintenance rTMS after

maintenance ECT in refractory bipolar disorder." Brain Stimul 3(4): 238-239.

Bschor, T. and M. Bauer (2013). "[Side effects and risk profile of lithium:
critical assessment of a systematic review and meta-analysis]." Nervenarzt 84(7):
860-863.
Lithium is the only drug that obtained the highest level of recommendation
for maintenance therapy in the recent German S3 guidelines on bipolar disorders. In
addition it is the only drug with proven efficacy for the prevention of manic as
well as depressive episodes in studies with a non-enriched design. Therefore, it is
highly welcomed that The Lancet recently published a systematic review and meta-
analysis on the risks and side effects of lithium. This is the most comprehensive
review on this topic so far.The glomerular filtration rate and maximum urinary
concentration ability are slightly reduced under lithium. More patients suffered
from renal failure compared to controls; however, renal failure remains a very rare
event. The review confirmed the well known suppressive effects of lithium on the
thyroid. An increase of serum calcium could be observed relatively frequently,
therefore, regular control of serum calcium under lithium therapy is recommended. A
relevant increase in body weight is more frequent under lithium than under placebo
but less frequent than under olanzapine. No statistically significant increase
could be found for hair loss, skin disorders or major congenital
abnormalities.Lithium treatment is a safe therapy when clinicians follow the
established recommendations. Data indicate that a risk for renal failure exists
especially in patients without regular monitoring or with too high lithium serum
levels. A (subclinical) hypothyroidism is not an indication to stop administration
of lithium but is an indication for l-thyroxin substitution therapy. In pregnancy
the risks of continuing lithium should be balanced against the risks of stopping
lithium together with the patient.

Bschor, T., et al. (2014). "[New facts of long-term prophylaxis for bipolar
affective disorder]." Nervenarzt 85(9): 1166-1170.
Lithium and with restrictions, carbamazepine, valproic acid, lamotrigine,
olanzapine, aripiprazole and quetiapine, are approved in Germany for maintenance
treatment of bipolar disorder. Lithium is the only drug that (I) proved to be
effective for the prevention of depressive as well as manic episodes in state-of-
the-art studies without an enriched design and that (II) is approved for the
maintenance treatment of bipolar disorders without restrictions. It (III) is also
the only drug which is recommended for maintenance treatment by the current German
S3 guidelines on bipolar disorders with the highest degree of recommendation (A)
and (IV) is the only drug with a well proven suicide preventive effect. Hence,
lithium is the mood stabilizer of first choice. No patient should be deprived of
lithium without a specific reason. Side effects and risks are manageable if both
the physician and the patient are well informed. Detailed and practical information
on a safe use of lithium can be found in the S3 guidelines on bipolar disorders.
For patients who do not respond sufficiently to lithium, have contraindications or
non-tolerable side effects, other mood stabilizers should be used. Restrictions in
their respective approval as well as specific side effects and risks have to be
taken into account. Because maintenance treatment is a long-term treatment,
particular concern should be paid to drugs with the potential risk of a metabolic
syndrome, particularly atypical antipsychotics.

Bulbul, F., et al. (2013). "Maintenance therapy with electroconvulsive therapy in a

patient with a codiagnosis of bipolar disorder and obsessive-compulsive disorder."
J ECT 29(2): e21-22.
Obsessive-compulsive disorder (OCD) is defined as the most commonly seen
anxiety disorder accompanying the bipolar disorder, and this concomitance causes
the difficulties in the therapy. Although electroconvulsive therapy (ECT) is
efficient in both manic and depressive episodes of the bipolar disorder, it is
considered as a therapeutic option in cases of OCD with depression comorbidity. In
this article, we aimed to present a case in which depressive episode of bipolar
disorder and OCD comorbidity were present; both depressive and OCD symptoms were
resolved using ECT. Symptoms of both diseases recurred after the discontinuation of
ECT, and well-being sustained with maintenance ECT.

Calabrese, J. R., et al. (2014). "Efficacy and safety of adjunctive armodafinil in

adults with major depressive episodes associated with bipolar I disorder: a
randomized, double-blind, placebo-controlled, multicenter trial." J Clin Psychiatry
75(10): 1054-1061.
OBJECTIVE: To examine the efficacy and safety of adjunctive armodafinil for
major depressive episodes associated with bipolar I disorder. METHOD: Adults
meeting DSM-IV-TR criteria for bipolar I disorder and currently experiencing a
major depressive episode while taking at least 4 weeks of conventional maintenance
medication were enrolled in a placebo-controlled evaluation of adjunctive
armodafinil 150 or 200 mg (conducted January 2010-March 2012). The primary efficacy
measure was change from baseline to week 8 on the 30-item Inventory of Depressive
Symptomatology-Clinician-Rated (IDS-C30) total score in the 150-mg armodafinil
group versus placebo. RESULTS: Of 786 patients screened, 433 were randomized
(placebo, n = 199; armodafinil 150 mg, n = 201; armodafinil 200 mg, n = 33). The
200-mg armodafinil group was discontinued by protocol amendment due to lower than
expected patient enrollment. For the 150-mg armodafinil group versus placebo, there
was a significantly greater decrease in least squares mean (standard error of mean
[SEM]) IDS-C30 total score at week 8 (-21.7 [1.1] vs -17.9 [1.1]; P = .0097; Cohen
d therapeutic effect size = 0.28). The proportion of IDS-C30 responders (>/= 50%
decrease from baseline) was significantly higher for the 150-mg armodafinil group
versus placebo at final visit (46% [91/197] vs 34% [67/196]; P = .0147). The
proportion of IDS-C30 remitters (total score </= 11) was 21% (42/197) for
armodafinil 150 mg versus 17% (34/196) for placebo (P = .3343) at final visit.
Adverse events (AEs) observed in > 5% of either the armodafinil 150 mg or placebo
groups and more frequently with 150 mg armodafinil were diarrhea (9% [17/198] vs 7%
[13/199]), and nausea (6% [11/198] vs 5% [9/199]), respectively. In the 200-mg
armodafinil group, there were 2 serious AEs (n = 1, hepatic failure leading to
death; n = 1, acute hepatitis). The death was not considered related to study
treatment. CONCLUSIONS: Adjunctive armodafinil 150 mg significantly improved
symptoms of major depressive episodes associated with bipolar I disorder versus
placebo and was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov
identifier: NCT01072929.

Calabrese, J. R., et al. (2017). "Efficacy and Safety of Aripiprazole Once-Monthly

in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-
Controlled, 52-Week Randomized Withdrawal Study." J Clin Psychiatry.
OBJECTIVE: To evaluate efficacy, safety, and tolerability of long-acting
injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) as maintenance
treatment for bipolar I disorder (BP-I). METHODS: In a double-blind, placebo-
controlled, 52-week randomized withdrawal study conducted from August 2012 to April
2016, patients with a DSM-IV-TR diagnosis of BP-I currently experiencing a manic
episode were stabilized sequentially on oral aripiprazole and AOM 400 and then
randomized to AOM 400 or placebo. The primary end point was time from randomization
to recurrence of any mood episode. Other end points included proportion of patients
with recurrence of any mood episode and recurrence by mood episode type. RESULTS:
Of 266 randomized patients, 64 (48.1%) of 133 in the AOM 400 group and 38 (28.6%)
of 133 in the placebo group completed the study. AOM 400 significantly delayed the
time to recurrence of any mood episode compared with placebo (hazard ratio: 0.45;
95% CI, 0.30 to 0.68; P < .0001). Significantly fewer patients (P < .0001)
experienced recurrence of any mood episode with AOM 400 (35/132; 26.5%) compared
with placebo (68/133; 51.1%), with the effects observed predominantly on manic
episodes (P < .0001). Patients were not depressed at study entry, and between-group
differences in depressive episodes were not significant (P < .864). The treatment-
emergent adverse events (incidence > 5%) that were reported at higher rates with
AOM 400 than placebo were weight increase, akathisia, insomnia, and anxiety.
CONCLUSIONS: AOM 400 delayed the time to and reduced the rate of recurrence of mood
episodes and was generally safe and well tolerated. These findings support the use
of AOM 400 for maintenance treatment of BP-I. TRIAL REGISTRATION:
ClinicalTrials.gov identifier: NCT01567527.

Callari, A., et al. (2013). "Treatment of depression in patients with breast

cancer: a critical review." Tumori 99(5): 623-633.
AIMS AND BACKGROUND: To summarize current knowledge on psychopharmacological
and psychotherapeutic options for patients with breast cancer and comorbid
depression, starting from the psychiatric viewpoint. Issues on diagnostic
boundaries of depression and outcome measures are raised. METHODS: We completed a
literature review from the last 30 years (until March 2012) using PubMed by pairing
the key words: 'breast cancer and depression treatment' (about 1431 works,
including 207 reviews), 'breast cancer and antidepressants' (about 305 works,
including 66 reviews), and in particular 'selective serotonin reuptake inhibitors
and breast cancer' (38 works, including 10 reviews) and 'breast cancer and
psychotherapy' (603 works, including 84 reviews). Papers in the English language
were selected, including recent reviews. RESULTS: There is little evidence for the
superiority of any one specific intervention with pharmacological options or
psychotherapy. The heterogeneity of assessment criteria, the small number of
subjects collected in systematic studies, the difficulty in adopting standardized
outcome measures, and the limited numbers of available drugs with a favorable side
effect profile are the main limitations that emerge from the literature. No
conclusive findings are available on mid-term/long-term treatment strategies, or
when depression is part of a bipolar disorder. CONCLUSIONS: Further research is
necessary to define the most appropriate approach to depression when it occurs in
comorbidity with breast cancer. A more accurate definition of the clinical
phenotypes of depression in the special population of patients with breast cancer
is suggested as a key issue.

Campos, R. N., et al. (2010). "LICAVAL: combination therapy in acute and

maintenance treatment of bipolar disorder." Trials 11: 72.
BACKGROUND: The challenge of Bipolar Disorder (BD) treatment is due to the
complexity of the disease. Current guidelines represent an effort to help
clinicians in their everyday practice but still have limitations, specially
concerning to long term treatment. LICAVAL (efficacy and tolerability of the
combination of LIthium and CArbamazepine compared to lithium and VALproic acid in
the treatment of young bipolar patients) study aim to evaluate acute and
maintenance phase of BD treatment with two combined drugs. METHODS: LICAVAL is a
single site, parallel group, randomized, outcome assessor blinded trial. BD I
patients according to the DSM-IV-TR, in depressive, manic,/hypomanic or mixed
episode, aged 18 to 35 years are eligible. After the diagnostic assessments, the
patients are allocated for one of the groups of treatment (lithium + valproic acid
or lithium + carbamazepine). Patients will be followed up for 8 weeks in phase I
(acute treatment), 6 months in phase II (continuation treatment) and 12 months in
phase III (maintenance treatment). Outcome assessors are blind to the treatment.
The main outcome is the evaluation of changes in mean scores on CGI-BP-M between
baseline and endpoint at the end of each phase of the study. RESULTS: LICAVAL is
currently in progress, with patients in phase I, II or III. It will extended until
august 2012. CONCLUSIONS: Trials comparing specific treatments efficacy in BD (head
to head) can show relevant information in clinical practice. Long term treatment is
an issue of great important and should be evaluated carefully in more studies as
long as BD is a chronic disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:
NCT00976794.

Carvalho, A. F., et al. (2014). "Predominant polarity as a course specifier for

bipolar disorder: a systematic review." J Affect Disord 163: 56-64.
BACKGROUND: Predominant polarity (PP) is a proposed course specifier for
bipolar disorder, which was not incorporated in the DSM-5 as a descriptor for the
nosology of bipolar disorder (BD). Here we perform a systematic review of original
studies about PP. METHODS: A computerized search of MEDLINE/Pubmed, EMBASE and Web
of Science databases from inception to October 6th, 2013 was performed with
keywords, including 'bipolar disorder', 'polarity' and 'predominant polarity'.
RESULTS: A total of 19 studies met inclusion criteria. A unifying definition and
conceptualization for PP is lacking. A PP is found in approximately half of BD
patients. Most studies that included type I BD patients found the manic PP to be
more prevalent, while studies that included type II BD participants found a higher
prevalence of depressive PP. The depressive PP has been consistently associated
with a depressive onset of illness, a delayed diagnosis of BD, type II BD and
higher rates of suicidal acts. The manic PP is associated with a younger onset of
illness, a first episode manic/psychotic and a higher rate of substance abuse.
Evidence suggests that PP may influence responses to acute treatment for bipolar
depression. Furthermore, evidences indicate that PP should be considered for the
selection of maintenance treatments for BD. LIMITATIONS: There are few prospective
studies on PP. There were disparate definitions for PP across studies. CONCLUSIONS:
The concept of PP provides relevant information for clinicians. Future studies
should investigate the genetic and biological underpinnings of PP.

Carvalho, A. F., et al. (2014). "Treatment implications of predominant polarity and

the polarity index: a comprehensive review." Int J Neuropsychopharmacol 18(2).
BACKGROUND: Bipolar disorder (BD) is a serious and recurring condition that
affects approximately 2.4% of the global population. About half of BD sufferers
have an illness course characterized by either a manic or a depressive
predominance. This predominant polarity in BD may be differentially associated with
several clinical correlates. The concept of a polarity index (PI) has been recently
proposed as an index of the antimanic versus antidepressive efficacy of various
maintenance treatments for BD. Notwithstanding its potential clinical utility,
predominant polarity was not included in the DSM-5 as a BD course specifier.
METHODS: Here we searched computerized databases for original clinical studies on
the role of predominant polarity for selection of and response to pharmacological
treatments for BD. Furthermore, we systematically searched the Pubmed database for
maintenance randomized controlled trials (RCTs) for BD to determine the PI of the
various pharmacological agents for BD. RESULTS: We found support from naturalistic
studies that bipolar patients with a predominantly depressive polarity are more
likely to be treated with an antidepressive stabilization package, while BD
patients with a manic-predominant polarity are more frequently treated with an
antimanic stabilization package. Furthermore, predominantly manic BD patients
received therapeutic regimens with a higher mean PI. The calculated PI varied from
0.4 (for lamotrigine) to 12.1 (for aripiprazole). CONCLUSIONS: This review supports
the clinical relevance of predominant polarity as a course specifier for BD. Future
studies should investigate the role of baseline, predominant polarity as an outcome
predictor of BD maintenance RCTs.

Cawkwell, P., et al. (2016). "Staying Up at Night: Overlapping Bipolar and

Obsessive-Compulsive Disorder Symptoms in an Adolescent with Autism Spectrum
Disorder." J Child Adolesc Psychopharmacol 26(1): 74-77.

Chen, C. H., et al. (2014). "Variant GADL1 and response to lithium therapy in
bipolar I disorder." N Engl J Med 370(2): 119-128.
BACKGROUND: Lithium has been a first-line choice for maintenance treatment of
bipolar disorders to prevent relapse of mania and depression, but many patients do
not have a response to lithium treatment. METHODS: We selected subgroups from a
sample of 1761 patients of Han Chinese descent with bipolar I disorder who were
recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium
treatment using the Alda scale and performed a genomewide association study on
samples from one subgroup of 294 patients with bipolar I disorder who were
receiving lithium treatment. We then tested the single-nucleotide polymorphisms
(SNPs) that showed the strongest association with a response to lithium for
association in a replication sample of 100 patients and tested them further in a
follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries,
and part of the promoter of the gene encoding glutamate decarboxylase-like protein
1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did
not have a response in the genomewide association sample. RESULTS: Two SNPs in high
linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns
of GADL1 showed the strongest associations in the genomewide association study
(P=5.50x10(-37) and P=2.52x10(-37), respectively) and in the replication sample of
100 patients (P=9.19x10(-15) for each SNP). These two SNPs had a sensitivity of 93%
for predicting a response to lithium and differentiated between patients with a
good response and those with a poor response in the follow-up cohort. Resequencing
of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene,
is in complete linkage disequilibrium with rs17026688 and is predicted to affect
splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response
to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese
descent. (Funded by Academia Sinica and others.).

Chen, C. H. and S. K. Lin (2012). "Carbamazepine treatment of bipolar disorder: a

retrospective evaluation of naturalistic long-term outcomes." BMC Psychiatry 12:
47.
BACKGROUND: Carbamazepine (CBZ) has been used in the treatment of bipolar
disorder, both in acute mania and maintenance therapy, since the early 1970s. Here,
we report a follow-up study of CBZ-treated bipolar patients in the Taipei City
Psychiatric Centre. METHODS: Bipolar patients diagnosed according to the DSM-IV
system and treated with CBZ at the Taipei City Psychiatric Centre had their charts
reviewed to evaluate the efficacy and side effects of this medication during an
average follow-up period of 10 years. RESULTS: A total of 129 bipolar patients (45
males, mean age: 45.7 +/- 10.9 year) were included in the analysis of CBZ efficacy
used alone (n = 63) or as an add-on after lithium (n = 50) or valproic acid (n =
11), or the both of them (n = 5). The mean age of disease onset was 24.6 +/- 9.5
years. The mean duration of CBZ use was 10.4 +/- 5.2 year. The mean dose used was
571.3 +/- 212.6 mg/day with a mean plasma level of 7.8 +/- 5.9 mug/mL. Mean body
weight increased from 62.0 +/- 13.4 kg to 66.7 +/- 13.1 kg during treatment. The
frequencies of admission per year before and after CBZ treatment were 0.33 +/- 0.46
and 0.14 +/- 0.30, respectively. The most common side effects targeted the central
nervous system (24%), including dizziness, ataxia and cognitive impairment. Other
common side effects were gastrointestinal disturbances (3.6%), tremor (3.6%), skin
rash (2.9%), and blurred vision (2.9%). Eighty-eight patients (68.2%) were taking
antipsychotics concomitantly. Ninety-six patients (74.4%) needed to use
benzodiazepines concomitantly. Sixty-three (48.8%) patients had zero episodes in a
10-year follow-up period, compared to all patients having episodes prior to
treatment. Using variable analysis, we found better response to CBZ in males than
in females. CONCLUSIONS: CBZ is efficacious in the maintenance treatment of bipolar
disorder in naturalistic clinical practice, either as monotherapy or in combination
with other medications. CBZ is well tolerated by most patients in this patient
group.

Chen, C. K., et al. (2016). "GADL1 variant and medication adherence in predicting
response to lithium maintenance treatment in bipolar I disorder." BJPsych Open
2(5): 301-306.
BACKGROUND: Genetic variants and medication adherence have been identified to
be the main factors contributing to lithium treatment response in bipolar
disorders. AIMS: To simultaneously examine effects of variant glutamate
decarboxylase-like protein 1 (GADL1) and medication adherence on response to
lithium maintenance treatment in Han Chinese patients with bipolar I (BPI)
disorder. METHOD: Frequencies of manic and depressive episodes between carriers and
non-carriers of the effective GADL1 rs17026688 T allele during the cumulative
periods of off-lithium, poor adherence to lithium treatment and good adherence to
lithium treatment were compared in Han Chinese patients with BPI disorder (n=215).
RESULTS: GADL1 rs17026688 T carriers had significantly lower frequencies of
recurrent affective episodes than non-T carriers during the cumulative period of
good adherence, but not during those of poor adherence. CONCLUSIONS: GADL1
rs17026688 and medication adherence jointly predict response to lithium maintenance
treatment in Han Chinese BPI patients. DECLARATION OF INTEREST: None. COPYRIGHT AND
USAGE: (c) The Royal College of Psychiatrists 2016. This is an open access article
distributed under the terms of the Creative Commons Non-Commercial, No Derivatives
(CC BY-NC-ND) license.

Chengappa, K. N., et al. (2013). "Randomized placebo-controlled adjunctive study of

an extract of withania somnifera for cognitive dysfunction in bipolar disorder." J
Clin Psychiatry 74(11): 1076-1083.
OBJECTIVE: Cognitive impairments contribute significantly to inadequate
functional recovery following illness episodes in bipolar disorder, yet data on
treatment interventions are sparse. We assessed the cognitive effects of a
standardized extract of the medicinal herb Withania somnifera (WSE) in bipolar
disorder. METHOD: Sixty euthymic subjects with DSM-IV bipolar disorder were
enrolled in an 8-week, double-blind, placebo-controlled, randomized study of WSE
(500 mg/d) as a procognitive agent added adjunctively to the medications being used
as maintenance treatment for bipolar disorder. Study enrollment and data analyses
were completed between December 2008 and September 2012. Cognitive testing at
baseline and 8 weeks assessed primary efficacy outcomes. Psychopathology and
adverse events were monitored at scheduled visits. RESULTS: Fifty-three patients
completed the study (WSE, n = 24; placebo, n = 29), and the 2 groups were matched
in terms of demographic, illness, and treatment characteristics. Compared to
placebo, WSE provided significant benefits for 3 cognitive tasks: digit span
backward (P = .035), Flanker neutral response time (P = .033), and the social
cognition response rating of the Penn Emotional Acuity Test (P = .045). The size of
the WSE treatment effect for digit span backward was in the medium range (Cohen d =
0.51; 95% CI, 0.25-0.77). None of the other cognitive tasks showed significant
between-group differences. Mood and anxiety scale scores remained stable, and
adverse events were minor. CONCLUSIONS: Although results are preliminary, WSE
appears to improve auditory-verbal working memory (digit span backward), a measure
of reaction time, and a measure of social cognition in bipolar disorder. Given the
paucity of data for improving cognitive capacity in bipolar disorder, WSE offers
promise, appears to have a benign side-effects profile, and merits further study.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00761761.
Cheniaux, E. (2011). "[The pharmacological treatment of bipolar disorder: a
systematic and critical review of the methodological aspects of modern clinical
trials]." Rev Bras Psiquiatr 33(1): 72-80.
OBJECTIVE: To review systematically the main clinical trials on the
pharmacological treatment of bipolar disorder and to make a critical analysis of
their methodological aspects. METHOD: A search in Medline, ISI and PsycINFO
databases was conducted, using the following search terms: "bipolar", "randomized",
"placebo" e "controlled". Randomized, double-blind, placebo-controlled clinical
trials on the pharmacological treatment of bipolar disorder were selected. Besides,
according to our criteria, samples had to consist of at least 100 patients and
experimental drug had to be used as monotherapy. RESULTS: 34 articles met our
selection criteria. All drugs currently indicated for mania, bipolar depression and
maintenance treatment of bipolar disorder were more effective than placebo in at
least one clinical trial. However, these studies had highly selected samples, high
dropout rates and low response rates. CONCLUSION: Modern clinical trials on
pharmacological treatment of bipolar disorder have important methodological
limitations. So, their results should be taken with caution.

Chiesa, A., et al. (2012). "Quetiapine for bipolar depression: a systematic review
and meta-analysis." Int Clin Psychopharmacol 27(2): 76-90.
Quetiapine has been proposed for depression in bipolar patients but a
quantitative analysis is lacking. In the present paper, we review and meta-analyze
available data about the short-term and long-term efficacy and tolerability of
quetiapine for the depressive phase of bipolar disorder or bipolar depression. A
literature research was carried out using three electronic databases. Studies
providing measures of efficacy and tolerability of quetiapine, either as
monotherapy or as augmentation, for bipolar depression were considered. Seven
short-term studies and four maintenance studies were included. Short-term studies
suggested that patients treated with quetiapine monotherapy were significantly more
likely than patients treated with placebo and further active comparators to achieve
higher response and remission rates as well as more clinical improvements at the
endpoint. Such benefits were significant from the first weeks of treatment onward.
Maintenance studies suggested that the combination of quetiapine and mood
stabilizers was significantly better than placebo plus mood stabilizers for the
prevention of both depressive and manic relapses. Quetiapine was generally well
tolerated. Furthermore, several clinical variables moderated outcomes under
investigation. In conclusion, quetiapine could have some advantages over
traditional treatments for the treatment of bipolar depression.

Chiesa, A. and A. Serretti (2011). "Mindfulness based cognitive therapy for

psychiatric disorders: a systematic review and meta-analysis." Psychiatry Res
187(3): 441-453.
Mindfulness- based Cognitive Therapy (MBCT) is a meditation program based on
an integration of Cognitive behavioural therapy and Mindfulness-based stress
reduction. The aim of the present work is to review and conduct a meta-analysis of
the current findings about the efficacy of MBCT for psychiatric patients. A
literature search was undertaken using five electronic databases and references of
retrieved articles. Main findings included the following: 1) MBCT in adjunct to
usual care was significantly better than usual care alone for reducing major
depression (MD) relapses in patients with three or more prior depressive episodes
(4 studies), 2) MBCT plus gradual discontinuation of maintenance ADs was associated
to similar relapse rates at 1year as compared with continuation of maintenance
antidepressants (1 study), 3) the augmentation of MBCT could be useful for reducing
residual depressive symptoms in patients with MD (2 studies) and for reducing
anxiety symptoms in patients with bipolar disorder in remission (1 study) and in
patients with some anxiety disorders (2 studies). However, several methodological
shortcomings including small sample sizes, non-randomized design of some studies
and the absence of studies comparing MBCT to control groups designed to distinguish
specific from non-specific effects of such practice underscore the necessity for
further research.

Cho, D. H., et al. (2014). "Valproic acid increases NO production via the SH-PTP1-
CDK5-eNOS-Ser(116) signaling cascade in endothelial cells and mice." Free Radic
Biol Med 76: 96-106.
Valproic acid (VPA) with its inhibitory activity of histone deacetylase has
been used in the treatment of epilepsy and bipolar disorder associated with
cerebrovascular dysfunction. Because nitric oxide (NO) produced by endothelial NO
synthase (eNOS) plays a role in the maintenance of vascular function, NO is likely
to mediate VPAs drug effect, but its effect on NO production remains controversial.
We investigated whether and how VPA regulates NO production in bovine aortic
endothelial cells (BAECs) and mice. VPA increased NO production in BAECs, which was
accompanied by a decrease in phosphorylation of eNOS at serine 116 (eNOS-Ser(116))
and cyclin-dependent kinase 5 at tyrosine 15 (CDK5-Tyr(15)). Ectopic expression of
p25, a CDK5 activator, restored the VPA-inhibited eNOS-Ser(116) phosphorylation. In
silico analysis revealed that the CDK5-Tyr(15) residue might be a substrate for SH2
domain-containing protein tyrosine phosphatase 1 (SH-PTP1), and CDK5 actually
interacted with SH-PTP1. VPA increased SH-PTP1 expression and its activity.
Stibogluconate, a specific SH-PTP1 inhibitor, reversed the VPA-inhibited
phosphorylation of CDK5-Tyr(15) and eNOS-Ser(116). Knockdown of SH-PTP1 using small
interfering RNA also reversed all the observed effects of VPA. Finally, both serum
NO level and acetylcholine-induced aortic relaxation increased in VPA-medicated
male mice. These increases were accompanied by increased SH-PTP1 expression and
decreased phosphorylation of CDK5-Tyr(15) and eNOS-Ser(116) in mouse aortas. In
conclusion, VPA increases NO production by inhibiting the CDK5-Tyr(15)-eNOS-
Ser(116) phosphorylation axis; this process is mediated by SH-PTP1. VPA may be
useful in the treatment of NO-related cerebrocardiovascular diseases.

Christodoulou, T., et al. (2012). "Dissociable and common deficits in inhibitory

control in schizophrenia and bipolar disorder." Eur Arch Psychiatry Clin Neurosci
262(2): 125-130.
Current research focuses on delineating the neurobiological boundaries
between familial risk for schizophrenia (SZ) and bipolar disorder (BD). Available
evidence suggests that inhibitory control may be affected in both disorders.
Inhibitory control relies on the dual processes of contextual information
maintenance and response inhibition. This study investigated the effect of familial
risk of SZ or BD on these two aspects of inhibitory control. Seventeen healthy
first-degree relatives of patients with BD (BD-R), 15 healthy relatives of patients
with SZ (SZ-R) and 23 demographically matched controls were compared in terms of
their performance during Controlled Oral Word Association (COWA), which measures
contextually driven response selection, and during the Hayling Sentence Completion
Test (HSCT), which assesses contextual response selection and inhibition. Compared
to controls and BD-R, SZ-R showed deficits in contextual information processing
that resulted in spontaneous errors in the COWA as well as deficits in response
inhibition during the HSCT that resulted in higher error rates. BD-R also showed
deficits in response inhibition during the HSCT relative to controls, which were,
however, less pronounced than for SZ-R. Both relatives groups had longer response
times. Our results suggest that failure in contextual maintenance is primarily
associated with familial risk for SZ, while response inhibition may be a shared
marker of familial risk for both disorders.

Chue, P. and J. Chue (2016). "A critical appraisal of paliperidone long-acting

injection in the treatment of schizoaffective disorder." Ther Clin Risk Manag 12:
109-116.
Schizoaffective disorder (SCA) is a chronic and disabling mental illness that
presents with mixed symptoms of schizophrenia and affective disorders. SCA is
recognized as a discrete disorder, but with greater heterogeneity and symptom
overlap, leading to difficulty and delay in diagnosis. Although the overall
prognosis is intermediate between schizophrenia and mood disorders, SCA is
associated with higher rates of suicide and hospitalization than schizophrenia. No
treatment guidelines exist for SCA, and treatment is frequently complex, involving
off-label use and polypharmacy (typically combinations of antipsychotics, mood
stabilizers, and antidepressants). Oral paliperidone extended-release was the first
agent to be approved for the treatment of SCA. As in schizophrenia and bipolar
disorder, adherence to oral medications is poor, further contributing to suboptimal
outcomes. The use of an antipsychotic in a long-acting injection (LAI) addresses
adherence issues, thus potentially reducing relapse. Paliperidone palmitate
represents the LAI formulation of paliperidone. In a long-term, double-blind,
randomized, controlled trial of adult patients (n=334; intent-to-treat [ITT]) with
SCA, paliperidone long-acting injection (PLAI) significantly delayed risk of
relapse compared to placebo (hazard ratio 2.49, 95% confidence interval, 1.55-3.99;
P<0.001). This study demonstrated the efficacy and safety of PLAI when used as
either monotherapy or adjunctive therapy for the maintenance treatment of SCA. The
results are consistent with a similarly designed study conducted in patients with
schizophrenia, which suggests a benefit in the long-term control of not only
psychotic but also affective symptoms. No new safety signals were observed. When
used in monotherapy, PLAI simplifies treatment by reducing complex pharmacotherapy
and obviating the necessity for daily oral medications. PLAI is the second agent,
and the first LAI, to be approved for the treatment of SCA; as an LAI formulation,
there is the advantage of improved adherence and simplified treatment in the long-
term management of SCA.

Chung, A. K. (2012). "Atypical presentation of tardive dyskinesia associated with

risperidone long-acting injection as maintenance treatment in bipolar affective
disorder: a case report." Curr Drug Saf 7(1): 21-23.
Second-generation antipsychotics have been growingly implicated in the acute
and maintenance treatment for bipolar affective disorder (BAD). Risperidone long-
acting injection (LAI) has been the first second-generation depot indicated for its
maintenance treatment. However, its long-term motor side-effects, especially
tardive dyskinesia (TD), has not been commonly reported or studied. The case
reported here a bipolar patient with atypical presentation of TD involving only the
crico-hyoid region of the neck associated with the use of risperidone LAI in
adjunct to lithium and sodium valproate as maintenance therapy.

Chung, K. H., et al. (2015). "Risk of psychiatric disorders in patients with

chronic insomnia and sedative-hypnotic prescription: a nationwide population-based
follow-up study." J Clin Sleep Med 11(5): 543-551.
STUDY OBJECTIVES: Previous epidemiological studies have established insomnia
as a major risk factor for mood, anxiety, and substance use disorders. However, the
associations between insomnia with sedative-hypnotic prescriptions and various
psychiatric disorders have not been thoroughly examined. The current study involved
evaluating the risk of psychiatric disorders, namely schizophrenia, mood, anxiety,
somatoform, and substance-related disorders, over a 6-y follow-up period in three
groups: patients with insomnia and sedative-hypnotic prescriptions (Inso-Hyp),
those with insomnia and without sedative-hypnotic prescriptions (Inso-NonHyp), and
those with neither insomnia nor sedative-hypnotic prescriptions (NonInso-NonHyp).
METHODS: We used a historical cohort study design to compare the risk of
psychiatric disorders among the three groups. Data regarding these patients were
derived from reimbursement claims recorded in Taiwan's National Health Insurance
Research Database. Cox proportional hazards regression was used to compare the 6-y
risk of subsequent psychiatric disorders among the Inso-Hyp, Inso-NonHyp, and
NonInso-NonHyp groups. RESULTS: Compared with the Inso-NonHyp and NonInso-NonHyp
group patients, the Inso-Hyp group patients exhibited a higher risk of psychiatric
disorders, particularly bipolar disorders (adjusted hazard ratio [AHR]: 7.60; 95%
confidence interval [CI]: 5.31-10.89 and AHR: 14.69; 95% CI: 11.11-19.43,
respectively). Moreover, among the Inso-Hyp patient group, insomnia prescribed with
benzodiazepine, a longer duration of sedative-hypnotic action, and higher doses of
sedativehypnotics were significantly associated with a higher risk of depressive
and anxiety disorders. CONCLUSION: The Inso-Hyp group exhibited a higher risk of
developing psychiatric disorders than did the Inso-NonHyp and NonInso-NonHyp
groups. The results regarding patients with insomnia and sedative-hypnotic
prescriptions associated with the risk of psychiatric disorders can serve as a
reference for care providers when managing sleep disturbances.

Cipriani, A., et al. (2014). "Clinical and regulatory implications of active run-in
phases in long-term studies for bipolar disorder." Acta Psychiatr Scand 129(5):
328-342.
OBJECTIVE: The integration of new treatments into the market and routine
clinical practice should be dependent on robustness of evidence from randomised
controlled trials (RCTs). We assessed study designs of long-term studies for
bipolar disorder of all second-generation antipsychotics (SGAs) submitted to the
Food and Drug Administration (FDA) and the completeness of evidence submitted to
the regulatory agency. METHOD: Systematic review of double-blind RCTs comparing
SGAs with placebo or active drugs in adults. FDA website and electronic databases
were searched until July 2013. RESULTS: Six placebo-controlled trials comparing
aripiprazole, olanzapine, quetiapine and ziprasidone were found in the FDA website.
Electronic searches found four additional RCTs about aripiprazole, olanzapine or
quetiapine. All RCTs (either submitted to FDA or not) selected patients who
responded to acute treatment to increase the treatment effect observed in the long-
term phase (enrichment design). By contrast, in the prescribing information sheets
for all SGAs, the reported indication was 'maintenance treatment of bipolar
disorder'. CONCLUSION: Extrapolation of results from enrichment studies to the more
general population of patients should be carried out cautiously because average
treatment benefits are likely to be less in unselected patients. Clear guidance for
regulatory submission of RCTs is needed.

Cipriani, A., et al. (2013). "Valproic acid, valproate and divalproex in the
maintenance treatment of bipolar disorder." Cochrane Database Syst Rev(10):
CD003196.
BACKGROUND: Bipolar disorder is a recurrent illness that is amongst the top
30 causes of disability worldwide and is associated with significant healthcare
costs. In the past, emphasis was placed solely on the treatment of acute episodes
of bipolar disorder; recently, the importance of episode prevention and of
minimisation of iatrogenicity has been recognised. For many years, lithium was the
only mood stabiliser in common use, and it remains an agent of first choice in the
preventative treatment of bipolar disorder. However, an estimated 20% to 40% of
patients may not respond adequately to lithium. Valproate is an anticonvulsant drug
that has been shown to be effective in acute mania and is frequently used in
maintenance treatment of bipolar disorder. When the acceptability of long-term
treatment is considered, together with efficacy, the adverse event profile of a
medication is also important. This is an update of a Cochrane review first
published in 2001 and last updated in 2009. OBJECTIVES: 1. To determine the
efficacy of valproate continuation and maintenance treatment:a) in preventing or
attenuating manic, depressive and mixed episodes of bipolar disorder;b) in
preventing or attenuating episodes of bipolar disorder in patients with rapid
cycling disorder; and; c) in improving patients' general health and social
functioning, as measured by global clinical impression, employment and marital
stability.2. To review the acceptability to patients of long-term valproate
treatment, as measured by numbers of dropouts and reasons for dropping out, by
compliance and by reference to patients' expressed views regarding treatment.3. To
investigate the adverse effects of valproate treatment (including general
prevalence of side effects) and overall mortality rates. SEARCH METHODS: Search of
the Cochrane Register of Controlled Trials and the Cochrane Depression, Anxiety and
Neurosis Group Register (CCDANCTR) (to January 2013), which includes relevant
randomised controlled trials from the following bibliographic databases: The
Cochrane Library (all years), EMBASE, (1974 to date), MEDLINE (1950 to date) and
PsycINFO (1967 to date). No language restrictions were applied. Reference lists of
relevant papers and previous systematic reviews were handsearched. Pharmaceutical
companies marketing valproate and experts in this field were contacted for
supplemental data. SELECTION CRITERIA: Randomised controlled trials allocating
participants with bipolar disorder to long-term treatment with valproate or any
other mood stabiliser, or antipsychotic drugs, or placebo. Maintenance treatment
was defined as treatment instituted specifically or mainly to prevent further
episodes of illness. DATA COLLECTION AND ANALYSIS: Three review authors
independently extracted data. A double-entry procedure was employed by two review
authors. Information extracted included study characteristics, participant
characteristics, intervention details and outcome measures in terms of efficacy,
acceptability and tolerability. For dichotomous data, risk ratios were calculated
with 95% confidence intervals (CIs). For statistically significant results, we
calculated the number needed to treat for an additional beneficial outcome (NNTB)
and the number needed to treat for an additional harmful outcome (NNTH). For
continuous data, mean differences (MDs) or standardised mean differences (SMDs)
were calculated along with 95% CIs. MDs were used when the same scale was used to
measure an outcome; SMDs were employed when different scales were used to measure
the same outcome. The primary analysis used a fixed-effect model. Binary outcomes
were calculated on a strict intention-to-treat (ITT) basis; dropouts were included
in this analysis. When data were missing and the method of "last observation
carried forward" (LOCF) had been used to do an ITT analysis, then the LOCF data
were used. MAIN RESULTS: Six randomised controlled trials (overall 876
participants) lasting 6 to 24 months were included. Two studies (overall 312
participants) compared valproate with placebo, four studies (overall 618
participants) valproate with lithium, one study (overall 23 participants) valproate
with olanzapine and one study (overall 220 participants) valproate with the
combination of valproate plus lithium. In terms of study quality, most studies
reported the methods used to generate random sequence; however, only one study
reported enough details on allocation concealment. Four of six included studies
described their design as "double blind", but only two trials reported full details
about blinding. Valproate was more effective than placebo in preventing study
withdrawal due to any mood episode (RR 0.68, 95% CI 0.49 to 0.93; NNTB 8), but no
difference in efficacy was found between valproate and lithium (RR 1.02, 95% CI
0.87 to 1.20). Valproate was associated with fewer participants dropping out of
treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71
to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively). However, combination
therapy with lithium plus valproate was more likely to prevent relapse than was
monotherapy with valproate (RR 0.78, 95% CI 0.63 to 0.96). Significant differences
in adverse event frequencies were found, and lithium was associated with more
frequent diarrhoea, polyuria, increased thirst and enuresis, whereas valproate was
associated with increased sedation and infection. AUTHORS' CONCLUSIONS: Limited
evidence supports the efficacy of valproate in the long-term treatment of bipolar
disorder. Clinicians and patients should consider acceptability and tolerability
profile when choosing between lithium and valproate-their combination or other
agents-as long-term treatment for bipolar disorder.

Citrome, L. (2010). "Ziprasidone HCl capsules for the adjunctive maintenance

treatment of bipolar disorder in adults." Expert Rev Neurother 10(7): 1031-1037.
This article reviews the evidence for the use of ziprasidone for the
maintenance treatment of bipolar I disorder in adults as an adjunct to lithium or
valproate, as approved by the US FDA in 2009. Ziprasidone is an 'atypical' or
'second-generation' antipsychotic that has garnered clinical interest because of
its metabolically friendly tolerability profile. A placebo-controlled trial was
conducted in subjects whose most recent episode was manic or mixed, with or without
psychotic features, and with symptoms that began no more than 90 days prior to the
screening visit. Patients were stabilized during a 10-16-week, open-label period on
the combination of ziprasidone 80-160 mg/day plus lithium (0.6-1.2 mEq/l) or
valproate (50-125 microg/ml). Patients whose symptoms stabilized for 8 consecutive
weeks were randomized to either continue combination treatment with adjunctive
ziprasidone or receive lithium or valproate with adjunctive placebo for up to 24
weeks of double-blind treatment. The primary outcome measure was time to
intervention for a mood episode during the double-blind period, tested
statistically using survival analysis and assessing Kaplan-Meier curves. Of the 584
patients enrolled in the open-label period, 241 (41%) completed. A total of 238
subjects were analyzed for efficacy in the double-blind period (ziprasidone 127,
placebo 111). Ziprasidone was superior to placebo in increasing the time to
recurrence of a mood episode (p = 0.0104) during the 6 months of double-blind
treatment. Only 19.7% (25 out of 127) of the ziprasidone subjects required
intervention for a mood episode, compared with 32.4% (36 out of 111) of the placebo
subjects (number needed to treat [NNT] 8; 95% CI: 5-62). The most robust effects
were noted for the combination of ziprasidone and lithium and for the avoidance of
manic/mixed episodes. Ziprasidone had no remarkable effect on weight or blood
glucose. Limitations of this study include the enriched sample and exclusion of the
most severely ill, and the inclusion of only those patients whose most recent
bipolar episode was manic or mixed. Indirect comparisons of adjunctive ziprasidone
with adjunctive quetiapine reveals a lower (i.e., more robust) NNT for quetiapine
in terms of proportions of subjects experiencing a mood event (NNT: 4), but a
higher incidence of bodyweight gain of at least 7% from baseline.

Citrome, L. (2011). "Role of sublingual asenapine in treatment of schizophrenia."

Neuropsychiatr Dis Treat 7: 325-339.
Asenapine tablets are a new option for the treatment of schizophrenia.
Sublingual administration is essential because bioavailability if ingested is less
than 2%. Efficacy is supported by acute and long-term randomized controlled studies
conducted by the manufacturer, with asenapine 5 mg twice daily evidencing
superiority over placebo in six-week studies of acute schizophrenia, and flexibly-
dosed asenapine (modal dose 10 mg twice daily) superior to placebo in a 26-week
maintenance of response study. Tolerability advantages over some second-generation
antipsychotics, such as olanzapine, include a relatively favorable weight and
metabolic profile, as demonstrated in a 52-week randomized, head-to-head, double-
blind clinical trial. Although dose-related extrapyramidal symptoms and akathisia
can be present, the frequency of these effects is lower than that for haloperidol
and risperidone. Somnolence may also occur, and appears to be somewhat dose-
dependent when examining rates of this among patients receiving asenapine for
schizophrenia and bipolar disorder. Prolactin elevation can occur, but at a rate
lower than that observed for haloperidol or risperidone. Unique to asenapine is the
possibility of oral hypoesthesia, occurring in about 5% of participants in the
clinical trials. Obstacles to the use of asenapine are the recommendations for
twice-daily dosing and the need to avoid food or liquids for 10 minutes after
administration, although the bioavailability is only minimally reduced if food or
liquids are avoided for only two minutes.

Citrome, L. (2012). "Lurasidone in schizophrenia: new information about dosage and

place in therapy." Adv Ther 29(10): 815-825.
Lurasidone is a newer "atypical" or "secondgeneration" antipsychotic that has
received regulatory approval in the US and Canada for the treatment of
schizophrenia. Recent changes in lurasidone product labeling include an expansion
of the recommended dose range from 40-80 mg/day to 40-160 mg/day, administered
once-daily with food. The recommended starting dose is 40 mg/day. Initial dose
titration is not required. Efficacy for the treatment of acute episodes of
schizophrenia was established in five, 6-week, fixed-dose, randomized, placebo-
controlled trials. Additional short-term studies in patients with schizophrenia
include a 3-week, randomized, double-blind trial comparing lurasidone with
ziprasidone on safety and tolerability outcomes, and a 6-week, randomized, open-
label switch study. Available long-term data includes a 12-month, doubleblind
safety and tolerability study comparing lurasidone with risperidone; a 6-month,
openlabel extension study for one of the shortterm registration studies where
patients were initially randomized to receive lurasidone, olanzapine, or placebo;
and a 12-month, doubleblind extension study comparing lurasidone with quetiapine
extended-release after having received lurasidone, quetiapine extendedrelease, or
placebo for 6 weeks. The totality of the evidence supports the overall tolerability
of lurasidone, with minimal weight gain and no clinically-meaningful alterations in
glucose, lipids, or the electrocardiogram corrected QT (ECG QTc) interval. The most
commonly encountered adverse events that can be observed with lurasidone are
somnolence, akathisia, nausea, and parkinsonism. Additional clinical trials are
underway for the use of lurasidone in patients with bipolar disorder, including
major depressive episodes in patients with bipolar I disorder, and in bipolar and
schizophrenia maintenance. Principal advantages over some other second-generation
antipsychotics are lurasidone's highly favorable metabolic profile and once-daily
dosing regimen. Additional studies are desirable to directly compare and contrast
lurasidone's efficacy with other antipsychotic agents.

Citrome, L. (2014). "Treatment of bipolar depression: making sensible decisions."

CNS Spectr 19 Suppl 1: 4-11; quiz 11-13, 12.
A major challenge in the treatment of major depressive episodes associated
with bipolar disorder is differentiating this illness from major depressive
episodes associated with major depressive disorder. Mistaking the former for the
latter will lead to incorrect treatment and poor outcomes. None of the classic
antidepressants, serotonin specific reuptake inhibitors, or serotonin-
norepinephrine reuptake inhibitors have ever received regulatory approval as
monotherapies for the treatment of bipolar depression. At present, there are only 3
approved medication treatments for bipolar depression: olanzapine/fluoxetine
combination, quetiapine (immediate or extended release), and lurasidone
(monotherapy or adjunctive to lithium or valproate). All 3 have similar efficacy
profiles, but they differ in terms of tolerability. Number needed to treat (NNT)
and number needed to harm (NNH) can be used to quantify these similarities and
differences. The NNTs for response and remission for each of these interventions vs
placebo range from 4 to 7, and 5 to 7, respectively, with overlap in terms of their
95% confidence intervals. NNH values less than 10 (vs placebo) were observed for
the spontaneously reported adverse events of weight gain and diarrhea for
olanzapine/fluoxetine combination (7 and 9, respectively) and somnolence and dry
mouth for quetiapine (3 and 4, respectively). There were no NNH values less than 10
(vs placebo) observed with lurasidone treatment. NNH values vs placebo for weight
gain of at least 7% from baseline were 6, 16, 58, and 36, for olanzapine/fluoxetine
combination, quetiapine, lurasidone monotherapy, and lurasidone combined with
lithium or valproate, respectively. Individualizing treatment decisions will
require consideration of the different potential adverse events that are more
likely to occur with each medication. The metric of the likelihood to be helped or
harmed (LHH) is the ratio of NNH to NNT and can illustrate the tradeoffs inherent
in selecting medications. A more favorable LHH was noted for treatment with
lurasidone. However, OFC and quetiapine monotherapy may still have utility in high
urgency situations, particularly in persons who have demonstrated good outcomes
with these interventions in the past, and where a pressing clinical need for
efficacy mitigates their potential tolerability shortcomings. In terms of
maintenance therapy, adjunctive quetiapine is the only agent where the NNT vs
lithium or valproate alone is less than 10 for both the prevention of mania and the
prevention of depression.

Compier, M. G., et al. (2013). "Duty-cycled bipolar/unipolar radiofrequency

ablation for symptomatic atrial fibrillation induces significant pulmonary vein
narrowing at long-term follow-up." Europace 15(5): 690-696.
AIMS: A novel duty-cycled bipolar/unipolar ablation catheter pulmonary vein
ablation catheter (PVAC) has been developed to achieve pulmonary vein (PV)
isolation in patients with atrial fibrillation (AF). Ablation with PVAC was
recently found to induce PV narrowing at 3 months follow-up. The long-term effects
of this catheter on PV dimensions are however unknown and were evaluated with this
study. METHODS AND RESULTS: Patients (n = 62, 71% male, age 60 +/- 7 years) with
drug-refractory AF scheduled for a first ablation procedure were evaluated. A
multi-slice computed tomography (MSCT) scan was performed before and 1 year after
the initial procedure. Pulmonary vein dimensions and left atrial (LA) volume were
measured on MSCT. To correct for reverse remodelling of the LA, the ostial area/LA
volume ratio before and after PVAC was calculated. As reverse remodelling may
depend on procedural outcome, patients were divided in two groups depending on
sinus rhythm (SR) maintenance or AF recurrence 1 year after ablation. Baseline
characteristics were comparable between the SR group (n = 41) and the AF recurrence
group (n = 21). At one year follow-up, ostial area of the PVs (n = 219) was
significantly reduced from 236 +/- 7.0 to 173 +/- 7.4 mm(2) (27% narrowing, P <
0.01), independent of ablation outcome. Pulmonary vein narrowing was mild in 37% of
PVs (25-50%), 9% was moderate (50-70%), and 3% severe (>70%). Left atrial volumes
were found to be significantly reduced after ablation (14 and 5% for the SR group
and AF recurrence group, respectively, P < 0.01). After adjustment for LA volume
reduction, narrowing of PV ostial area remained significant in these patients (P <
0.01). CONCLUSION: Ablation with PVAC results in a significant decrease in PV
dimensions after long-term follow-up. In line with previous literature, PV
narrowing was mild and patients did not develop any clinical symptoms.

Conell, J., et al. (2015). "[Is there an increased risk for renal tumors during
long-term treatment with lithium?]." Nervenarzt 86(9): 1157-1161.
Lithium salts are the recommended first-line treatment (gold standard) in
national and international treatment guidelines for acute and maintenance treatment
of affective disorders, such as bipolar disorders. Lithium has also been shown to
have a unique protective effect against suicide in patients suffering from
affective disorders. Despite the well-known acute and long-term adverse effects
lithium therapy can be safely administered if patients are properly educated and
carefully monitored. A recent study from France now shows that patients with
severely impaired renal function who had been treated with lithium salts for more
than 10 years could have an increased risk for kidney tumors (benign and
malignant). This resulted in an adjustment concerning information within the
package leaflet by European authorities. The authors of this article reflect the
currently available data in order to better understand and handle this new finding
and to warn about uncritical reactions including withdrawal of lithium in
successfully treated patients. This article provides clinical recommendations to
provide further insight relating to the risk of kidney cancer in long-term lithium
therapy.

Connolly, K. R., et al. (2012). "Effectiveness of transcranial magnetic stimulation

in clinical practice post-FDA approval in the United States: results observed with
the first 100 consecutive cases of depression at an academic medical center." J
Clin Psychiatry 73(4): e567-573.
INTRODUCTION: Transcranial magnetic stimulation (TMS) is a US Food and Drug
Administration-approved treatment for major depressive disorder (MDD) in patients
who have not responded to 1 adequate antidepressant trial in the current episode.
In a retrospective cohort study, we examined the effectiveness and safety of TMS in
the first 100 consecutive patients treated for depression (full DSM-IV criteria for
major depressive episode in either major depressive disorder or bipolar disorder)
at an academic medical center between July 21, 2008, and March 25, 2011. METHOD:
TMS was flexibly dosed in a course of up to 30 sessions, adjunctive to current
medications, for 85 patients treated for acute depression. The primary outcomes
were response and remission rates at treatment end point as measured by the
Clinical Global Impressions-Improvement scale (CGI-I) at 6 weeks. Secondary
outcomes included change in the Hamilton Depression Rating Scale (HDRS); Quick
Inventory of Depressive Symptomatology, self-report (QIDS-SR); Beck Depression
Inventory (BDI); Beck Anxiety Inventory (BAI); and the Sheehan Disability Scale
(SDS). Enduring benefit was assessed over 6 months in patients receiving
maintenance TMS treatment. Data from 12 patients who received TMS as maintenance or
continuation treatment after prior electroconvulsive therapy (ECT) or TMS given in
a clinical trial setting were also reviewed. RESULTS: The clinical cohort was
treatment resistant, with a mean of 3.4 failed adequate trials in the current
episode. Thirty-one individuals had received prior lifetime ECT, and 60% had a
history of psychiatric hospitalization. The CGI-I response rate was 50.6% and the
remission rate was 24.7% at 6 weeks. The mean change was -7.8 points in HDRS score,
-5.4 in QIDS-SR, -11.4 in BDI, -5.8 in BAI, and -6.9 in SDS. The HDRS response and
remission rates were 41.2% and 35.3%, respectively. Forty-two patients (49%)
entered 6 months of maintenance TMS treatment. Sixty-two percent (26/42 patients)
maintained their responder status at the last assessment during the maintenance
treatment. TMS treatment was well tolerated, with a discontinuation rate of 3% in
the acute treatment phase. No serious adverse events related to TMS were observed
during acute or maintenance treatment. CONCLUSIONS: Adjunctive TMS was found to be
safe and effective in both acute and maintenance treatment of patients with
treatment-resistant depression.

Connolly, K. R. and M. E. Thase (2011). "The clinical management of bipolar

disorder: a review of evidence-based guidelines." Prim Care Companion CNS Disord
13(4).
OBJECTIVE: To discuss the criteria used to diagnose the mood episodes that
constitute bipolar disorder, the approach to the differential diagnosis of these
presentations, and the evidence-based treatments that are currently available. DATA
SOURCES: A search for evidence-based guidelines for the diagnosis and treatment of
adults with bipolar disorder was performed on May 5, 2010, using the National
Guideline Clearinghouse database, the Agency for Healthcare Research and Quality
Evidence Reports database, and the Cochrane Database of Systematic Reviews. In
addition, a clinical query of the PubMed database (completed March 1, 2010) and
searches of drug manufacturers' Web sites (for unpublished trials) were performed
to identify randomized, controlled trials and meta-analyses evaluating strategies
to treat resistant depression. STUDY SELECTION: Guidelines were selected based on
data from randomized, controlled trials; meta-analyses; and well-conducted
naturalistic trials that were published since 2005. DATA EXTRACTION: Four evidence-
based treatment guidelines for bipolar disorder were included. Three were published
in 2009: those put forth as part of an Australian project, those of the British
Association for Psychopharmacology, and those produced by the International Society
for Bipolar Disorders and the Canadian Network for Mood and Anxiety Treatments. The
most recent US guidelines are that of the Texas Implementation of Medication
Algorithms project, last updated in 2005. DATA SYNTHESIS: Recommendations from all
4 guidelines were reviewed and are presented with a focus on using them to improve
clinical care. The recommendations with the most agreement and highest level of
clinical evidence were as follows: (1) mania should be treated first-line with
lithium, divalproex, or an atypical antipsychotic medication; (2) mixed episodes
should be treated first-line with divalproex or an atypical antipsychotic; (3)
bipolar depression should be treated with quetiapine, olanzapine/fluoxetine
combination, or lamotrigine; and (4) all patients should be offered group or
individual psychoeducation. Additionally, recommendations for therapeutic drug
monitoring are presented due to their importance for patient safety, particularly
for the primary care physician, although these are based on consensus guidelines.
CONCLUSIONS: Bipolar disorder is a lifelong illness that is complicated by high
comorbidity and risk of poor health outcomes, making the primary care physician's
role vital in improving patient quality of life. The management of acute mood
episodes should focus first on safety, should include psychiatric consultation as
soon as possible, and should begin with an evidence-based treatment that may be
continued into the maintenance phase. Long-term management focuses on maintenance
of euthymia, requires ongoing medication, and may benefit from adjunctive
psychotherapy.

Coumans, J. V., et al. (2016). "Proteomic and Microscopic Strategies towards the
Analysis of the Cytoskeletal Networks in Major Neuropsychiatric Disorders." Int J
Mol Sci 17(4).
 Mental health disorders have become worldwide health priorities. It is
estimated that in the next 20 years they will account for a 16 trillion United
State dollars (US$) loss. Up to now, the underlying pathophysiology of psychiatric
disorders remains elusive. Altered cytoskeleton proteins expression that may
influence the assembly, organization and maintenance of cytoskeletal integrity has
been reported in major depressive disorders, schizophrenia and to some extent
bipolar disorders. The use of quantitative proteomics, dynamic microscopy and
super-resolution microscopy to investigate disease-specific protein signatures
holds great promise to improve our understanding of these disorders. In this
review, we present the currently available quantitative proteomic approaches use in
neurology, gel-based, stable isotope-labelling and label-free methodologies and
evaluate their strengths and limitations. We also reported on
enrichment/subfractionation methods that target the cytoskeleton associated
proteins and discuss the need of alternative methods for further characterization
of the neurocytoskeletal proteome. Finally, we present live cell imaging approaches
and emerging dynamic microscopy technology that will provide the tools necessary to
investigate protein interactions and their dynamics in the whole cells. While these
areas of research are still in their infancy, they offer huge potential towards the
understanding of the neuronal network stability and its modification across
neuropsychiatric disorders.

Crespi, B. J. (2016). "Oxytocin, testosterone, and human social cognition." Biol

Rev Camb Philos Soc 91(2): 390-408.
I describe an integrative social-evolutionary model for the adaptive
significance of the human oxytocinergic system. The model is based on a role for
this hormone in the generation and maintenance of social familiarity and
affiliation across five homologous, functionally similar, and sequentially co-opted
contexts: mothers with offspring, female and male mates, kin groups, individuals
with reciprocity partners, and individuals within cooperating and competing social
groups defined by culture. In each situation, oxytocin motivates, mediates and
rewards the cognitive and behavioural processes that underlie the formation and
dynamics of a more or less stable social group, and promotes a relationship between
two or more individuals. Such relationships may be positive (eliciting neurological
reward, reducing anxiety and thus indicating fitness-enhancing effects), or
negative (increasing anxiety and distress, and thus motivating attempts to
alleviate a problematic, fitness-reducing social situation). I also present
evidence that testosterone exhibits opposite effects from oxytocin on diverse
aspects of cognition and behaviour, most generally by favouring self-oriented,
asocial and antisocial behaviours. I apply this model for effects of oxytocin and
testosterone to understanding human psychological disorders centrally involving
social behaviour. Reduced oxytocin and higher testosterone levels have been
associated with under-developed social cognition, especially in autism. By
contrast, some combination of oxytocin increased above normal levels, and lower
testosterone, has been reported in a notable number of studies of schizophrenia,
bipolar disorder and depression, and, in some cases, higher oxytocin involves
maladaptively 'hyper-developed' social cognition in these conditions. This pattern
of findings suggests that human social cognition and behaviour are structured, in
part, by joint and opposing effects of oxytocin and testosterone, and that extremes
of such joint effects partially mediate risks and phenotypes of autism and
psychotic-affective conditions. These considerations have direct implications for
the development of therapies for alleviating disorders of social cognition, and for
understanding how such disorders are associated with the evolution of human
cognitive-affective architecture.

Crowe, M. and R. Porter (2014). "Inpatient treatment for mania: A review and
rationale for adjunctive interventions." Aust N Z J Psychiatry 48(8): 716-721.
OBJECTIVE: To examine the evidence for adjunctive non-pharmacological
interventions in the treatment of mania in an acute inpatient setting. METHOD: A
selective review of original and review papers was conducted. The electronic
databases PsycINFO and PubMed were searched using the following MeSH terms: mania,
mania treatment and inpatient. RESULTS: Four studies were identified in the search
for non-psychopharmacological interventions for mania that commenced in an
inpatient setting: Interpersonal and Social Rhythm Therapy (IPSRT), Group Cognitive
Behavioural Therapy (G-CBT), sensory room, and dark room therapy. Only two of these
were designed exclusively for patients with bipolar disorder and the other two
included these patients in a heterogeneous group of acute psychiatric inpatients.
CONCLUSIONS: Sleep and circadian regulation (Social Rhythm Therapy) that focuses on
the establishment and maintenance of regular daily rhythms, particularly in
relation to sleep-wake times, meal times and socialization, provides a potentially
useful model for managing mania in the inpatient setting. However, there is an
urgent need for further research into the effective treatment of mania.

Culpepper, L. (2014). "The diagnosis and treatment of bipolar disorder: decision-

making in primary care." Prim Care Companion CNS Disord 16(3).
Bipolar disorder is a chronic episodic illness, characterized by recurrent
episodes of manic or depressive symptoms. Patients with bipolar disorder frequently
present first to primary care, but the diversity of the potential symptoms and a
low index of suspicion among physicians can lead to misdiagnosis in many patients.
Frequently, co-occurring psychiatric and medical conditions further complicate the
differential diagnosis. A thorough diagnostic evaluation at clinical interview,
combined with supportive case-finding tools, is essential to reach an accurate
diagnosis. When treating bipolar patients, the primary care physician has an
integral role in coordinating the multidisciplinary network. Pharmacologic
treatment underpins both short- and long-term management of bipolar disorder.
Maintenance treatment to prevent relapse is frequently founded on the same
pharmacologic approaches that were effective in treating the acute symptoms.
Regardless of the treatment approach that is selected, monitoring over the long
term is essential to ensure continued symptom relief, functioning, safety,
adherence, and general medical health. This article describes key decision-making
steps in the management of bipolar disorder from the primary care perspective: from
initial clinical suspicion to confirmation of the diagnosis to decision-making in
acute and longer-term management and the importance of patient monitoring.

Curran, G. and A. Ravindran (2014). "Lithium for bipolar disorder: a review of the
recent literature." Expert Rev Neurother 14(9): 1079-1098.
Lithium is a commonly prescribed treatment for bipolar disorder. Many early
studies on which its use has been historically based no longer meet current
research standards. A large number of studies with more modern designs have been
recently published warranting a review. New research adds to the evidence for
lithium's efficacy in mania and maintenance. There is also additional evidence,
albeit less robust, to support its benefit in bipolar depression and mixed
episodes. Meta-analyses of mainly observational data have found reduced suicidal
behavior in bipolar patients taking lithium. Careful monitoring and prescribing can
reduce the risk of adverse effects.

Cusin, C., et al. (2012). "Long-term maintenance with intramuscular ketamine for
treatment-resistant bipolar II depression." Am J Psychiatry 169(8): 868-869.

Daglas, R., et al. (2016). "A single-blind, randomised controlled trial on the
effects of lithium and quetiapine monotherapy on the trajectory of cognitive
functioning in first episode mania: A 12-month follow-up study." Eur Psychiatry 31:
20-28.
BACKGROUND: Cognitive deficits have been reported during the early stages of
bipolar disorder; however, the role of medication on such deficits remains unclear.
The aim of this study was to compare the effects of lithium and quetiapine
monotherapy on cognitive performance in people following first episode mania.
METHODS: The design was a single-blind, randomised controlled trial on a cohort of
61 participants following first episode mania. Participants received either lithium
or quetiapine monotherapy as maintenance treatment over a 12-month follow-up
period. The groups were compared on performance outcomes using an extensive
cognitive assessment battery conducted at baseline, month 3 and month 12 follow-up
time-points. RESULTS: There was a significant interaction between group and time in
phonemic fluency at the 3-month and 12-month endpoints, reflecting greater
improvements in performance in lithium-treated participants relative to quetiapine-
treated participants. After controlling for multiple comparisons, there were no
other significant interactions between group and time for other measures of
cognition. CONCLUSION: Although the effects of lithium and quetiapine treatment
were similar for most cognitive domains, the findings imply that early initiation
of lithium treatment may benefit the trajectory of cognition, specifically verbal
fluency in young people with bipolar disorder. Given that cognition is a major
symptomatic domain of bipolar disorder and has substantive effects on general
functioning, the ability to influence the trajectory of cognitive change is of
considerable clinical importance.

Dallaspezia, S., et al. (2016). "Sleep homeostatic pressure and PER3 VNTR gene
polymorphism influence antidepressant response to sleep deprivation in bipolar
depression." J Affect Disord 192: 64-69.
BACKGROUND: Combined Total sleep deprivation (TSD) and light therapy (LT)
cause a rapid improvement in bipolar depression which has been hypothesized to be
paralleled by changes in sleep homeostasis. Recent studies showed that bipolar
patients had lower changes of EEG theta power after sleep and responders to
antidepressant TSD+LT slept less and showed a lower increase of EEG theta power
then non-responders. A polymorphism in PER3 gene has been associated with diurnal
preference, sleep structure and homeostatic response to sleep deprivation in
healthy subjects. We hypothesized that the individual variability in the
homeostatic response to TSD could be a correlate of antidepressant response and be
influenced by genetic factors. METHODS: We administered three TSD+LT cycles to
bipolar depressed patients. Severity of depression was rated on Hamilton Depression
Rating Scale. Actigraphic recordings were performed in a group of patients.
RESULTS: PER3 polymorphism influenced changes in total sleep time (F=2.24;
p=0.024): while PER3(4/4) and PER3(4/5) patients showed a reduction in it after
treatment, PER3(5/5) subjects showed an increase of about 40min, suggesting a
higher homeostatic pressure. The same polymorphism influenced the change of
depressive symptomatology during treatment (F=3.72; p=0.028). LIMITATIONS: Sleep
information was recorded till the day after the end of treatment: a longer period
of observation could give more information about the possible maintenance of
allostatic adaptation. CONCLUSIONS: A higher sleep homeostatic pressure reduced the
antidepressant response to TSD+LT, while an allostatic adaptation to sleep loss was
associated with better response. This process seems to be under genetic control.

Darwish, M., et al. (2015). "Evaluation of Potential Pharmacokinetic Drug-Drug

Interaction between Armodafinil and Aripiprazole in Healthy Adults."
Pharmacopsychiatry 48(4-5): 170-175.
INTRODUCTION: Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4,
has been studied as adjunctive therapy to maintenance medications for major
depressive episodes associated with bipolar I disorder. We evaluated the effect of
daily dosing with armodafinil on the pharmacokinetics and safety of the CYP3A4
substrate aripiprazole, an atypical antipsychotic used to treat bipolar I disorder.
METHODS: Healthy adults received 15 mg aripiprazole alone and after armodafinil
(250 mg/day) pretreatment. Pharmacokinetic parameters were derived from plasma
concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole,
obtained over 16 days after each aripiprazole administration. Steady-state
pharmacokinetics of armodafinil and its 2 circulating metabolites was assessed.
RESULTS: Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis.
Armodafinil reduced systemic exposure to aripiprazole (Cmax, - 8%; AUC0-infinity,
-34%) and dehydro-aripiprazole, which is both formed and eliminated in part via
CYP3A4 (Cmax, - 10%; AUC0-infinity, - 32%). Adverse events were generally
consistent with known safety profiles of each agent. DISCUSSION: Systemic exposure
to aripiprazole and dehydro-aripiprazole was moderately reduced following
armodafinil pretreatment. The combination was generally well tolerated under the
conditions studied.

de Bartolomeis, A. and G. Perugi (2012). "Combination of aripiprazole with mood

stabilizers for the treatment of bipolar disorder: from acute mania to long-term
maintenance." Expert Opin Pharmacother 13(14): 2027-2036.
INTRODUCTION: Bipolar disorder is characterized by a complex set of symptoms,
including recurrent manic, depressive or mixed episodes. Acute and long-term
treatment of patients with bipolar disorder is mandatory to prevent symptom relapse
and episode recurrences. Outcomes with monotherapy are often unsatisfactory in
clinical practice, hence combinations of mood stabilizers and antipsychotics are
widely utilized in patients showing no or partial response to, as well as
intolerance to, monotherapies. This may offer a therapeutic advantage, however, the
possibility of an increased incidence of side effects should be considered. AREAS
COVERED: This paper reviews the current treatment guidelines for the treatment of
bipolar disorder and examines the rationale behind the use of aripiprazole in
combination with mood stabilizers for acute and long-term treatment of bipolar
disorder. EXPERT OPINION: The combination of aripiprazole and mood stabilizers
seems to offer an effective and relatively well-tolerated option for the treatment
of acute mania and for the maintenance treatment of patients with bipolar I
disorder. The combination presents a lower risk of metabolic side effects compared
with other combination therapies, but increases the risk of extrapyramidal side
effects with long-term treatment. The aripiprazole-valproate combination seems to
be particularly promising in the treatment of patients with comorbidities such as
anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well
as in mixed depressive disorder. Controlled trials are necessary in order to
confirm these observations and to provide a useful insight for improving the use of
drug combinations in bipolar patients.

De Fazio, P., et al. (2010). "Aripiprazole in acute mania and long-term treatment
of bipolar disorder: a critical review by an Italian working group." Clin Drug
Investig 30(12): 827-841.
Bipolar disorder (BD) is a chronic illness that is characterized by recurrent
episodes of mania, depression or mixed symptoms. BD has a prevalence of
approximately 2-4% in the general population and is associated with a substantial
burden in terms of morbidity and mortality. Mania is one of the most difficult to
treat manifestations of BD and antipsychotic drugs play a major therapeutic role in
this respect. Acting mainly at dopamine receptors, first-generation antipsychotics
are effective in controlling symptoms of BD; however, these drugs cause troublesome
extrapyramidal symptoms (EPS) and hyperprolactinaemia. The more recently developed
second-generation antipsychotics, which act at other receptors, provide a broader
spectrum of clinical efficacy and have a more favourable tolerability profile than
first-generation antipsychotics. Some second-generation antipsychotics are,
however, associated with adverse effects such as weight gain and metabolic
disorders, which may be cause for concern. Aripiprazole, a recently introduced
second-generation antipsychotic, has a unique receptor-binding profile and
mechanism of action, which are thought to account for its low propensity for weight
gain, metabolic disturbances and sedation. Aripiprazole is approved in the US and
in Europe for the acute management and maintenance of manic and mixed episodes
associated with bipolar I disorder. In both the acute and long-term maintenance
settings, clinical trials have shown aripiprazole to be clinically effective in
terms of response rates, remission rates and prevention of relapse. The lack of a
sedative effect does not affect the efficacy of aripiprazole in controlling mania
and agitation. With both short- and long-term aripiprazole treatment, adverse event
rates were similar to placebo and significantly lower than seen with comparators;
one exception to this is the occurrence of EPS, which was observed more frequently
in aripiprazole recipients than in patients receiving placebo, but less frequently
than in patients treated with haloperidol. Aripiprazole is likely to promote
treatment adherence because of its favourable tolerability profile, but more
specifically focused studies are required to confirm this hypothesis. The efficacy
and favourable metabolic profile of aripiprazole make it a good option in the
management of acute mania and maintenance treatment, especially in an outpatient
setting. Thus, aripiprazole provides clinicians with a valuable additional
therapeutic option for BD. Cognizant of the lack of standardized strategies for
aripiprazole dosing, switching, and prevention and management of adverse effects,
an expert consensus meeting was held in Italy with the aim of producing guidelines
for the use of aripiprazole in acute and long-term management of BD mania. The
resulting dosage, administration and switching recommendations outlined in this
report are based on empirical results from well designed aripiprazole clinical
trials and clinical experience, and are in accord with the manufacturer's
prescribing information. However, careful evaluation of the individual patient and
a thorough risk/benefit assessment should be made prior to initiating any treatment
plan.

de Souza, C., et al. (2013). "Bipolar disorder and medication: adherence, patients'
knowledge and serum monitoring of lithium carbonate." Rev Lat Am Enfermagem 21(2):
624-631.
OBJECTIVES: this study featured patients with affective bipolar disorder who
were making use of lithium and received care at an outpatient care center located
in a country town in the state of Sao Paulo in 2009; it assessed the adherence and
knowledge of these patients in relation to the medication prescribed to them and
verified the proportion of blood tests performed per year in the service, for each
individual, to measure lithium levels in the blood. METHOD: descriptive study with
quantitative approach, involving 36 participants. Structured interviews and review
of medical records were used for data collection and descriptive statistics for
data analysis. RESULTS: difficulties in reporting the dosage of the medication
prescribed and a high rate of non-adherence were identified among the participants.
None of the participants in the study was submitted to two tests a year to measure
lithium levels in the blood, which is the minimum proportion of tests recommended
by the literature for maintenance treatment using lithium carbonate. CONCLUSION:
this study highlights the critical factors for the promotion of patients' safety in
monitoring lithium drug therapy.

Deans, P. J., et al. (2016). "Psychosis Risk Candidate ZNF804A Localizes to

Synapses and Regulates Neurite Formation and Dendritic Spine Structure." Biol
Psychiatry.
BACKGROUND: Variation in the gene encoding zinc finger binding protein 804A
(ZNF804A) is associated with schizophrenia and bipolar disorder. Evidence suggests
that ZNF804A is a regulator of gene transcription and is present in nuclear and
extranuclear compartments. However, a detailed examination of ZNF804A distribution
and its neuronal functions has yet to be performed. METHODS: The localization of
ZNF804A protein was examined in neurons derived from human neural progenitor cells,
human induced pluripotent stem cells, or in primary rat cortical neurons. In
addition, small interfering RNA-mediated knockdown of ZNF804A was conducted to
determine its role in neurite formation, maintenance of dendritic spine morphology,
and responses to activity-dependent stimulations. RESULTS: Endogenous ZNF804A
protein localized to somatodendritic compartments and colocalized with the putative
synaptic markers in young neurons derived from human neural progenitor cells and
human induced pluripotent stem cells. In mature rat neurons, Zfp804A, the homolog
of ZNF804A, was present in a subset of dendritic spines and colocalized with
synaptic proteins in specific nanodomains, as determined by super-resolution
microscopy. Interestingly, knockdown of ZNF804A attenuated neurite outgrowth in
young neurons, an effect potentially mediated by reduced neuroligin-4 expression.
Furthermore, knockdown of ZNF804A in mature neurons resulted in the loss of
dendritic spine density and impaired responses to activity-dependent stimulation.
CONCLUSIONS: These data reveal a novel subcellular distribution for ZNF804A within
somatodendritic compartments and a nanoscopic organization at excitatory synapses.
Moreover, our results suggest that ZNF804A plays an active role in neurite
formation, maintenance of dendritic spines, and activity-dependent structural
plasticity.

Decloedt, E. H., et al. (2017). "Renal safety of lithium in HIV-infected patients

established on tenofovir disoproxil fumarate containing antiretroviral therapy:
analysis from a randomized placebo-controlled trial." AIDS Res Ther 14(1): 6.
BACKGROUND: The prevalence of bipolar disorder in HIV-infected patients is
higher than the general population. Lithium is the most effective mood stabiliser,
while tenofovir disoproxil fumarate (TDF) is frequently used as part of combination
antiretroviral therapy (ART). Both TDF and lithium are associated with renal
tubular toxicity, which could be additive, or a pharmacokinetic interaction may
occur at renal transporters with a decrease in TDF elimination. OBJECTIVE: We
report on the change in estimated glomerular filtration rate (eGFR) using the
modification of diet in renal disease formula in participants who received ART
including TDF and were enrolled in a 24 week randomised trial of lithium versus
placebo in patients with HIV-associated neurocognitive impairment. METHODS: We
included HIV-infected adults with cognitive impairment established on ART for at
least 6 months with a suppressed viral load attending public sector ART clinics in
Cape Town, South Africa. We excluded participants with an eGFR <60 mL/min and
treated with medications predisposing to lithium toxicity. We reviewed participants
weekly for the first month for adverse events followed by 4 weekly visits for renal
function assessment, adverse event monitoring and adherence. Lithium dose was
titrated to achieve the maintenance target plasma concentration of between 0.6 and
1.0 mmol/L. Sham lithium concentrations were generated for participants receiving
placebo. RESULTS: We included 23 participants allocated to the lithium arm and 30
participants allocated to the placebo arm. Baseline characteristics were not
statistically different with a mean age of 37.7 and 40.8 years, a median time on
ART of 33 and 40 months and an eGFR of 139.3 and 131.0 mL/min in the lithium and
placebo arms respectively. There was no statistical significant difference in the
reduction in eGFR or increase in potassium between the two arms during the 24
weeks. CONCLUSIONS: We found that 24-week treatment of HIV-infected patients with
lithium and TDF did not result in increased nephrotoxicity. Trial registration The
study was registered on the Pan African Clinical Trials Registry (PACTR) with the
identifier number PACTR201310000635418. Registered 11 October 2013 before the first
participant was enrolled.

Deeks, E. D. (2010). "Risperidone long-acting injection: in bipolar I disorder."

Drugs 70(8): 1001-1012.
A long-acting intramuscular formulation of the atypical antipsychotic agent
risperidone is now indicated for the maintenance treatment of patients with bipolar
I disorder. The formulation utilizes a novel drug delivery system of biodegradable
microspheres and is bioequivalent to the oral formulation of the drug. Moreover,
fluctuations in plasma drug concentrations at steady state were 1.7-fold lower with
long-acting than with oral risperidone. Maintenance treatment with risperidone
long-acting injection, as monotherapy in adults with stabilized bipolar I disorder
or as an adjunct to standard therapy in adults with stabilized, frequently
relapsing bipolar I disorder, was effective in delaying relapse to symptoms in two
well designed trials with maintenance phases of 1 or 2 years' duration. The time to
relapse to any mood episode (primary endpoint) was significantly longer with
risperidone long-acting injection than with placebo in both studies. Risperidone
long-acting injection also significantly reduced the risk of relapse relative to
placebo in these trials. Maintenance treatment with risperidone long-acting
injection was generally well tolerated in patients with bipolar disorder, both as
monotherapy and adjunctive therapy, with most adverse reactions being of mild to
moderate severity.

Degenhardt, E. K., et al. (2012). "Predictors of relapse or recurrence in bipolar I

disorder." J Affect Disord 136(3): 733-739.
OBJECTIVES: Bipolar disorder represents a major public health concern and,
despite treatment, is characterized by recurring episodes of mania, depression, or
mixed states. Prevention of relapse or recurrence is a primary treatment objective
in the management of the disorder. The objective of the current study was to
identify predictors of relapse/recurrence in patients with bipolar I disorder
treated with olanzapine, lithium, divalproex, or olanzapine plus
divalproex/lithium. METHODS: Data from four clinical trials studying the efficacy
of olanzapine compared to placebo and active comparators (lithium, divalproex,
olanzapine plus divalproex/lithium) for bipolar I disorder were pooled for this
analysis. Patients achieving remission after pharmacological treatment and entering
randomized double-blind maintenance phase for 44 to 72 weeks were included. Cox
Proportional Hazard models and Kaplan-Meier analyses were used to determine
predictors of relapse/recurrence for the pooled data and within each treatment
group. RESULTS: A total of 929 patients meeting the criteria for remission and
followed by maintenance treatment were included in this analysis, and 427 patients
(46.0%) experienced symptomatic relapse/recurrence during the follow-up period. A
21-item Hamilton Depression Rating Scale (HAMD-21) total score<4, gender, rapid
cycling and treatment emerged as significant predictors of relapse/recurrence and
may be generalized to treatment with olanzapine and to some extent to treatment
with lithium and divalproex. The results on treatment-specific predictors of
relapse/recurrence are considered to be exploratory and no adjustments were made
for multiple comparisons. CONCLUSION: The major findings from this study suggest
that a HAMD-21 total score<4 may be a better predictor of maintenance of remission
in bipolar I patients than HAMD-21 total score<8. The prophylactic effect of
olanzapine, lithium, divalproex, olanzapine plus divalproex or lithium, and placebo
was assessed and baseline predictors of relapse/recurrence were identified.

Del Grande, C., et al. (2012). "[Long-term treatment of bipolar disorder: how
should we use lithium salts?]." Riv Psichiatr 47(6): 515-526.
UNLABELLED: Despite the great quantity of evidence supporting the efficacy of
lithium in the maintenance treatment of bipolar disorder (BD), its use has often
been limited because of issues about the management of this compound. W aimed to
evaluate the use of lithium in common clinical practice and to identify possible
relationships between the trend over time of serum lithium levels and clinical
course of the illness. METHODS: 98 patients with bipolar I and bipolar II disorder
(DSM-IV-TR) on maintenance treatment with lithium salts were recruited and followed
up in a naturalistic trial at the Day Hospital of Psychiatric Clinic of Pisa.
Diagnosis was confirmed using a structured interview, the SCID-I. During symptom
assessment, the Clinical Global Impression-Bipolar Version Scale (CGI-BP) was used.
RESULTS: The sample is made up mainly of BI patients (87.8%) and lithium is used in
association with anticonvulsants in 63%. Less than half of the sample (48%)
presents average serum lithium levels in the therapeutic range (0.5-0.8 mEq/L);
serum values of lithium within the range were seen more frequently in patients with
manic/mixed episode, with manic/mixed polarity of onset, with a greater number of
previous episodes, with a higher percentage of rapid cycling and in subjects
treated with lithium associated with anticonvulsants. During the follow-up patients
with average serum lithium levels within the therapeutic range obtained a clinical
improvement in a significantly greater proportion compared to patients with average
serum lithium levels lower than 0.50 mEq/L. DISCUSSION: In clinical practice,
lithium is often used at doses determining serum levels at the lower limits of the
therapeutic range. Preliminary data on the prospective course of the illness
support the importance of maintaining serum values of lithium within the
therapeutic range.

Del-Ben, C. M., et al. (2010). "[Differential diagnosis of first episode psychosis:

importance of optimal approach in psychiatric emergencies]." Rev Bras Psiquiatr 32
Suppl 2: S78-86.
OBJECTIVE: To review the literature regarding the diagnosis of first episode
psychosis in the context of emergency psychiatry. METHOD: Review of empirical and
review articles selected by electronic search in the database PubMed. RESULTS:
Specific features of emergency care--single, brief and cross section assessment,
and with little information--may jeopardize the diagnostic process. These
limitations can be circumvented by application of operational diagnostic criteria,
the use of scales and structured interviews and a short period of observation,
between 24-72 hours. Diagnoses of bipolar disorder, schizophrenia, psychotic
depression and delusional disorder developed in the context of emergency have good
stability, but not the diagnoses of brief psychotic disorder, schizophreniform
disorder and schizoaffective disorder. First episode psychosis can occur in the
course of the use of psychoactive substances, with relatively frequent maintenance
of psychotic symptoms even after cessation of the use of the substance. The
rational use of subsidiary tests may help the differential diagnosis of psychotic
episodes due to general medical conditions. CONCLUSION: Diagnoses of first
psychotic episode can be adequately performed during psychiatric emergencies, if
routines are implemented based on scientific evidence.

Delle Chiaie, R., et al. (2013). "Group psychoeducation normalizes cortisol

awakening response in stabilized bipolar patients under pharmacological maintenance
treatment." Psychother Psychosom 82(4): 264-266.

Dell'Osso, B., et al. (2014). "Augmentative transcranial direct current stimulation

(tDCS) in poor responder depressed patients: a follow-up study." CNS Spectr 19(4):
347-354.
OBJECTIVES: Transcranial direct current stimulation (tDCS) is a non-invasive
neurostimulation technique that has received increasing interest in the area of
mood disorders over the last several years. While acute, double-blind, sham-
controlled studies have already reported positive findings in terms of efficacy and
safety for tDCS, follow-up data are lacking. This need prompted the present follow-
up study, which assesses post-acute effects of tDCS (no maintenance stimulation was
performed), in the mid-term, in a sample of major depressives. METHODS: After
completing an acute, open trial of tDCS, 23 outpatients with either major
depressive disorder or bipolar disorder entered a naturalistic follow-up (T1) with
clinical evaluations at one week (T2), 1 month (T3), and 3 months (T4). A
quantitative analysis of Hamilton Depression Rating Scale (HAM-D), Montgomery-
Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) total
scores, through repeated measures analysis of variance (ANOVA) (T1-T4) and paired
t-test for comparing specific time points (T1-T2, T2-T3, and T3-T4), was performed.
In addition, a qualitative analysis on the basis of treatment response and
remission (HAM-D) was performed. RESULTS: Even though a progressive reduction of
follow-up completers was observed from T2 to T4 (95.6% at T2, 65.2% at T3, and
47.8% at T4), the antidepressant effects of acute tDCS persisted over 3 months in
almost half of the sample. Of note, no post-acute side effects emerged during the
follow-up observation. The most frequent causes of drop-out from this study
included major modifications in therapeutic regimen (30%) and poor adherence to
follow-up visits (17%). CONCLUSIONS: In this mid-term, open, follow-up study, tDCS
showed mixed results. Further controlled studies are urgently needed to assess its
effects beyond the acute phase.

Dell'osso, B., et al. (2011). "Long-term efficacy after acute augmentative

repetitive transcranial magnetic stimulation in bipolar depression: a 1-year
follow-up study." J ECT 27(2): 141-144.
BACKGROUND: : The efficacy of repetitive transcranial magnetic stimulation
(rTMS) has been poorly investigated in the long-term. The present follow-up study
was aimed to assess the long-term efficacy and the discontinuation effects of rTMS
in a sample of depressed bipolar patients. METHODS: : After the completion of an
acute trial with augmentative, low-frequency, navigated rTMS, 11 drug-resistant
depressed bipolar subjects (Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition [Text Revision] criteria) entered a naturalistic follow-up with
monthly evaluations through the Hamilton Depression Rating Scale and the Young
Mania Rating Scale. RESULTS: : After 1 year of follow-up, results showed that the
achievement of remission after acute rTMS was predictive of maintenance of response
at 1 year. On the other hand, the absence of acute rTMS response predicted the
absence of subsequent response in the long-term. CONCLUSIONS: : This first report
on the long-term discontinuation effects after acute rTMS suggests that immediate
remission is predictive of sustained benefit after 1 year. Larger controlled
studies are needed to confirm present preliminary findings.

Dennis, N. M., et al. (2017). "Electroconvulsive Therapy and All-Cause Mortality in

Texas, 1998-2013." J ECT 33(1): 22-25.
INTRODUCTION: Electroconvulsive therapy (ECT) remains an effective treatment
for major depressive disorder. Since 1995, Texas has maintained an ECT database
including patient diagnoses and outcomes, and reporting any deaths within 14 days
of receiving an ECT treatment, encompassing a total of 166,711 ECT treatments
administered in Texas over the previously unreported period of 1998 to 2013.
METHODS: Descriptive analysis summarized information on deaths reported during the
16-year period-cause of death, type of treatment (index or maintenance) and patient
demographics. Multiple logistic regression of death incidence by treatment session
was performed to determine whether patient age, sex, race, diagnosis, or year of
treatment was associated with death after ECT. RESULTS: Of those deaths occurring
within 1 day of an ECT treatment, the death rate was 2.4 per 100,000 treatments.
Looking at all deaths within 14 days of an ECT treatment, the death rate increased
to 18 per 100,000 treatments but included all deaths regardless of likelihood of
causal association with ECT, for example, accidents and suicides, the latter a
leading cause of death among individuals with severe major depression or other
disorders for which ECT is indicated. Death rate increased significantly with
increasing patient age (P = 0.001) and male sex (P = 0.009), and there was a
nonsignificant trend toward increased death amongst patients with bipolar disorder
or schizophrenia (P = 0.058) versus depression. CONCLUSIONS: Our data indicate that
ECT is in general a safe procedure with respect to the likelihood of immediate
death. Suicide remains a significant risk in ECT patients, despite evidence that
ECT reduces suicidal ideation.

Devulapalli, K. K., et al. (2010). "Why do persons with bipolar disorder stop their
medication?" Psychopharmacol Bull 43(3): 5-14.
OBJECTIVE: Non-adherence to maintenance medication regimens is a major
problem, limiting outcomes for many persons with bipolar disorder. The aim of this
paper is to determine the most relevant aspects of adherence attitudes in a sample
of bipolar patients selected for problems with adherence behavior. METHODS: Among a
larger sample of bipolar disorder patients participating in a prospective follow-up
study (N = 140), a subsample of patients were selected for non-adherent behavior
defined as missing >/= 30% of medication during the past month (n = 27; 19.3%).
Adherence attitudes were assessed with the Rating of Medication Influences scale
(ROMI), a self-reported attitudinal measure assessing reasons for and against
adherence. Multiple logistic regression models for non-adherence vs. adherence were
estimated with each of the 19 ROMI items in the model, while controlling for sex,
age, ethnicity, education, duration of illness, and substance abuse. RESULTS: Mean
score of ROMI items corresponding to reasons for treatment adherence was greater
among adherent participants, whereas the mean score of ROMI items corresponding to
reasons for treatment non-adherence was greater among nonadherent participants. The
ROMI item identifying that the individual believes that medications are unnecessary
had the strongest influence for non-adherence (p < 0.0001). This was followed by
ROMI items corresponding to no perceived daily benefit (p = 0.0008), perceived
change in appearance (p = 0.0057), and perceived interference with life goals (p =
0.0033). The ROMI item identifying fear of relapse was the strongest predictor for
adherence (p = 0.0017). CONCLUSIONS: Non-adherent patients with bipolar disorder
differ from adherent patients with bipolar disorder on reasons for adherence and
non-adherence. Utilization of tools that evaluate medication treatment attitudes,
such as the ROMI or similar measures, may assist clinicians in the selection of
interventions that are most likely to modify future treatment adherence.

Dhillon, S. (2012). "Aripiprazole: a review of its use in the management of mania

in adults with bipolar I disorder." Drugs 72(1): 133-162.
Aripiprazole (Abilify(R)) is an atypical antipsychotic indicated for the
treatment of mania associated with bipolar I disorder. It is unique in its class,
as it is a partial agonist of dopamine D(2) and D(3), and serotonin 5-HT(1A)
receptors and a modest antagonist of 5-HT(2A) receptors. This article reviews the
pharmacological properties, clinical efficacy and tolerability of oral aripiprazole
in the management of mania associated with bipolar I disorder in adults. In well
designed clinical trials in patients with recent manic or mixed episodes associated
with bipolar I disorder, oral aripiprazole monotherapy or adjunctive therapy to
lithium or valproate improved symptoms of mania following short-term (</=12 weeks)
or maintenance (</=100 weeks) treatment. In addition, maintenance treatment with
aripiprazole (as monotherapy or adjunctive therapy) prevented the recurrence of any
mood episodes or manic episodes (but not depressive episodes) in patients who had
previously been stabilized and maintained on aripiprazole. Aripiprazole was
generally well tolerated in these studies and was associated with a low risk of
prolactin elevation, corrected QT interval prolongation and metabolic disturbances.
Extrapyramidal symptoms occurred in up to 28% of aripiprazole recipients, but after
longer-term treatment (</=100 weeks), symptom severity did not differ significantly
from that in placebo recipients. Aripiprazole treatment generally did not increase
bodyweight to a clinically relevant extent; however, more patients receiving
aripiprazole monotherapy than placebo had clinically significant bodyweight gain
during 100 weeks' treatment. Additionally, in a comparative trial, aripiprazole
monotherapy was at least as effective as haloperidol monotherapy in terms of
improving symptoms of mania, but had the advantage of a lower incidence of some
adverse events, such as extrapyramidal symptom-related adverse events. Further
trials comparing aripiprazole with other agents, including atypical antipsychotics,
would help to definitively position aripiprazole relative to these agents. Current
guidelines recommend aripiprazole as a first-line option (as monotherapy or
adjunctive therapy) for the short-term treatment of mania associated with bipolar I
disorder, and as a first-line (as monotherapy) or second-line (as adjunctive
therapy) option for preventing the recurrence of mood episodes during longer-term
therapy.

Diaz-Caneja, C. M., et al. (2014). "Practitioner review: Long-term pharmacological

treatment of pediatric bipolar disorder." J Child Psychol Psychiatry 55(9): 959-
980.
BACKGROUND: Although long-term treatment is a core aspect of the management
of children and adolescents with bipolar disorder (BD), most clinical
recommendations are based on results from short-term studies or adult data. In
order to guide clinical practice, we review the efficacy and safety profile of mood
stabilizers, antipsychotics, and other pharmacological strategies for the long-term
treatment of BD in pediatric patients. METHODS: A MEDLINE, EMBASE, Cochrane and
PsycInfo search (inception through November 2013) was performed to identify
prospective studies longer than 12 weeks assessing the use of pharmacological
strategies for the long-term treatment of BD in pediatric patients (0-18 years of
age). RESULTS: Four randomized controlled trials (RCT) [three placebo-controlled
(assessing aripiprazole (2) and flax oil), and one head-to-head comparison of
lithium vs. divalproex], and thirteen noncontrolled studies (six open-label studies
assessing lithium or anticonvulsants, five assessing second-generation
antipsychotics (SGAs) and four assessing combination strategies) were included in
the review. Aripiprazole has shown efficacy for relapse prevention in children with
pediatric bipolar disorder (PBD) 4-9 years of age in one placebo-controlled RCT.
Positive results have been reported in noncontrolled studies with quetiapine and
lithium for relapse prevention, as well as with lithium, quetiapine, ziprasidone,
and the combination of risperidone and divalproex or lithium for long-term symptom
reduction in PBD. The most frequently reported adverse events in children and
adolescents treated with lithium and anticonvulsants are gastrointestinal and
neurological, whereas use of SGAs is mainly related to weight gain and sedation.
CONCLUSION: According to the limited empirical evidence, aripiprazole can be useful
for relapse prevention in children with PBD. Given the lack of consistent efficacy
data, clinical decision making should be based on individual clinical aspects and
safety concerns.

Dimitrakopoulos, S. and G. Konstantakopoulos (2015). "Pharmacological agents under

research for the maintenance treatment in bipolar disorder." Psychiatriki 26(3):
169-180.
The treatment of bipolar disorder is a current challenge for clinicians and
despite progress in psychopharmacology, options remain limited and results are
often unsatisfactory. Current research focuses on finding new pharmaceutical agents
for all phases of bipolar disorder, i.e. mania, bipolar depression and maintenance.
Particularly, relapse prevention and longterm stabilization is a major therapeutic
target. Combination treatment and polypharmacy are the most common choices
concerning relapse prevention. Furthermore, during maintenance phase patients often
experience residual mood symptoms, cognitive deficits and functional decline, which
altogether illustrate the inadequate effectiveness of existing treatments and the
need for new, targeted, effective and safe treatments for bipolar disorder. This
review focuses on active agents for maintenance treatment in bipolar disorder
investigated during the last 5 years. The compounds under investigation have been
tried or tested either as monotherapy or as an add-on treatment in clinical trials
that have progressed up to phase 3 or in preclinical models of bipolar disorder.
While awaiting the completion of many ongoing studies, the results so far indicate
that paliperidone and pregabalin may have a position in the maintenance treatment
of bipolar disorder. Additionally, dextromethorphan, which acts primarily as a NMDA
antagonist, may be an interesting compound for further study. However, results on
memantine, another NMDA antagonist, were not encouraging. The effects of omega-3
fatty acids and cytidine were not superior to placebo, although they both have
neurotrophic and neuroprotective properties. Eslicarbazepine, which has
antiepileptic action, provided some evidence of efficacy as monotherapy. Regarding
preclinical studies in experimental models, the pharmacological agents under
investigation seem to follow the neurobiological pathways related to mechanism of
action of lithium, which is still the "golden standard" for preventing recurrence
in bipolar disorder. Major therapeutic targets are synthetic glucose kinase 3 (GSK-
3) and the path of phosphoinositol (IMP), both probably involved in the action of
lithium. Furthermore, the role of circadian rhythms maintenance is being studied in
preclinical and clinical trials investigating the efficacy and safety of compounds
CK-01 and ramelteon, respectively. Research also focuses on pharmacological agents
based on epigenetic changes and gene expression modulation, as the inhibitor of
histone deacetylase (HDAC). Of note, the development of valid and reliable
experimental models for bipolar disorder, which currently remains quite
controversial, will contribute to the understanding of the pathogenic mechanisms
and the development of new effective treatments. Improving methodology aspects of
clinical trials, such as diagnosis, clinical heterogeneity, monitoring time, gender
differences and comorbidities, may promote research. Current studies seem promising
for the development of novel pharmacological agents in the near future, although
there are methodological limitations in the search for the maintenance treatment in
bipolar disorder. New therapeutic targets include not only the already known
mechanisms of action, but also novel pathophysiological pathways, probably
implicated in bipolar disorder.

Ding, S., et al. (2010). "A potent chemotherapeutic strategy for bladder cancer:
(S)-methoxy-trityl-L-cystein, a novel Eg5 inhibitor." J Urol 184(3): 1175-1181.
PURPOSE: Eg5, which has an essential role in the formation and maintenance of
a bipolar mitotic spindle, was recently identified as an attractive target in
cancer chemotherapy. We examined the anticancer activity of a novel Eg5 inhibitor
for bladder cancer with particular reference to metastatic disease. MATERIALS AND
METHODS: We examined bladder cancer cell lines and clinical tissue samples for Eg5
expression and analyzed the antiproliferative activity of 5 Eg5 inhibitors in cell
lines by cell viability assay. The anticancer efficacy of the most potent Eg5
inhibitor was investigated in vitro by apoptosis assay with Hoechst nuclear
staining and flow cytometry. Immunofluorescence and immunostaining were used to
elucidate the inhibitory mechanism. We evaluated the inhibitory effect in vivo in
subcutaneous xenograft and metastatic cancer models. RESULTS: Eg5 expression was
increased in bladder cancer samples vs that in normal bladder epithelium samples.
(S)-methoxy-trityl-L-cystein showed the strongest antiproliferative activity of the
5 Eg5 inhibitors and induced cell death after mitotic arrest via the caspase
dependent apoptotic pathway. In vivo (S)-methoxy-trityl-L-cystein effectively
suppressed tumor growth in subcutaneous and metastatic xenograft models. Survival
time in (S)-methoxy-trityl-L-cystein treated nude mice was significantly longer
than in untreated mice (p <0.001). CONCLUSIONS: (S)-methoxy-trityl-L-cystein is a
promising, novel anticancer agent for bladder cancer. Our data indicates its
potential as effective therapy for metastatic bladder cancer.

D'Souza, R., et al. (2011). "Use of lithium in the treatment of bipolar disorder in
late-life." Curr Psychiatry Rep 13(6): 488-492.
Lithium is the oldest and still one of the most frequently prescribed mood
stabilizers in the treatment of bipolar disorder. Nonetheless, the evidence for
lithium efficacy in older patients with bipolar disorder is almost entirely
extrapolated from younger adult patients. Here we review the literature on lithium
in older patients with bipolar disorder, concentrating on the past 3 years. A
definitive study demonstrating the efficacy and safety of lithium in older patients
with bipolar disorder is still missing. However, several lines of indirect evidence
suggest that it is beneficial and advantageous over other mood stabilizers in the
acute and maintenance treatment of late-life bipolar disorder. In addition, lithium
may have unique properties as a regenerative therapeutic with specific benefits in
reducing the cognitive impairment and suicide rates associated with bipolar
disorder across the adult lifespan. Aging-associated pharmacokinetic and
pharmacodynamic changes as well as increased rates of medical comorbidities and
polypharmacy predispose older patients to a higher risk of lithium toxicity.
Careful monitoring and adjustment of lithium dosage is especially important in
older adults to minimize the risk of toxicity.

Dubovsky, S. L. and A. N. Dubovsky (2011). "Ziprasidone for maintenance treatment

of bipolar I disorder in adults." Expert Opin Pharmacother 12(5): 817-824.
INTRODUCTION: Antipsychotic drugs are increasingly used in the maintenance
treatment of bipolar disorder. This review addresses the evidence supporting the
use of one of these medications for this indication in order to place available
data in perspective for the clinician. AREAS COVERED: The approval of ziprasidone
for maintenance treatment of bipolar I disorder was based on two open-label
extensions of industry-sponsored 3-week monotherapy trials in mania, involving a
total of 189 patients and an industry-sponsored study using sample enrichment of
584 outpatients who had either ziprasidone or a placebo added to lithium or
valproate. Patients enrolled in maintenance studies did not have refractory mood
disorders or comorbid conditions or risk of dangerousness, and they were able to
give sustained consent. Ziprasidone is generally well tolerated, but should be
taken with food. Primary interactions of concern are those with other serotonergic
medications and other medications that prolong the QT interval. EXPERT OPINION:
Although antipsychotic drugs are used frequently for maintenance treatment, current
guidelines recommend that an attempt be made to withdraw them after acute
treatment. The use of these medications as part of a maintenance regimen is most
appropriate in cases of persistent psychosis or failure to respond to standard mood
stabilizer combinations.

Dumas, R., et al. (2012). "[Repetitive transcranial magnetic stimulation in major

depression: response factor]." Encephale 38(4): 360-368.
OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a brain
stimulation technique that has been investigated as a novel treatment for
psychiatric disorders, notably in major depression, and has shown statistically
significant effects. The authors found it necessary to propose an up-to-date review
of positive predictors for antidepressive response to repetitive transcranial
magnetic stimulation. METHOD: Based on an exhaustive consultation of Medline data,
supplemented by a manual research, only works evaluating response factors of rTMS
in major depression were retained. RESULTS: Twenty-nine studies were retained,
including meta-analyses, reviews, randomized controlled trials and open trials. The
most concordant data clearly indicate that a high score of treatment resistance, a
long duration of current episode, advanced age, and psychotic symptoms are negative
predictors for treatment response to rTMS. In the older patients, menopausal women
are especially concerned. However, some parameters should be adapted to the degree
of cortical atrophy such as intensity of stimulation or total number of rTMS
sessions. Previous response to rTMS therapy seems to be a good predictor contrary
to non-response to electroconvulsive therapy. Adjunctive antidepressant treatment
shows greater responsiveness to rTMS contrary to benzodiazepine or anticonvulsant
treatment. To our knowledge, no study compares unipolar and bipolar depression, the
profile of depression is not established yet. Imaging studies show that TMS
antidepressant responders differed from non-responders in inferior frontal
activity, at baseline, and even more so following treatment. Furthermore, reduced
baseline cerebral metabolism in cerebellar, temporal, anterior cingulate and
occipital regions of the brain was correlated with improvement after two weeks of
fast (20Hz) left dorsolateral prefrontal cortex (DLPFC) rTMS. Additionally, a right
frontal region emerges with divergent polarity in the metabolic prediction of
response to low rTMS. Inhibiting right DLPFC or stimulating DLPFC shows similar
results, the choice on the side of stimulation does not seem determining. Bilateral
stimulation for the moment does not seem superior to unilateral stimulation.
Parameters of stimulation associated with effectiveness of rTMS are an intensity of
stimulation higher than 100% of the motor threshold, a number of stimulations per
sessions superior to 1000, and a full number of days of treatment greater than 10.
DISCUSSION: Parameters of stimulation must be adapted according to the treated
patients. For example, older patients who present cortical atrophy need higher
intensity of stimulation. Other criteria could influence effectiveness of rTMS in
the same way. Would it be necessary, for example, to adapt the duration or the
intensity of stimulation according to the severity of the depressive episode or its
duration of evolution? Do antecedents of resistance to a pharmacological treatment
oblige us to stimulate differently? Few studies exceed 10 days of treatment; will
longer duration of treatment be more effective? Also, we did not find any data on
the interest of maintenance treatment among responders. Should the characteristics
of the depressive disorder or its evolution require maintenance treatment? What
will be its rhythm and its duration? Should we adapt rTMS parameters to
abnormalities highlighted by functional neuroimagery? The prospects for work remain
numerous.

Duque, B. A., et al. (2012). "[Rattus norvegicus as an indicator of circulation of

Capillaria hepatica and Taenia taeniaeformis on a groceries trade center of
Medellin, Colombia]." Biomedica 32(4): 510-518.
INTRODUCTION: Rattus norvegicus, the Norway rat, plays a pivotal role in the
maintenance and spread of several zoonotic bacterial, viral and parasitic pathogens
of public health interest. The presence of helminthic infections near susceptible
human populations can, under appropriate environmental conditions, become a risk
factor for their transmission. OBJECTIVE: Frequencies of infection were reported
for Capillaria hepatica and larval forms of Taenia taeniaeformis in wild rats (R.
norvegicus) captured in an urban area. MATERIALS AND METHODS: Two hundred and
fifty-four adult specimens of R. norvegicus were collected in an urban zone of
Medellin, Colombia. The livers of 54 specimens that showed macroscopic hepatic
lesions during necropsy were examined by conventional histopathology. RESULTS: The
frequency of infestation with C. hepatica was 20.1% (51/254). Six livers (2.4%)
were also positive for larvae of T. taeniaeformis. Livers infested with C. hepatica
exhibited adult or juvenile parasites and oval eggs with bipolar opercula, and were
associated with mild to moderate multifocal granulomatous hepatitis with leucocyte
infiltrate. Granulomatous lesions and calcified residual fibroses were found with
eggs but without adult parasites. Those animals with cysticerci of T. taeniaeformis
showed a high frequency of hepatic cysts containing larvae as well as inflammed and
fibrotic lesions. CONCLUSION: Zoonotic helminths circulate at high frequency in R.
norvegicus that occur in urban environments. Further research about the
distribution of these parasites will determine the level of health threat they
present for susceptible human and domestic animal populations.

Dwivedi, T. and H. Zhang (2014). "Lithium-induced neuroprotection is associated

with epigenetic modification of specific BDNF gene promoter and altered expression
of apoptotic-regulatory proteins." Front Neurosci 8: 457.
Bipolar disorder (BD), one of the most debilitating mental disorders, is
associated with increased morbidity and mortality. Lithium is the first line of
treatment option for BD and is often used for maintenance therapy. Recently, the
neuroprotective action of lithium has gained tremendous attention, given that BD is
associated with structural and functional abnormalities of the brain. However, the
precise molecular mechanism by which lithium exerts its neuroprotective action is
not clearly understood. In hippocampal neurons, the effects of lithium (1 and 2 mM)
on neuronal viability against glutamate-induced cytotoxicity, dendritic length and
number, and expression and methylation of BDNF promoter exons and expression of
apoptotic regulatory genes were studied. In rat hippocampal neurons, lithium not
only increased dendritic length and number, but also neuronal viability against
glutamate-induced cytotoxicity. While lithium increased the expression of BDNF as
well as genes associated with neuroprotection such as Bcl2 and Bcl-XL, it decreased
the expression of pro-apoptotic genes Bax, Bad, and caspases 3. Interestingly,
lithium activated transcription of specific exon IV to induce BDNF gene expression.
This was accompanied by hypomethylation of BDNF exon IV promoter. This study
delineates mechanisms by which lithium mediates its effects in protecting neurons.

Egashira, T., et al. (2011). "Adjunctive gabapentin for treatment-resistant

insomnia of bipolar disorder: a case report." Clin Neuropharmacol 34(3): 129-130.
We report a case with bipolar II disorder having mixed features, in which
refractory insomnia persisted. We diagnosed his case as mixed depression with mood
fluctuations because increased impulsivity and buying sprees became remarkable,
with diminished ability to think or concentrate. Switching to carbamazepine and
risperidone improved his mood fluctuations and impulsivity. Nevertheless, his
intermittent awakening (fragmentation of the sleep-wake rhythm), related
dysfunctional beliefs, anxiety about sleep, and mild impulsivity persisted. The
addition of various benzodiazepine sleeping drugs, bromovalerylurea, and
antipsychotics did not improve insomnia. His intractable insomnia was markedly
responsive to gabapentin, engendering further improvement of mood symptoms.
Eventually, its efficacy achieved his reinstatement at work. Results of this case
suggest the clinical use of gabapentin for treating bipolar disorder, especially in
cases with intractable insomnia, which is a very important point in the symptoms
and therapeutics of bipolar disorder.

Eidelman, P., et al. (2010). "Sleep architecture as correlate and predictor of

symptoms and impairment in inter-episode bipolar disorder: taking on the challenge
of medication effects." J Sleep Res 19(4): 516-524.
This study was designed to clarify the association between inter-episode
bipolar disorder (BD) and sleep architecture. Participants completed a baseline
symptom and sleep assessment and, 3 months later, an assessment of symptoms and
impairment. The effects of psychiatric medications on sleep architecture were also
considered. Participants included 22 adults with BD I or II (inter-episode) and 22
non-psychiatric controls. The sleep assessment was conducted at the Sleep and
Psychological Disorders Laboratory at the University of California, Berkeley.
Follow-up assessments 3 months later were conducted over the phone. Results
indicate that, at the sleep assessment, BD participants exhibited greater rapid eye
movement sleep (REM) density than control participants with no other group
differences in sleep architecture. Sleep architecture was not correlated with
concurrent mood symptoms in either group. In the BD group, duration of the first
REM period and slow-wave sleep (SWS) amount were positively correlated with manic
symptoms and impairment at 3 months, while REM density was positively correlated
with depressive symptoms and impairment at 3 months. The amount of Stage 2 sleep
was negatively correlated with manic symptoms and impairment at 3 months. In
contrast, for the control group, REM density was negatively correlated with
impairment at 3 months. SWS and Stage 2 sleep were not correlated with symptoms or
impairment. Study findings suggest that inter-episode REM sleep, SWS and Stage 2
sleep are correlated with future manic and depressive symptoms and impairment in
BD. This is consistent with the proposition that sleep architecture may be a
mechanism of illness maintenance in BD.

Ekman, M., et al. (2012). "Cost effectiveness of quetiapine in patients with acute
bipolar depression and in maintenance treatment after an acute depressive episode."
Pharmacoeconomics 30(6): 513-530.
BACKGROUND: Bipolar disorder has a significant impact upon a patient's
quality of life, imposing a considerable economic burden on the individual, family
members and society as a whole. Several medications are indicated for the acute
treatment of mania and depression associated with bipolar disorder as well as for
maintenance therapy; however, these have varying efficacy, tolerability and costs.
OBJECTIVE: The objective of this study was to develop a new discrete-event
simulation model to analyse the long-term consequences of pharmacological therapy
for the management of bipolar I and II disorders (acute treatment of episodes of
mania and depression as well as maintenance therapy). METHODS: Probabilities of
remission and relapse were obtained from clinical trial data and meta-analyses.
Costs (year 2011 values) were assessed from a UK healthcare payer's perspective,
and included pharmacological therapy and resource use associated with the treatment
of mood events and selected adverse events. The health effects were measured in
terms of QALYs. RESULTS: For a patient starting with acute depression or in
remission at 40 years of age (which was the average age in the clinical trials),
quetiapine 300 mg/day was a cost-effective strategy compared with olanzapine 15
mg/day over a 5-year time frame. With acute bipolar depression as a starting
episode, the 5-year medical costs were pound323 higher and QALYs were 0.038 higher
for quetiapine compared with olanzapine, corresponding to a cost-effectiveness
ratio of pound8600 per QALY gained. CONCLUSION: Compared with olanzapine, the
results suggest that quetiapine is cost effective as a maintenance treatment for
bipolar depression.

El-Hage, W. and S. A. Surguladze (2010). "Emerging treatments in the management of

bipolar disorder - focus on risperidone long acting injection." Neuropsychiatr Dis
Treat 6: 455-464.
Bipolar disorder is a life-long psychiatric illness characterized by a high
frequency of relapses and substantial societal costs. Almost half of the patients
are prescribed second generation antipsychotics for treatment of manic states, or
as the maintenance therapy. Risperidone long acting injection (RLAI) as a
monotherapy or as adjunctive therapy to lithium or valproate for the maintenance
treatment of bipolar I disorder was approved by Food and Drug Administration (FDA)
in United States in May 2009. In this review we will consider the aspects of
pharmacology, pharmacokinetics, metabolism, safety and tolerability, and clinical
trials focusing on the efficacy of RLAI in bipolar disorder. The patients'
perspective and attitudes to long-acting injections will also be discussed.

El-Khalili, N. (2012). "Update on extended release quetiapine fumarate in

schizophrenia and bipolar disorders." Neuropsychiatr Dis Treat 8: 523-536.
 The atypical antipsychotic quetiapine fumarate is available both as an
immediate release (IR) and as an extended release (XR) formulation allowing
flexibility of dosing for individual patients. Approved uses of quetiapine XR
include the treatment of schizophrenia (including maintenance therapy for
prevention of relapse), the treatment of bipolar disorder (manic and depressive
episodes), and the prevention of recurrence in patients with bipolar disorder who
respond to quetiapine XR. This narrative review provides an update on quetiapine XR
in these indications. The pharmacological profile of quetiapine, including a
moderate affinity for dopamine D(2) receptors and higher affinity for serotonin 5-
hydroxytryptophan (5-HT)(2A) receptors, may explain its broad efficacy and low
propensity for extrapyramidal symptoms (EPS). The XR formulation has similar
bioavailability but prolonged plasma levels compared with the IR formulation,
allowing for less frequent (once-daily) dosing. Clinical studies have confirmed the
efficacy of quetiapine XR in relieving the acute symptoms of schizophrenia during
short-term trials, and reducing the risk for relapse in long-term studies. Direct
switching from the IR formulation to the same dose of the XR formulation did not
reveal any loss of efficacy or tolerability issues, and switching patients to
quetiapine XR from conventional or other atypical antipsychotics (for reasons of
insufficient efficacy or tolerability) also proved to be beneficial and generally
well tolerated. In bipolar disorder, quetiapine XR has also proven effective in
relieving acute depressive and manic symptoms. Adverse events with quetiapine XR in
patients with either schizophrenia or bipolar disorder are similar to those
associated with the IR formulation, the most common being sedation, dry mouth,
somnolence, dizziness, and headache. The low propensity for EPS is maintained with
the XR formulation. Overall, evidence from clinical trials suggests that quetiapine
XR is an effective and generally well-tolerated treatment option in patients with
schizophrenia and bipolar disorder.

El-Mallakh, R. S., et al. (2010). "Bipolar disorder: an update." Postgrad Med

122(4): 24-31.
There has been a recent increase in the number of clinical trials and
treatment options for bipolar disorder. This research has resulted in new treatment
options. Most second-generation antipsychotics have demonstrated efficacy in the
treatment of mania, both in monotherapy and as adjuncts to mood stabilizers. For
bipolar depression, nearly all randomized, placebo-controlled studies have
demonstrated that antidepressants do not provide any additional benefit to ongoing
mood stabilizers. Additionally, antidepressants carry a risk of destabilization of
bipolar disorder with an increase in mania, cycling, and chronic irritable
dysphoria. Newer non-antidepressant treatments for depression include quetiapine,
lamotrigine, modafinil, and pramipexole. These agents are effective for acute
treatment and appear to be effective in maintenance. The least-studied phase of
bipolar disorder is the maintenance phase. The use of multiple agents appears to be
superior to monotherapy in relapse prevention. Despite the many advances in the
pharmacotherapy of bipolar disorder, the overall prognosis of this severe illness
does not appear to have changed.

El-Mallakh, R. S., et al. (2010). "Long-term use of pramipexole in bipolar

depression: a naturalistic retrospective chart review." Psychiatr Q 81(3): 207-213.
A naturalistic retrospective chart review of all patients given pramipexole
for bipolar depression in addition to their mood stabilizers was undertaken.
Sixteen patients were followed for an average of 6.7 +/- SD 9.0 months. Half of the
patients stopped the pramipexole an average of 2 months after starting it. For all
patients, depressed mood, and the total profile of depressive symptoms improved
significantly within 4 weeks and remained significantly improved for as long as 36
weeks. Both global function (GAF), and global impression (CGI) improved with
pramipexole. Irritability and insomnia both increased slightly initially, and then
subsided. There were no changes in mania ratings for up to 36 months. Long-term
outcome of adjunctive pramipexole appears to be adequate, with apparent maintenance
of effect for over 9 months.
El-Mallakh, R. S., et al. (2015). "Antidepressants worsen rapid-cycling course in
bipolar depression: A STEP-BD randomized clinical trial." J Affect Disord 184: 318-
321.
BACKGROUND: The use of antidepressants in rapid-cycling bipolar disorder has
been controversial. We report the first randomized clinical trial with modern
antidepressants on this topic. METHODS: As part of the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a
priori secondary outcome, rapid cycling as a predictor of response in 68 patients
randomized to continue vs. discontinue antidepressant treatment, after initial
response for an acute major depressive episode. Outcomes assessed were percent time
well and total number of episodes. All patients received standard mood stabilizers.
RESULTS: In those continued on antidepressants (AD), rapid cycling (RC) subjects
experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44)
more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean
difference in depressive episodes per year RC vs. NRC was 0.85 +/- 0.37 (SE), df =
28, p = 0.03). In the AD continuation group, RC patients also had 28.8% less time
in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p = 0.004).
No such differences between RC and NRC subjects were seen in the AD discontinuation
group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent
with the above comparisons between RC and NRC subjects, stratified by maintenance
antidepressant treatment, though limited by sample size. CONCLUSIONS: In an a
priori analysis, despite preselection for good antidepressant response and
concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling
was associated with worsened maintenance outcomes, especially for depressive
morbidity, vs. antidepressant discontinuation.

Erickson, S. C., et al. (2012). "New-onset treatment-dependent diabetes mellitus

and hyperlipidemia associated with atypical antipsychotic use in older adults
without schizophrenia or bipolar disorder." J Am Geriatr Soc 60(3): 474-479.
OBJECTIVES: To examine the association between atypical antipsychotic
medications and incident treatment for diabetes mellitus or hyperlipidemia in
elderly adults without diagnoses of schizophrenia or bipolar disorder. DESIGN: Two
case-control studies using medical and pharmacy claims data. SETTING: United States
managed care population from multiple insurance plans. PARTICIPANTS: Individuals
aged 65 and older enrolled in a Medicare Advantage or commercial (health
maintenance organization) managed care health plan in the western United States
with no claims indicating diagnosis of schizophrenia or bipolar disorder in the 1
year pre-index period. Cases were defined as persons newly initiated on an
antidiabetic (n = 13,075) or antihyperlipidemic (n = 63,829) medication on the
index date. For the new diabetes mellitus analysis, 65,375 controls were matched to
cases based on age, sex, health-plan type, and index date year. In the new
hyperlipidemia analysis, 63,829 controls were matched to cases based on the same
variables. MEASUREMENTS: Conditional logistic regressions were performed to
determine the odds of initiated antidiabetic or antihyperlipidemic medication for
participants exposed to atypical antipsychotics compared with those with no
exposure. The models included comorbidities possibly associated with the outcome.
RESULTS: Exposure to atypical antipsychotics was associated with significantly
greater adjusted odds of starting an antidiabetic medication (1.32, 95% confidence
interval (CI) = 1.10-1.59) but significantly lower odds of starting an
antihyperlipidemic medication (0.76, 95% CI = 0.67-0.87). CONCLUSION: Use of
atypical antipsychotics in older adults for conditions other than schizophrenia and
bipolar disorder was associated with incident treatment of diabetes mellitus but
not of hyperlipidemia, suggesting that older adults may be susceptible to the
adverse metabolic consequences of these agents.

Evins, A. E., et al. (2014). "Maintenance treatment with varenicline for smoking
cessation in patients with schizophrenia and bipolar disorder: a randomized
clinical trial." JAMA 311(2): 145-154.
 IMPORTANCE: It is estimated that more than half of those with serious mental
illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation
aids improve short-term abstinence, but most who attain abstinence relapse rapidly
after discontinuation of pharmacotherapy. OBJECTIVE: To determine whether smokers
diagnosed with schizophrenia and bipolar disease have higher rates of prolonged
tobacco abstinence with maintenance pharmacotherapy than with standard treatment.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled,
parallel-group, relapse-prevention clinical trial conducted in 10 community mental-
health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from
March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive
behavioral therapy and 87 met abstinence criteria to enter the relapse prevention
intervention. INTERVENTIONS: Participants who had 2 weeks or more of continuous
abstinence at week 12 of open treatment were randomly assigned to receive cognitive
behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from
weeks 12 to 52. Participants then discontinued study treatment and were followed up
to week 76. MAIN OUTCOMES AND MEASURES: Seven-day rate of continuous abstinence at
study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon
monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through
64 based on biochemically verified abstinence and weeks 12 through 76, based on
self-reported smoking behavior. RESULTS: Sixty-one participants completed the
relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo)
and were considered to have relapsed for the analyses; 18 of these had relapsed
prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the
varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio
[OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64, 45% (18 of 40)
among those in the varenicline group vs 15% (7 of 47) in the placebo group were
continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12
through 76, 30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo
group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were
no significant treatment effects on psychiatric symptom ratings or psychiatric
adverse events. CONCLUSIONS AND RELEVANCE: Among smokers with serious mental
illness who attained initial abstinence with standard treatment, maintenance
pharmacotherapy with varenicline and cognitive behavioral therapy improved
prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone
after 1 year of treatment and at 6 months after treatment discontinuation. TRIAL
REGISTRATION: clinicaltrials.gov Identifier: NCT00621777.

Evins, A. E., et al. (2016). "Maintenance pharmacotherapy normalizes the relapse

curve in recently abstinent tobacco smokers with schizophrenia and bipolar
disorder." Schizophr Res.
OBJECTIVE: To compare the effect of maintenance pharmacotherapy on sustained
abstinence rates between recently abstinent smokers with schizophrenia and bipolar
disorder (SBD) and general population smokers without psychiatric illness. METHOD:
We performed a person-level, pooled analysis of two randomized controlled trials of
maintenance varenicline, conducted in adult smokers with SBD and general population
smokers, controlling for severity of dependence. Smokers abstinent after 12-weeks
of open varenicline treatment were randomly assigned to >/=12-weeks maintenance
varenicline or identical placebo. RESULTS: In those assigned to maintenance
placebo, the abstinence rate at week-24 was lower in those with SBD than for those
without psychiatric illness (29.4+/-1.1% vs. 61.8+/-0.4%, OR:0.26, 95% CI: 0.13,
0.52, p<0.001). In smokers assigned to maintenance pharmacotherapy, however, there
was no effect of diagnosis on abstinence rates at week-24 (87.2+/-0.8% vs. 81.9+/-
0.2%, OR: 1.68, 95% CI: 0.53, 5.32, p=0.38). Time to first lapse was shortest in
those with SBD assigned to maintenance placebo (Q1=12days, 95%CI: 4, 16), longer in
those without psychiatric illness assigned to maintenance placebo (Q1=17days,
95%CI: 17, 29), still longer in general-population smokers assigned to maintenance
varenicline (Q1=88, 95% CI:58,91, and longest in those with SBD who received
maintenance varenicline (Q1>95days, 95%CI:non-est), (Chi23df=96.99, p<0.0001; all
pairwise comparisons p<0.001). CONCLUSIONS: Following a standard 12-week course of
pharmacotherapy, people with schizophrenia and bipolar disorder were more likely to
relapse to smoking without maintenance varenicline treatment. Maintenance
pharmacotherapy could improve longer-term tobacco abstinence rates and reduce known
smoking-related health disparities in those with SMI.

Fagiolini, A., et al. (2010). "Risperidone long-acting injection as monotherapy and

adjunctive therapy in the maintenance treatment of bipolar I disorder." Expert Opin
Pharmacother 11(10): 1727-1740.
IMPORTANCE OF THE FIELD: It is very rare for patients with bipolar disorder
to have a single episode of mania or depression over a lifetime and the vast
majority of these individuals need long-term prophylactic/maintenance treatment.
However, treatment nonadherence is a major issue for close to half of subjects with
bipolar disorder who are prescribed medications. Risperidone long-acting injection
(LAI) has proven efficacious for the maintenance phase of bipolar disorder and may
mitigate the problem of nonadherence in the substantial group of patients for whom
this is a significant concern. AREAS COVERED IN THIS REVIEW: This paper comprises a
review and commentary regarding the use of risperidone LAI in bipolar disorder.
WHAT THE READER WILL GAIN: The reader will gain an understanding regarding the
risks and benefits of risperidone LAI in bipolar disorder. We review the available
evidence and discuss the strengths and weaknesses of published studies, providing
an opinion about the clinical usefulness of risperidone LAI as well as suggestions
for future research. TAKE HOME MESSAGE: The use of risperidone LAI, through
improved adherence, has the potential to ameliorate the course of bipolar disorder.

Fagiolini, A., et al. (2011). "Aripiprazole for the treatment of bipolar disorder:
a review of current evidence." Expert Opin Pharmacother 12(3): 473-488.
INTRODUCTION: several medications are available for the treatment of
different phases of bipolar disorder, yet many of the drugs that are currently
approved carry a substantial burden of side effects or do not lead all treated
patients to remission. AREAS COVERED: this paper comprises a review and commentary
regarding the use of oral and intramuscular aripiprazole in the acute and
maintenance phases of bipolar disorder. Basic principles in dosing, switching,
management of side effects and co-administration of aripiprazole with other
medications are provided. This paper presents practical strategies to translate the
data from clinical research into clinical practice. EXPERT OPINION: aripiprazole
has proven to be an effective medication for the acute treatment of manic and mixed
episodes, as well as for the prophylactic-maintenance phase of bipolar disorder in
patients recovering from a manic/mixed episode. Choosing the appropriate dosing and
tapering strategy, addressing the side effects, controlling withdrawal symptoms
from previous medications and using adjunctive medications when necessary are key
to successful treatment with aripiprazole.

Fang, F., et al. (2017). "Is there a 'weight neutral' second-generation

antipsychotic for bipolar disorder?" Expert Rev Neurother: 1-12.
INTRODUCTION: Antipsychotic-induced weight gain (WG) and metabolic
abnormalities are major concerns. This review was untaken to answer if there is a
weight-neutral second-generation antipsychotic for bipolar disorder (BPD). Areas
covered: English-language literature in MEDLINE was searched with the keywords of
antipsychotic/second-generation antipsychotic or generic/brand name of second-
generation antipsychotic, and BPD/mania/depression or bipolar maintenance, and
safety/tolerability or WG/weight increase, and randomized, placebo-controlled
trial. Difference between an antipsychotic monotherapy and placebo in absolute
weight gain (AWG) and/or >/= 7% (WG in three phases of BPD was compared based on
the data from original publications. The number needed to treat to harm was used
for the comparison of >/= 7% WG. Among antipsychotics with short-term (mania and/or
bipolar depression) and long-term (maintenance) studies, olanzapine, asenapine,
quetiapine, risperidone had significant WG compared to placebo in both short-term
and long-term trials. Aripiprazole did not cause significant WG compared to placebo
in short-term studies, but caused significant WG in long-term studies.
Paliperidone-ER-induced WG was significant in a mania study as measured with AWG,
and ziprasidone caused significant WG in a mania study measured with >/= 7% WG.
Expert commentary: These data suggest that it is unlikely there is a weight-neutral
second-generation antipsychotic in BPD.

Fatemi, S. H. and T. D. Folsom (2015). "GABA receptor subunit distribution and

FMRP-mGluR5 signaling abnormalities in the cerebellum of subjects with
schizophrenia, mood disorders, and autism." Schizophr Res 167(1-3): 42-56.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the
brain. GABAergic receptor abnormalities have been documented in several major
psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal
expression of mRNA and protein for multiple GABA receptors has also been observed
in multiple brain regions leading to alterations in the balance between
excitatory/inhibitory signaling in the brain with potential profound consequences
for normal cognition and maintenance of mood and perception. Altered expression of
GABAA receptor subunits has been documented in fragile X mental retardation 1
(FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental
retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem
studies from our laboratory have shown reduced expression of FMRP in the brains of
subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP
acts as a translational repressor and, under normal conditions, inhibits
metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X
syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5
signaling, ultimately resulting in the behavioral and intellectual impairments
associated with this disorder. Our laboratory has identified changes in mGluR5
expression in autism, schizophrenia, and mood disorders. In the current review
article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels
and compare our results with other laboratories. Finally, we discuss the
interactions between these molecules and the potential for new therapeutic
interventions that target these interconnected signaling systems.

Faurholt-Jepsen, M., et al. (2015). "Electronic monitoring of psychomotor activity

as a supplementary objective measure of depression severity." Nord J Psychiatry
69(2): 118-125.
BACKGROUND: Rating scales used to assess the severity of depression e.g. the
Hamilton Depression Rating Scale 17-item (HDRS-17) partly rely on the patient's
subjective experience and reporting. Such subjective measures tend to have low
reliability and adding objective measures to complement the assessment of
depression severity would be a major step forward. AIMS: To investigate
correlations between electronic monitoring of psychomotor activity and severity of
depression according to HDRS-17. METHODS: A total of 36 patients with unipolar
disorder (n = 18) or bipolar disorder (n = 18) and 31 healthy control persons aged
18-60 years were included. Psychomotor activity was measured using a combined heart
rate and movement sensor device (Actiheart) for 3 consecutive days, 24 h a day.
RESULTS: We found that sleeping heart rate (beats/min) correlated with HDRS-17 in
both patients with unipolar disorder and bipolar disorder (unadjusted model: B =
0.46, 95% CI 0.037-0.89, P = 0.034). In contrast, correlations between activity
energy expenditure (kJ/kg/day), cardio-respiratory fitness (mlO2/min/kg) and HDRS-
17 were non-significant. CONCLUSIONS: These results suggest that measuring sleeping
heart rate in non-experimental daily life could be an objective supplementary
method to measure the severity of depression and perhaps indicate presence of
insomnia.

Felix, P., et al. (2010). "[Lithium and chronic kidney disease: a pathology which
remains relevant]." Rev Med Suisse 6(238): 448-452.
Lithium continues to be the standard for acute and maintenance treatment of
bipolar mood disorders despite the availability of alternative agents. Lithium has
a narrow therapeutic index and can result in considerable toxicity. Acute renal
intoxication is well-known but chronic kidney disease should be in each doctor's
mind. The main manifestations are nephrogenic diabetes insipidus (NDI) and
tubulointerstitial nephritis. For NDI, the potassium sparing diuretic amiloride or
a thiazide diuretic can improve polyuria. Lithium-induced ESRD in chronic
tubulointerstitial nephritis is not uncommon and more prevalent (> 1% among long-
term lithium patients) than previously thought. The risk of renal failure may
persist even after lithium discontinuation. Additional kidney manifestations of
lithium exposure include renal tubular acidosis and hypercalcemia.

Ferensztajn-Rochowiak, E. and J. K. Rybakowski (2016). "The effect of lithium on

hematopoietic, mesenchymal and neural stem cells." Pharmacol Rep 68(2): 224-230.
Lithium has been used in modern psychiatry for more than 65 years,
constituting a cornerstone for the long-term treatment of bipolar disorder. A
number of biological properties of lithium have been discovered, including its
hematological, antiviral and neuroprotective effects. In this article, a systematic
review of the effect of lithium on hematopoietic, mesenchymal and neural stem cells
is presented. The beneficial effects of lithium on the level of hematopoietic stem
cells (HSC) and growth factors have been reported since 1970s. Lithium improves
homing of stem cells, the ability to form colonies and HSC self-renewal. Lithium
also exerts a favorable influence on the proliferation and maintenance of
mesenchymal stem cells (MSC). Studies on the effect of lithium on neurogenesis have
indicated an increased proliferation of progenitor cells in the dentate gyrus of
the hippocampus and enhanced mitotic activity of Schwann cells. This may be
connected with the neuroprotective and neurotrophic effects of lithium, reflected
in an improvement in synaptic plasticity promoting cell survival and inhibiting
apoptosis. In clinical studies, lithium treatment increases cerebral gray matter,
mainly in the frontal lobes, hippocampus and amygdala. Recent findings also suggest
that lithium may reduce the risk of dementia and exert a beneficial effect in
neurodegenerative diseases. The most important mediators and signaling pathways of
lithium action are the glycogen synthase kinase-3 and Wnt/beta-catenin pathways.
Recently, to study of bipolar disorder pathogenesis and the mechanism of lithium
action, the induced pluripotent stem cells (iPSC) obtained from bipolar patients
have been used.

Filgueiras, A., et al. (2014). "Latent structure of the symptomatology of

hospitalized patients with bipolar mania." Eur Psychiatry 29(7): 431-436.
Several studies have attempted to understand the dimensions of psychiatric
symptoms in manic episodes, but only a few have been able to model the latent
structure of mania in bipolar disorder patients using confirmatory factor analysis.
The objective of the present study was to search for the best model of the
symptomatology of hospitalized manic patients. To achieve this goal, 117 manic
inpatients during a manic crisis participated in this research. Exploratory factor
analysis was conducted followed by confirmatory factor analysis using an
exploratory factor analysis solution and three other theory-based models. The
exploratory factor analysis results revealed a six-factor structure: depression,
suicide, insomnia, mania, psychosis, and anxiety. This solution also presented the
best fit to the data when tested with confirmatory factor analysis. A five-factor
solution, without suicide as a separate dimension, appeared to be more
theoretically suitable. Another important finding was that anxiety was an
independent dimension in mania. Some hypotheses are discussed in light of
contemporary theories, and future studies should investigate this aspect further.

Findling, R. L. (2016). "Evidence-Based Pharmacologic Treatment of Pediatric

Bipolar Disorder." J Clin Psychiatry 77 Suppl E1: e2.
Pharmacotherapy is an important component of treatment for children and
adolescents with bipolar disorder. The body of evidence supporting safe and
effective treatments in this population is growing. Available data provide
information on the risks and benefits of pharmacologic agents used for acute manic,
mixed, and depressive episodes as well as for maintenance treatment. Lithium,
anticonvulsants, and antipsychotics comprise the armamentarium for treating
pediatric bipolar disorder. When selecting treatment, clinicians must consider the
efficacy and side effect profile of potential pharmacotherapies, as well as the
patient's history, including the presence of comorbidities, in order to develop a
treatment plan that will ensure optimal outcomes.

Findling, R. L., et al. (2015). "Adjunctive Maintenance Lamotrigine for Pediatric

Bipolar I Disorder: A Placebo-Controlled, Randomized Withdrawal Study." J Am Acad
Child Adolesc Psychiatry 54(12): 1020-1031 e1023.
OBJECTIVE: This study aimed to compare the efficacy of lamotrigine versus
placebo in 10- to 17-year-olds with bipolar I disorder (BP-I) who were receiving
conventional bipolar disorder treatment. METHOD: In this randomized withdrawal
trial, patients with BP-I of at least moderate severity received lamotrigine during
an </=18-week open-label phase. Patients who maintained a stable lamotrigine dose
for >/=2 weeks and Clinical Global Impression-Bipolar Severity of Illness (CGI-
BP[S]) score of </=3 for >/=6 consecutive weeks were randomized to double-blind
lamotrigine or placebo for </=36 weeks. RESULTS: Of 301 patients enrolled, 298
comprised the open-label intention-to-treat population, with 173 (58%) randomized.
Of these patients, 41 (24%) completed the study. In the open-label phase, the mean
(SD) baseline CGI-BP(S) rating was 4.4 (0.57), and the mean (standard error [SE])
time to stabilization was 101 (1.6) days. During the randomized phase, mean (SE)
time to occurrence of a bipolar event (TOBE) for lamotrigine versus placebo
(primary endpoint) was 155 (14.7) versus 50 (3.8), 163 (12.2) versus 120 (12.2),
and 136 (15.4) versus 107 (13.8) days for the 3 index mood states (depressed,
manic/hypomanic, mixed). The primary stratified log-rank analysis of TOBE was not
statistically significant (hazard ratio [HR] = 0.63; p = .072); however, the
prespecified Cox regression analysis favored lamotrigine (p = .047). In 13- to 17-
year-olds, log-rank analysis of TOBE significantly favored lamotrigine (HR = 0.46;
p = .015), but not in 10- to 12-year-olds (HR = 0.93; p = .877). Dermatologic
events were reported in 4% (open-label phase) and 2% (randomized phase) of patients
receiving lamotrigine. Suicidality-related adverse events were reported in 7%
(open-label phase) and 7% (randomized phase) of patients receiving lamotrigine.
CONCLUSION: Although the primary analysis failed to detect a benefit of add-on
lamotrigine for BP-I in 10- to 17-year-olds, lamotrigine may be effective in a
subset of older adolescents. Clinical trial registration information-Lamictal as
Add-on Treatment for Bipolar I Disorder in Pediatric Patients;
http://clinicaltrials.gov/; NCT00723450.

Findling, R. L., et al. (2012). "Double-blind, randomized, placebo-controlled long-

term maintenance study of aripiprazole in children with bipolar disorder." J Clin
Psychiatry 73(1): 57-63.
BACKGROUND: This study evaluates the long-term efficacy of aripiprazole
compared to placebo in children with bipolar disorders. METHOD: Outpatients aged 4
to 9 years meeting DSM-IV criteria for a bipolar disorder (I, II, not otherwise
specified, cyclothymia) were eligible to receive up to 16 weeks of open-label
treatment with aripiprazole (phase 1). Patients were randomized into the 72-week
double-blind phase of the study once they met a priori response criteria for
stabilization (phase 2). During phase 2, patients either remained on their current
aripiprazole regimen or began a double-blind taper with aripiprazole discontinued
and switched to placebo. The primary outcome measure for phase 2 was time to
discontinuation due to a mood event. RESULTS: Patients were recruited between May
2004 and November 2008. Following phase 1, in which 96 patients received
aripiprazole, 30 patients (mean age = 7.1 years) were randomly assigned to continue
aripiprazole and 30 patients (mean age = 6.7 years) were randomly assigned to
placebo. The mean (SD) dose of aripiprazole prior to randomization for these
patients was 6.4 (2.1) mg/d. Patients randomly assigned to aripiprazole were
enrolled significantly longer until time to study discontinuation due to a mood
event (6.14 median weeks, SE +/- 11.88 weeks; P = .005) and discontinuation for any
reason (including mood events) (4.00 median weeks, SE +/- 3.91 weeks; P = .003)
than those randomly assigned to placebo (mood event, 2.29 median weeks, SE +/- 0.38
weeks; any reason, 2.00 median weeks, SE +/- 0.31 weeks). Regardless of random
assignment, both the aripiprazole and placebo groups showed substantial rates of
withdrawal from maintenance treatment over the initial 4 weeks (15/30 [50%] for
aripiprazole; 27/30 [90%] for placebo), suggesting a possible nocebo effect (ie,
knowledge of possibly switching from active medication to placebo increasing
concern about relapse). The most frequently reported adverse events during double-
blind aripiprazole therapy included stomach pain (n = 10, 33%), increased appetite
(n = 9, 30%), and headaches (n = 9, 30%). CONCLUSIONS: Despite the possibility of a
nocebo effect, these results suggest that aripiprazole may be superior to placebo
in the long-term treatment of pediatric patients following stabilization with open-
label aripiprazole. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00194077.

Fisk, C., et al. (2015). "Response styles, bipolar risk, and mood in students: The
Behaviours Checklist." Psychol Psychother 88(4): 412-426.
OBJECTIVES: An Integrative Cognitive Model of mood swings and bipolar
disorder proposes that extreme positive and negative appraisals about internal
states trigger ascent and descent behaviours, contributing to the onset and
maintenance of mood swings. This study investigated the reliability and validity of
a new inventory, the Behaviours Checklist (BC), by measuring associations with
appraisals, response styles to positive and negative affect, bipolar risk, mania,
and depression. DESIGN: Correlational analogue study. METHODS: Students (N = 134)
completed the BC alongside measures of appraisals, response styles to positive and
negative mood, mania, depression, and hypomanic personality (bipolar risk).
RESULTS: The BC was of adequate reliability and showed good validity. Ascent
behaviours and appraisals predicted bipolar risk, whereas descent behaviours and
appraisals were associated with depression. CONCLUSIONS: Appraisals, ascent, and
descent behaviours may play an important role in the development and maintenance of
mood swings. Limitations and research recommendations are outlined. PRACTITIONER
POINTS: Extreme positive and negative appraisals of internal states, and subsequent
behavioural responses (ascent and descent behaviours), are associated with bipolar
risk and bipolar mood symptoms in a student sample. These processes are involved
with mood dysregulation in clinical populations as well as bipolar risk in
students, with implications for mood management.

Fleck, D. E., et al. (2012). "Functional MRI of sustained attention in bipolar

mania." Mol Psychiatry 17(3): 325-336.
We examined sustained attention deficits in bipolar disorder and associated
changes in brain activation assessed by functional magnetic resonance imaging
(fMRI). We hypothesized that relative to healthy participants, those with mania or
mixed mania would (1) exhibit incremental decrements in sustained attention over
time, (2) overactivate brain regions required for emotional processing and (3)
progressively underactivate attentional regions of prefrontal cortex. Fifty
participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison
subjects (HC group) received an fMRI scan while performing a 15-min continuous
performance task (CPT). The data were divided into three consecutive 5-min
vigilance periods to analyze sustained attention. Composite brain activation maps
indicated that both groups activated dorsal and ventral regions of an anterior-
limbic network, but the BP group exhibited less activation over time relative to
baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally
greater behavioral CPT sustained attention decrement and more bilateral amygdala
activation than the HC group, respectively. Instead of differential activation in
prefrontal cortex over time, as predicted in hypothesis 3, the BP group
progressively decreased activation in subcortical regions of striatum and thalamus
relative to the HC group. These results suggest that regional activation decrements
in dorsolateral prefrontal cortex accompany sustained attention decrements in both
bipolar and healthy individuals. Stable amygdala overactivation across prolonged
vigils may interfere with sustained attention and exacerbate attentional deficits
in bipolar disorder. Differential striatal and thalamic deactivation in bipolar
disorder is interpreted as a loss of amygdala (emotional brain) modulation by the
ventrolateral prefrontal-subcortical circuit, which interferes with attentional
maintenance.

Folsom, T. D. and S. H. Fatemi (2013). "The involvement of Reelin in

neurodevelopmental disorders." Neuropharmacology 68: 122-135.
Reelin is a glycoprotein that serves important roles both during development
(regulation of neuronal migration and brain lamination) and in adulthood
(maintenance of synaptic function). A number of neuropsychiatric disorders
including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's
disease and lissencephaly share a common feature of abnormal Reelin expression in
the brain. Altered Reelin expression has been hypothesized to impair neuronal
connectivity and synaptic plasticity, leading ultimately to the cognitive deficits
present in these disorders. The mechanisms for abnormal Reelin expression in some
of these disorders are currently unknown although possible explanations include
early developmental insults, mutations, hypermethylation of the promoter for the
Reelin gene (RELN), miRNA silencing of Reelin mRNA, FMRP underexpression and Reelin
processing abnormalities. Increasing Reelin expression through pharmacological
therapies may help ameliorate symptoms resulting from Reelin deficits. This article
is part of the Special Issue entitled 'Neurodevelopmental Disorders'.

Fornaro, M., et al. (2012). "The argument of antidepressant drugs in the treatment
of bipolar depression: mixed evidence or mixed states?" Expert Opin Pharmacother
13(14): 2037-2051.
INTRODUCTION: The role of antidepressant drugs in acute and maintenance
treatment of bipolar depression is a matter of debate that cannot be decided from
the evidence available in the current literature. AREAS COVERED: This review
includes two sections: in the first, important contributions from the current
literature, emphasizing randomized controlled trials (RCTs) and meta-analysis,
highlight current controversies and methodological issues; in the second, the
impact of mixed depressive features in bipolar depression is evaluated from a
psychopathological perspective. EXPERT OPINION: Methodological issues may
complicate evaluation of the evidence from RCTs regarding antidepressants and mixed
states. Moreover, nosological constructs may also contribute to the inconclusive
findings, by introducing heterogeneity in patient selection and diagnosis.
Acknowledging the impact of mixed features in the course of bipolar depression,
essentially by the careful reading of classical Kraepelinian contributions, could
enhance clinical management. This would in turn allow a more judicious use of
antidepressants, ideally helping to shed some light on the much controversial
'antidepressant-related suicidality', and help to further clarify the reasons for
the current literature discordance on this topic.

Fornaro, M., et al. (2016). "Does the "Silver Bullet" Lose its Shine Over the Time?
Assessment of Loss of Lithium Response in a Preliminary Sample of Bipolar Disorder
Outpatients." Clin Pract Epidemiol Ment Health 12: 142-157.
BACKGROUND: Though often perceived as a "silver bullet" treatment for bipolar
disorder (BD), lithium has seldom reported to lose its efficacy over the time.
OBJECTIVE: The aim of the present study was to assess cases of refractoriness
toward restarted lithium in BD patients who failed to preserve maintenance. METHOD:
Treatment trajectories associated with re-instituted lithium following loss of
achieved lithium-based maintenance in BD were retrospectively reviewed for 37 BD-I
patients (median age 52 years; F:M=17:20 or 46% of the total) over an 8.1-month
period on average. RESULTS: In our sample only 4 cases (roughly 11% of the total,
of whom F:M=2:2) developed refractoriness towards lithium after its
discontinuation. Thirty-three controls (F:M=15:18) maintained lithium response at
the time of re-institution. No statistically significant difference between cases
and controls was observed with respect to a number of demographic and clinical
features but for time spent before first trial ever with lithium in life (8.5 vs. 3
years; U=24.5, Z=-2.048, p=.041) and length of lithium discontinuation until new
therapeutic attempt (5.5 vs. 2 years; U=8, Z=-2.927, p=.003) between cases vs.
controls respectively. Tapering off of lithium was significantly faster among cases
vs. controls (1 vs. 7 days; U=22, Z=-2.187), though both subgroups had worrisome
high rates of poor adherence overall. CONCLUSION: Although intrinsic limitations of
the present preliminary assessment hamper the validity and generalizability of
overall results, stating the clinical relevance of the topic further prospective
research is warranted. The eventual occurrence of lithium refractoriness may indeed
be associated with peculiar course trajectories and therapeutic outcomes ultimately
urging the prescribing clinicians to put efforts in preserving maintenance of BD in
the absence of any conclusive research insight on the matter.

Fountoulakis, K. N. (2012). "Refractoriness in bipolar disorder: definitions and

evidence-based treatment." CNS Neurosci Ther 18(3): 227-237.
Defining refractoriness in bipolar disorder is complex and should concern and
include either every phase and pole or the disorder as a whole. The data on the
treatment of refractory bipolar patients are sparse. Combination and add-on studies
suggest that in acutely manic patients partial responders to lithium, valproate, or
carbamazepine, a good strategy would be to add haloperidol, risperidone,
olanzapine, quetiapine, or aripiprazole. Adding oxcarbazepine to lithium is also a
choice. There are no reliable data concerning the treatment of refractory bipolar
depressives and also there is no compelling data for the maintenance treatment of
refractory patients. It seems that patients stabilized on combination treatment
might do worse if shifted from combination. Conclusively there are only limited and
sometimes confusing data on the treatment of refractory bipolar patients. Further
focused research is necessary on this group of patients.

Fountoulakis, K. N., et al. (2016). "[Non-conventional pharmacological agents for

the treatment of bipolar disorder: Alpha systematic review of the evidence]."
Psychiatriki 27(4): 253-263.
Bipolar disorder (BD) has a complex and variable clinical picture which is
characterized by many different phacets and phases and as a result its
therapeutical options are also complex and often unsatisfactory. Typically the so-
called "mood stabilizers" are used in the treatment of BD and in this class lithium
and specific antiepileptics are included. The present study aimed to systematically
review the literature concerning the presence of randomized double blind clinical
trials of 'non conventional' pharmaceutical treatment options. The present
systematic review utilized the PRISMA method and searched the MEDLINE through
January 1st 2015 with the use of appropriate key words. In order to identify
randomized controlled trials- RCTs a combination of the words "bipolar", "manic",
"mania", "manic depression" and "manic depressive" with "randomized" was used.
Webpages with lists of trials were also searched including
http://clinicaltrials.gov and http://www.clinicalstudyresults.org as well as the
official webpages of all pharma companies with products marketed in the treatment
of BD. The reference lists of various review papers were also searched. The MEDLINE
was searched with the combination of the words "guidelines" or "algorithms" with
"mania", "manic", "bipolar", "manicdepressive" or "manic depression" in order to
identify articles with treatment guidelines. The reference list of these articles
were also scanned. From 3,284 papers which were initially traced, only 47 papers
were included in the present study. From those agents studied in acute mania,
tamoxifen is efficacious as monotherapy and as combination therapy with lithium and
other mood stabilizers, however its safety profile is relatively poor. Allopurinol
manifests efficacy in combination with lithium but not with other agents and its
safety profile is satisfactory. Methoxyprogesterone is efficacious in combination
with mood stabilizers and its safety profile is very good. In acute bipolar
depression the combinations of FEWP with carbamazepine and ketamine, modafinil,
pramipexole, pregnenolone and maybe armodafinil with mood stabilizers are
efficacious. The safety profile of these combinations is medium. The use of
celecoxib, lisdexamfetamine and memantine have negative data. Concerning the
maintenance treatment, the data are negative for memantine and for Nacetylcysteine.
Although most of the data concerning the usefulness of "non-conventional"
pharmacotherapeutic agents in the treatment of bipolar disorder are negative, it is
encouraging that those agents who have been proven efficacious probably exert their
therapeutic effect through pathways which differ from usual and probably different
from those classically considered in most biological models of bipolar illness. In
this way there constitute new paradigms and open new horizons in the understanding
of the disease.

Fountoulakis, K. N., et al. (2011). "Class effect of pharmacotherapy in bipolar

disorder: fact or misbelief?" Ann Gen Psychiatry 10(1): 8.
BACKGROUND: Anecdotal reports suggests that most clinicians treat medications
as belonging to a class with regard to all therapeutic indications; this means that
the whole 'class' of drugs is considered to possesses a specific therapeutic
action. The present article explores the possible existence of a true 'class
effect' for agents available for the treatment of bipolar disorder. METHODS: We
reviewed the available treatment data from randomized controlled trials (RCTs) and
explored 16 'agent class'/'treatment issue' cases for bipolar disorder. Four
classes of agents were examined: first-generation antipsychotics (FGAs), second-
generation antipsychotics (SGAs), antiepileptics and antidepressants, with respect
to their efficacy on four treatment issues of bipolar disorder (BD) (acute mania,
acute bipolar depression, maintenance against mania, maintenance against
depression). RESULTS: From the 16 'agent class'/' treatment issue' cases, only 3
possible class effects were detected, and they all concerned acute mania and
antipsychotics. Four effect cases have not been adequately studied (FGAs against
acute bipolar depression and in maintenance protection from depression, and
antidepressants against acute mania and protection from mania) and they all concern
treatment cases with a high risk of switching to the opposite pole, thus research
in these areas is poor. There is no 'class effect' at all concerning
antiepileptics. CONCLUSIONS: The available data suggest that a 'class effect' is
the exception rather than the rule in the treatment of BD. However, the possible
presence of a 'class effect' concept discourages clinicians from continued
scientific training and reading. Focused educational intervention might be
necessary to change this attitude.

Fountoulakis, K. N., et al. (2012). "Efficacy of pharmacotherapy in bipolar

disorder: a report by the WPA section on pharmacopsychiatry." Eur Arch Psychiatry
Clin Neurosci 262 Suppl 1: 1-48.
The current statement is a systematic review of the available data concerning
the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE
search was made concerning the treatment of BP (RCTs) with the names of treatment
options as keywords. The search was updated on 10 March 2012. The literature
suggests that lithium, first and second generation antipsychotics and valproate and
carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the
olanzapine-fluoxetine combination are also efficacious for treating bipolar
depression. Antidepressants should only be used in combination with an antimanic
agent, because they can induce switching to mania/hypomania/mixed states/rapid
cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and
aripiprazole are efficacious during the maintenance phase. Lamotrigine is
efficacious in the prevention of depression, and it remains to be clarified whether
it is also efficacious for mania. There is some evidence on the efficacy of
psychosocial interventions as an adjunctive treatment to medication.
Electroconvulsive therapy is an option for refractory patients. In acute manic
patients who are partial responders to lithium/valproate/carbamazepine, adding an
antipsychotic is a reasonable choice. The combination with best data in acute
bipolar depression is lithium plus lamotrigine. Patients stabilized on combination
treatment might do worse if shifted to monotherapy during maintenance, and patients
could benefit with add-on treatment with olanzapine, valproate, an antidepressant,
or lamotrigine, depending on the index acute phase. A variety of treatment options
for BP are available today, but still unmet needs are huge. Combination therapy may
improve the treatment outcome but it also carries more side-effect burden. Further
research is necessary as well as the development of better guidelines and
algorithms for the step-by-step rational treatment.

Fountoulakis, K. N., et al. (2013). "A systematic review of the evidence on the
treatment of rapid cycling bipolar disorder." Bipolar Disord 15(2): 115-137.
OBJECTIVE: Rapid cycling is associated with longer illness duration and
greater illness severity in bipolar disorder. The aim of the present study was to
review the existing published randomized trials investigating the effect of
treatment on patients with rapid cycling bipolar disorder. METHODS: A MEDLINE
search was conducted using combinations of the following key words: bipolar and
rapid or rapid-cycling or rapid cycling and randomized. The search was conducted
through July 16, 2011, and no conference proceedings were included. RESULTS: The
search returned 206 papers and ultimately 25 papers were selected for review. Only
six randomized, controlled trials specifically designed to study a rapid cycling
population were found. Most data were derived from post hoc analyses of trials that
had included rapid cyclers. The literature suggested that: (i) rapid cycling
patients perform worse in the follow-up period; (ii) lithium and anticonvulsants
have comparable efficacies; (iii) there is inconclusive evidence on the comparative
acute or prophylactic efficacy of the combination of anticonvulsants versus
anticonvulsant monotherapy; (iv) aripiprazole, olanzapine, and quetiapine are
effective against acute bipolar episodes; (v) olanzapine and quetiapine appear to
be equally effective to anticonvulsants during acute treatment; (vi) aripiprazole
and olanzapine appear promising for the maintenance of response of rapid cyclers;
and (vii) there might be an association between antidepressant use and the presence
of rapid cycling. CONCLUSION: The literature examining the pharmacological
treatment of rapid cycling is still sparse and therefore there is no clear
consensus with respect to its optimal pharmacological management. Clinical trials
specifically studying rapid cycling are needed in order to unravel the appropriate
management of rapid cycling bipolar disorder.

Fountoulakis, K. N., et al. (2011). "Aripiprazole monotherapy in the treatment of

bipolar disorder: a meta-analysis." J Affect Disord 133(3): 361-370.
INTRODUCTION: Aripiprazole is approved for the acute and maintenance
treatment of manic and mixed episodes associated with bipolar I disorder. The aim
of the present work was to review and meta-analyze the findings of all the
available randomized double-blind controlled trials (RCTs) on the efficacy of
aripiprazole in the treatment of bipolar disorder. MATERIAL AND METHODS:
Aripiprazole RCTs were identified with a systematic search of MEDLINE and
repositories. Standard meta-analytic techniques were applied. RESULTS: Two thousand
three hundred and three patients took part in the aripiprazole acute mania RCTs. At
week 3 the pooled aripiprazole vs. placebo effect size was 0.34 and the NNT was 6
for response and 14 for remission. On average, response started at day 3. Suicide
rates were negligible for all groups in mania but they were not reported in the
acute depression trials. The meta-analysis of acute bipolar depression RCTs
revealed a significant difference at week 8 with a weak effect size equal to 0.17.
The analysis of maintenance data suggest that the median survival time for the
aripiprazole group was not evaluable (very long), while the median survival time
for placebo was 118-203 days depending on the clinical subpopulation. DISCUSSION:
The current meta-analysis supports the usefulness of aripiprazole during all phases
of bipolar illness. Its effect against acute bipolar depression is weak and the
efficacy during the maintenance phase is proven only against new manic episodes in
patients with an index manic episode who had previously responded to aripiprazole
during the acute phase.

Fountoulakis, K. N., et al. (2016). "The International College of Neuro-

Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults
(CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm."
Int J Neuropsychopharmacol.
BACKGROUND: The current paper includes a systematic search of the literature,
a detailed presentation of the results, and a grading of treatment options in terms
of efficacy and tolerability/safety. MATERIAL AND METHODS: The PRISMA method was
used in the literature search with the combination of the words 'bipolar,' 'manic,'
'mania,' 'manic depression,' and 'manic depressive' with 'randomized,' and
'algorithms' with 'mania,' 'manic,' 'bipolar,' 'manic-depressive,' or 'manic
depression.' Relevant web pages and review articles were also reviewed. RESULTS:
The current report is based on the analysis of 57 guideline papers and 531
published papers related to RCTs, reviews, posthoc, or meta-analysis papers to
March 25, 2016. The specific treatment options for acute mania, mixed episodes,
acute bipolar depression, maintenance phase, psychotic and mixed features, anxiety,
and rapid cycling were evaluated with regards to efficacy. Existing treatment
guidelines were also reviewed. Finally, Tables reflecting efficacy and
recommendation levels were created that led to the development of a precise
algorithm that still has to prove its feasibility in everyday clinical practice.
CONCLUSIONS: A systematic literature search was conducted on the pharmacological
treatment of bipolar disorder to identify all relevant random controlled trials
pertaining to all aspects of bipolar disorder and graded the data according to a
predetermined method to develop a precise treatment algorithm for management of
various phases of bipolar disorder. It is important to note that the some of the
recommendations in the treatment algorithm were based on the secondary outcome data
from posthoc analyses.

Fox, H. A. (2015). "Continuation and maintenance electroconvulsive therapy--a

conceptual framework?" J ECT 31(2): e27-28.

Frank, F., et al. (2015). "Effectiveness of a brief psychoeducational group

intervention for relatives on the course of disease in patients after inpatient
depression treatment compared with treatment as usual--study protocol of a
multisite randomised controlled trial." BMC Psychiatry 15: 259.
BACKGROUND: Relapses and rehospitalisations are common after acute inpatient
treatment in depressive disorders. Interventions for stabilising treatment outcomes
are urgently needed. Psychoeducational group interventions for relatives were shown
to be suitable for improving the course of disease in schizophrenia and bipolar
disorders. A small Japanese monocentre randomised controlled trial also showed
promising results for depressive disorders. However, the evidence regarding
psychoeducation for relatives of patients with depressive disorders is unclear.
METHODS/DESIGN: The study is conducted as a two-arm multisite randomised controlled
trial to evaluate the incremental effect of a brief psychoeducational group
intervention for relatives as a maintenance treatment on the course of disease
compared to treatment as usual. Primary outcome is the estimated number of
depression-free-days in patients within one year after discharge from inpatient
treatment. 180 patients diagnosed with unipolar depressive disorders as well as one
key relative per patient will be included during inpatient treatment and randomly
allocated to the conditions at discharge. In the intervention group, relatives will
participate in a brief psychoeducational group intervention following the patient's
discharge. The intervention consists of four group sessions lasting 90 to 120 min
each. Every group session contains informational parts as well as structured
training in problem-solving. In both study conditions, patients will receive
treatment as usual. Patients as well as relatives will be surveyed by means of
questionnaires at discharge and three, six, nine and twelve months after discharge.
In addition to the primary outcome, several patient-related and relative-related
secondary outcomes will be considered and health economics will be investigated.
DISCUSSION: Our study will provide evidence on the incremental effect of a brief
psychoeducational intervention for relatives as a maintenance treatment after
inpatient depression treatment. Positive results may have a major impact on health
care for depression. TRIAL REGISTRATION: German Clinical Trials Register (DRKS):
DRKS00006819; Trial registration date: 2014 Oktober 31; Universal Trial Number
(UTN): U1111-1163-5391.
Frecska, E., et al. (2012). "The message of the survival curves: I. Composite
analysis of long-term treatment studies in bipolar disorder." Neuropsychopharmacol
Hung 14(3): 155-164.
RATIONALE: There is a shortage of studies analyzing the time course of
recurrent episodes and comparing effectiveness of long-term treatments in bipolar
disorder. 'Number needed to treat' (NNT) analyses have been proven to be useful for
clinically meaningful comparisons, but results vary considerably among studies. The
survival curves of different trials also show a great variability preventing
reliable conclusions on the time course of maintenance therapies. The variance of
survival analyses on long-term medication management can be reduced with increasing
the statistical power by combining the life-tables of individual studies. METHODS:
In this study the survival tables of 28 studies on maintenance treatment of bipolar
disorder were reconstructed from the published diagrams, and the numbers of
relapsed patients in the original studies were estimated for plotting composite
survival curves of an inactive, mono- and combination therapy arm. The review was
finally based on 5231 subjects. RESULTS: The resulting composite diagrams indicate
that within the first year 48% of patients on monotherapy, and 35% on combination
therapy experienced recurrence of any affective episode ('early relapsers'). The
rest of the patient population was affected by recurrences in a smaller rate over a
more extended period of time ('late relapsers'). For a favorable outcome at 40
months of episode prevention in bipolar disorder the NNT was 6 for mono- and 3 for
combination therapy. Log-rank analyses of the composite data supported the
effectiveness of both medication protocols over placebo, and the superiority of
drug combination over monotherapy; though there were some indications of decreased
efficacy in the two treatment arms after extended maintenance. CONCLUSIONS:
Composite analysis offers increased statistical power for studying the time course
of survival data. Mood episodes in bipolar disorder are likely to recur early on
and relapses in "real-life" can be more frequent than the rates published here. Our
results favor combination therapy for the long-term management of bipolar disorder.
Concerns are expressed that NNT analyses have significant limitations when applied
to recurring events with cumulative deterioration instead of cases where cumulative
improvement is expected over time.

Friedrich, U., et al. (2011). "The Na/K-ATPase is obligatory for membrane anchorage
of retinoschisin, the protein involved in the pathogenesis of X-linked juvenile
retinoschisis." Hum Mol Genet 20(6): 1132-1142.
Mutations in the RS1 gene that encodes the discoidin domain containing
retinoschisin cause X-linked juvenile retinoschisis (XLRS), a common macular
degeneration in males. Disorganization of retinal layers and electroretinogram
abnormalities are hallmarks of the disease and are also found in mice deficient for
the orthologous murine protein, indicating that retinoschisin is important for the
maintenance of retinal cell integrity. Upon secretion, retinoschisin associates
with plasma membranes of photoreceptor and bipolar cells, although the components
by which the protein is linked to membranes in vivo are still unclear. Here, we
show that retinoschisin fails to bind to phospholipids or unilamellar lipid
vesicles. A recent proteomic approach identified the Na/K-ATPase subunits ATP1A3
and ATP1B2 as binding partners of retinoschisin. We analyzed mice deficient for
retinoschisin (Rs1h(-/Y)) and ATP1B2 (Atp1b2(-/-)) to characterize the role of
Na/K-ATPase interaction in the organization of retinoschisin on cellular membranes.
We demonstrate that both the Na/K-ATPase and retinoschisin are significantly
reduced in Atp1b2(-/-) retinas, suggesting that retinoschisin membrane association
is severely impaired in the absence of ATP1A3 and ATP1B2 subunits. Conversely, the
presence of ATP1A3 and ATP1B2 are obligatory for binding of exogenously applied
retinoschisin to crude membranes. Also, co-expression of ATP1A3 and ATP1B2 is
required for retinoschisin binding to intact Hek293 cells. Taken together, our data
support a predominant role of Na/K-ATPase in anchoring retinoschisin to retinal
cell surfaces. Furthermore, altered localization of ATP1A3 and ATP1B2 is a notable
consequence of retinoschisin deficiency and thus may be an important downstream
aspect of cellular pathology in XLRS.
Frye, M. A., et al. (2015). "Randomized, placebo-controlled, adjunctive study of
armodafinil for bipolar I depression: implications of novel drug design and
heterogeneity of concurrent bipolar maintenance treatments." Int J Bipolar Disord
3(1): 34.
BACKGROUND: Some, but not all, prior investigations suggest armodafinil may
have utility as an adjunctive treatment in bipolar I depression. METHODS:
Multicenter, randomized, double-blind study in patients aged 18 to 65 years
experiencing a depressive episode despite maintenance therapy for bipolar I
disorder. Patients were randomized to receive adjunctive armodafinil 150 mg/day or
adjunctive placebo for 8 weeks. Primary efficacy outcome was change from baseline
in 30-Item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total
score at week 8. Safety and tolerability were monitored. RESULTS: Of 656 patients
screened, 399 were randomized, of whom 308 (77 %) were taking a protocol-allowed
mood stabilizer as monotherapy. The primary efficacy outcome did not reach
statistical significance; however, several secondary efficacy outcomes demonstrated
statistically significant advantages for adjunctive armodafinil (n = 197) over
adjunctive placebo (n = 196), including Clinical Global Impression of Severity of
Illness for depression (weeks 6, 8, and endpoint; all P < 0.05), Global Assessment
of Functioning (weeks 4, 8, and endpoint; all P < 0.02), IDS-C30 remitter rates
(week 8 and endpoint; both P < 0.02), and mean change from baseline in IDS-C30
total score at week 7 (P < 0.05). Adjunctive armodafinil and adjunctive placebo
were generally well tolerated. Although adjunctive armodafinil compared with
adjunctive placebo yielded a higher headache rate (15 vs 8 %), it yielded similar
(generally favorably low) rates of all-cause discontinuation (16 vs 16 %), adverse
event discontinuation (4 vs 5 %), nausea (6 vs 4 %), >/=7 % weight gain (2 vs 5 %),
anxiety (4 vs 3 %), insomnia (3 vs 2 %), sedation/somnolence (1 vs 1 %), and
hypomania (0 vs <1 %). CONCLUSIONS: In this study, adjunctive armodafinil compared
with adjunctive placebo in bipolar I depression did not separate in the primary
efficacy outcome but demonstrated advantages for several secondary efficacy
outcomes and was generally well tolerated. Additional research is warranted and
necessary to better identify clinical predictors (e.g., atypical depressive
symptoms, specific anti-manic/mood-stabilizing agents used) that would provide
optimized, individualized therapeutics for bipolar depression. TRIAL REGISTRATION:
ClinicalTrials.gov: NCT01305408.

Fu, D. J., et al. (2015). "Paliperidone palmitate once-monthly reduces risk of

relapse of psychotic, depressive, and manic symptoms and maintains functioning in a
double-blind, randomized study of schizoaffective disorder." J Clin Psychiatry
76(3): 253-262.
OBJECTIVE: Schizoaffective disorder is a complex illness for which optimal
treatment is not well established. Results of the first controlled, relapse-
prevention study of paliperidone palmitate once-monthly injectable (paliperidone
monthly) in schizoaffective disorder are presented. METHOD: The study was conducted
between September 20, 2010, and October 22, 2013. Patients with schizoaffective
disorder (confirmed by the Structured Clinical Interview for DSM-IV Axis I
Disorders) experiencing acute exacerbation of psychotic and depressive/manic
symptoms were stabilized with paliperidone monthly as monotherapy or as adjunctive
therapy to mood stabilizers or antidepressants and randomly assigned (1:1) to
paliperidone monthly or placebo in a 15-month, double-blind, relapse-prevention
phase. Randomization was stratified by administration as monotherapy or adjunctive
therapy and by study center. The primary endpoint was time to relapse. RESULTS: 334
patients were evaluated. Paliperidone monthly significantly delayed time to relapse
for psychotic, depressive, and manic symptoms compared with placebo (P < .001, log-
rank test). Relapse risk was 2.49 times greater for placebo (hazard ratio = 2.49;
95% CI, 1.55 to 3.99; P < .001, Cox proportional hazards model). Overall relapse
rates were 33.5% for placebo and 15.2% for paliperidone monthly. For monotherapy,
relapse risk was 3.38 times greater with placebo (P = .002), and for adjunctive
treatment it was 2.03 times greater with placebo (P = .021). Paliperidone monthly
was superior to placebo in maintaining functioning as measured by the Personal and
Social Performance scale (P = .014, mixed-model repeated-measures analysis). The
most common adverse events (placebo, paliperidone monthly) were increased weight
(4.7%, 8.5%), insomnia (7.1%, 4.9%), schizoaffective disorder (5.9%, 3.0%),
headache (3.5%, 5.5%), and nasopharyngitis (3.5%, 5.5%). Incidence of any
extrapyramidal-related adverse event was 7.1% for placebo and 8.5% for paliperidone
monthly. CONCLUSIONS: Paliperidone monthly as monotherapy or adjunctive therapy
significantly delayed psychotic, depressive, and/or manic relapses; reduced their
risk; and better maintained functioning in patients with schizoaffective disorder.
Results support the value of maintenance treatment with paliperidone monthly in
schizoaffective disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier:
NCT01193153.

Furukawa, T. A., et al. (2016). "Using the contribution matrix to evaluate complex
study limitations in a network meta-analysis: a case study of bipolar maintenance
pharmacotherapy review." BMC Res Notes 9: 218.
BACKGROUND: Limitations in the primary studies constitute one important
factor to be considered in the grading of recommendations assessment, development,
and evaluation (GRADE) system of rating quality of evidence. However, in the
network meta-analysis (NMA), such evaluation poses a special challenge because each
network estimate receives different amounts of contributions from various studies
via direct as well as indirect routes and because some biases have directions whose
repercussion in the network can be complicated. FINDINGS: In this report we use the
NMA of maintenance pharmacotherapy of bipolar disorder (17 interventions, 33
studies) and demonstrate how to quantitatively evaluate the impact of study
limitations using netweight, a STATA command for NMA. For each network estimate,
the percentage of contributions from direct comparisons at high, moderate or low
risk of bias were quantified, respectively. This method has proven flexible enough
to accommodate complex biases with direction, such as the one due to the enrichment
design seen in some trials of bipolar maintenance pharmacotherapy. CONCLUSIONS:
Using netweight, therefore, we can evaluate in a transparent and quantitative
manner how study limitations of individual studies in the NMA impact on the quality
of evidence of each network estimate, even when such limitations have clear
directions.

Gao, K., et al. (2010). "Predictors of non-stabilization during the combination

therapy of lithium and divalproex in rapid cycling bipolar disorder: a post-hoc
analysis of two studies." Psychopharmacol Bull 43(1): 23-38.
OBJECTIVE: To study predictors of non-stabilization (i.e., not bimodally
stabilized for randomization or not randomized due to premature discontinuation)
during open-label treatment with lithium and divalproex in patients with rapid-
cycling bipolar disorder (RCBD) with or without comorbid recent substance use
disorders (SUDs). METHOD: Data from the open-label phase of two maintenance studies
were used. The reasons for non-stabilization were compared between patients with a
recent SUD and those without. Predictors for non-stabilization were explored with
logistic regression analyses. RESULTS: Of 149 patients with recent SUD and 254
without recent SUD enrolled into the open-label acute stabilization phase, 21% and
24% were stabilized and randomized, respectively. Compared to those without recent
SUD, patients with recent SUD were more likely to discontinue the study due to non-
adherence to the protocol, 53% versus 37% (OR = 1.92) or refractory
mania/hypomania, 15% versus 9% (OR = 1.87), but less likely due to refractory
depression 16% versus 25% (OR = 0.58) or adverse events, 10% versus19% (OR = 0.44).
A history of recent SUDs, early life verbal abuse, female gender, and late onset of
first depressive episode were associated with increased risk for non-stabilization
with ORs of 1.85, 1.74, 1.10, and 1.04, respectively. CONCLUSIONS: During open
treatment with lithium and divalproex in patients with RCBD, a recent SUD, a
lifetime history of verbal abuse, female gender, and late onset of first depression
independently predicted nonstabilization. The non-stabilization for patients with
SUD was related to non-adherence and refractory mania/hypomania.
Garay, R. P., et al. (2014). "Bipolar disorder: recent clinical trials and emerging
therapies for depressive episodes and maintenance treatment." Drug Discov Today
19(11): 1792-1800.
Bipolar disorder (BD) is one of the world's ten most disabling conditions.
More options are urgently needed for treating bipolar depressive episodes and for
safer, more tolerable long-term maintenance treatment. We reviewed 30 recent
clinical trials in depressive episodes (eight tested compounds) and 14 clinical
trials in maintenance treatment (ten tested compounds). Positive results in Phase
III trials, regulatory approval and/or new therapeutic indications were obtained
with some of the developing drugs, particularly for depressive episodes. The
current BD pipeline is encouraging with promising new compounds, acting on novel
pharmacological targets and on specific aspects of bipolar depression.

Garcia-Blanco, A., et al. (2014). "Attentional biases toward emotional images in

the different episodes of bipolar disorder: an eye-tracking study." Psychiatry Res
215(3): 628-633.
Attentional biases toward emotional information may represent vulnerability
and maintenance factors in bipolar disorder (BD). The present experimental study
examined the processing of emotional information in BD patients using the eye-
tracking technology. Bipolar patients in their different states (euthymia, mania,
depression) simultaneously viewed four pictures with different emotional valence
(happy, neutral, sad, threatening) for 20s while their eye movements were
monitored. A group of healthy individuals served as the control. The data revealed
the following: (i) a decrease in attention to happy images in BD patients in their
depressive episodes compared to healthy individuals, and (ii) an increase in
attention to threatening images in BD patients (regardless of their episode)
relative to the healthy controls. These biases appeared in the late stages of
information processing and were sustained over the 20s interval. Thus, the present
findings reveal that attentional biases toward emotional information can be a key
feature of BD, in that: (i) an anhedonic lack of sensitivity to positive stimuli
during the bipolar depressive episode may be considered a maintaining factor of
this clinical state, and (ii) the trait-bias toward threat, even in asymptomatic
patients, may reflect a marker of vulnerability in BD.

Geddes, J. R. and D. J. Miklowitz (2013). "Treatment of bipolar disorder." Lancet

381(9878): 1672-1682.
We review recent developments in the acute and long-term treatment of bipolar
disorder and identify promising future routes to therapeutic innovation. Overall,
advances in drug treatment remain quite modest. Antipsychotic drugs are effective
in the acute treatment of mania; their efficacy in the treatment of depression is
variable with the clearest evidence for quetiapine. Despite their widespread use,
considerable uncertainty and controversy remains about the use of antidepressant
drugs in the management of depressive episodes. Lithium has the strongest evidence
for long-term relapse prevention; the evidence for anticonvulsants such as
divalproex and lamotrigine is less robust and there is much uncertainty about the
longer term benefits of antipsychotics. Substantial progress has been made in the
development and assessment of adjunctive psychosocial interventions. Long-term
maintenance and possibly acute stabilisation of depression can be enhanced by the
combination of psychosocial treatments with drugs. The development of future
treatments should consider both the neurobiological and psychosocial mechanisms
underlying the disorder. We should continue to repurpose treatments and to
recognise the role of serendipity. We should also investigate optimum combinations
of pharmacological and psychotherapeutic treatments at different stages of the
illness. Clarification of the mechanisms by which different treatments affect sleep
and circadian rhythms and their relation with daily mood fluctuations is likely to
help with the treatment selection for individual patients. To be economically
viable, existing psychotherapy protocols need to be made briefer and more efficient
for improved scalability and sustainability in widespread implementation.
Geoffroy, P. A., et al. (2014). "Can the response to mood stabilizers be predicted
in bipolar disorder?" Front Biosci (Elite Ed) 6: 120-138.
Bipolar disorder (BD) is a severe chronic multifactorial disease that
requires maintenance therapy with mood stabilizers (MS). Even with medications, the
rate of response among patients with BD is low and the risk of relapse is high.
Therefore, in this context of the urgent need for reliable and reproducible
predictors of individual responses to MS, pharmacogenetics research is expected to
provide helpful progress. Most pharmacogenetic studies of MS have focused on the
response to lithium with several good putative candidate genes but informative
results are sparse. There have been few studies on valproate, lamotrigine or
atypical antipsychotics. Overall, the results of pharmacogenomics studies have not
provided sufficient data to change daily practices in BD significantly and further
investigation is warranted to identify highly relevant genetic predictors of
response their roles. Although progress still remains to be made, the clinical
assessment of a subject including the identification of specific individual
phenotypic and pharmacogenetic characteristics is likely to become a powerful
instrument for the development of personalized therapies.

Geoffroy, P. A., et al. (2012). "Combination therapy for manic phases: a critical
review of a common practice." CNS Neurosci Ther 18(12): 957-964.
All relevant guidelines recommend monotherapy as the initial treatment for
manic phases of bipolar disorder (BD), with combination therapy reserved for severe
cases or as a subsequent choice. However, in routine practice, monotherapy is often
not sufficiently effective for acute and/or maintenance therapy. As a consequence,
most patients are given combination therapies. An extensive search concerning
combination treatment for manic episodes was conducted for relevant international
randomized controlled studies, treatment guidelines and comprehensive reviews
published since 1980. The scientific literature is sufficiently rich to validate
the superiority of combination therapy over monotherapy in the manic phase in terms
of efficacy and prevention of relapse; its safety profile is acceptable. Side
effects are more frequent with combination therapy as a whole than with
monotherapy, and discontinuation rates due to adverse events are higher. Continued
administration of antipsychotics after a manic phase is controversial: drug
classification, the course of the disease and the predominant polarity should all
be considered before treatment is continued. Combinations including olanzapine and
asenapine and to a lesser extent risperidone are associated with weight gain, those
including quetiapine, haloperidol and asenapine with sedation, and those including
aripiprazole with akathisia. This review of literature leads us to suggest that
combination therapy including an atypical antipsychotic with lithium or valproate
may be considered as a first-line approach. An appropriate algorithm for making
decisions about combination treatment needs to be developed and included in future
guidelines.

Ghaleiha, A., et al. (2014). "Oral loading of sodium valproate compared to

intravenous loading and oral maintenance in acutely manic bipolar patients."
Neuropsychobiology 70(1): 29-35.
BACKGROUND: In patients suffering from bipolar disorders (BPD), we explored
to what extent oral loading of sodium valproate (SV) leads to more rapid symptom
improvement compared to intravenous loading and oral maintenance administration.
METHODS: Ninety patients (mean age: 35.00 years) with BPD and currently in an acute
manic state were randomly assigned to one of three study conditions: oral loading
(20 mg/kg oral single-dose SV on the first day, then 10-15 mg/kg SV daily, divided
dose), intravenous loading (20 mg/kg SV intravenous injection on the first day,
then 10-15 mg/kg orally, divided dose), or oral maintenance administration (15-20
mg/kg SV daily from the beginning) over the first 7 days of treatment. SV plasma
levels, side effects and symptoms were evaluated at baseline and on days 1, 3, and
7 after commencing treatment. RESULTS: There were significant Time-by-Group
interactions for symptom improvements, symptom severity, and SV plasma levels, with
positive values in the oral and intravenous loading conditions, compared to the
oral maintenance condition. Post hoc analyses showed that oral and intravenous
conditions led to similar improvements. CONCLUSIONS: Both oral and intravenous
loading of SV led to quicker and more efficient improvement and SV plasma levels as
compared to an oral maintenance regimen.

Gigante, A. D., et al. (2012). "Long-acting injectable antipsychotics for the

maintenance treatment of bipolar disorder." CNS Drugs 26(5): 403-420.
Depot antipsychotics have been used as a strategy to reduce non-adherence to
medications in schizophrenia and bipolar disorder (BD). This article reviews the
literature on the efficacy and safety of first- and second-generation depot
antipsychotics (FGDA and SGDA, respectively) for the maintenance treatment of BD.
Although FGDA have been studied in BD, they have not been approved for use in this
disease. Among the SGDA, only depot risperidone has been studied and approved for
the maintenance treatment of BD. We found eight studies on FGDA (three on
flupenthixol, two on depot haloperidol, one on fluphenazine and flupenthixol, two
on a mix of diverse antipsychotics) and ten studies on SGDA (all on depot
risperidone). Differences in efficacy and safety were found between the two classes
of depot antipsychotics. Although FGDA may be effective in reducing manic relapses,
they possibly increase the risk of worsening depression. Depot risperidone is
effective as a maintenance treatment in BD with effect noted predominantly for
preventing mania. However, no worsening in depression was observed. Depot
risperidone also is better tolerated than FGDA, mainly in relation to
extrapyramidal symptoms. Studies with the new depot antipsychotics, olanzapine
pamoate and paliperidone palmitate, are needed in BD patients. Further, there is
currently little information on the metabolic changes (apart from bodyweight gain)
that may occur with the use of depot risperidone in patients with bipolar disorder,
and this issue needs further investigation.

Gillhoff, K., et al. (2010). "Effects of a multimodal lifestyle intervention on

body mass index in patients with bipolar disorder: a randomized controlled trial."
Prim Care Companion J Clin Psychiatry 12(5).
OBJECTIVE: Patients with bipolar disorder are at increased risk of weight
gain, which in turn increases the risk for somatic disease and nonadherence to
maintenance therapy. Therefore, interventions addressing weight gain are expedient
for the management of this disorder. We set out to evaluate the effects of a
lifestyle intervention on body mass index (BMI) and cardiovascular and metabolic
parameters in patients with bipolar disorder undergoing mood-stabilizing
pharmacologic treatment. METHOD: Fifty outpatients with bipolar disorder undergoing
mood-stabilizing treatment participated in a randomized controlled trial (waiting
control group: n = 24 and multimodal lifestyle intervention group: n = 26). Groups
consisted of 2 cohorts (cohort 1: March 2005-February 2006; cohort 2: September
2005-August 2006). The intervention lasted 5 months and consisted of 11 group
sessions and weekly fitness training. BMI and body weight as well as cardiovascular
and metabolic parameters were determined at 3 assessment points: at pretreatment
baseline, at 5 months (end of treatment), and at 11 months (6-month follow-up).
RESULTS: Intention-to-treat analyses showed that the intervention significantly
reduced BMI over time (P = .03), with significant and stable mean differences in
BMI change between groups of 0.7 kg/m(2) (95% CI, 0.2-1.3) at 5 months and 0.8
kg/m(2) (95% CI, 0.1-1.6) at 11 months' follow-up assessment. The lifestyle
intervention had no significant effect on cardiovascular and metabolic parameters
(all nonsignificant). The BMI reduction was only seen in female patients (P = .
003). CONCLUSIONS: BMI in patients with bipolar disorder can be reduced with a
long-lasting effect by a multimodal lifestyle intervention. However, this effect
was only seen in female participants, indicating the need for gender-specific
interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00980863.

Gitlin, M. and M. A. Frye (2012). "Maintenance therapies in bipolar disorders."

Bipolar Disord 14 Suppl 2: 51-65.
 OBJECTIVE: Bipolar disorder is an inherently recurrent disorder, requiring
maintenance preventive treatments in the vast majority of patients. The authors
review the data on maintenance treatments in bipolar disorder, highlighting the
controlled trial literature. METHODS: Literature review using PubMed, Medline, and
a hand search of relevant literature. RESULTS: Over the last decade, a number of
effective maintenance treatments for bipolar disorder have been developed with an
evidence base for second-generation antipsychotics and some anticonvulsants.
Increasing numbers of patients, therefore, are appropriately treated with multiple
medications as a maintenance regimen. For some medications, maintenance treatment
has been demonstrated in randomized controlled trials for both monotherapy and in
combination with other mood stabilizers. Lithium continues as our oldest well-
established maintenance treatment in bipolar disorder with somewhat better efficacy
in preventing mania than depression. Lamotrigine, olanzapine, and quetiapine have
bimodal efficacy in preventing both mania and depression, although lamotrigine's
efficacy is more robust in preventing depression and olanzapine's efficacy is
greater in preventing mania. Aripiprazole, ziprasidone, and risperidone long-acting
injection all prevent mania, but not depression. Less controlled investigations
have suggested some evidence of maintenance mood stabilization with carbamazepine,
oxcarbazepine, and adjunctive psychotherapy. CONCLUSIONS: Despite the number of
agents with demonstrated efficacy as maintenance treatments in bipolar disorder,
optimal treatment regimens are still a combination of evidence-based therapy in
combination with individualized creative treatment algorithms.

Gitlin, M. J., et al. (2010). "Improving the design of maintenance studies for
bipolar disorder." Curr Med Res Opin 26(8): 1835-1842.
BACKGROUND: In contrast to the trial design of acute mania studies, there is
no standard design for bipolar maintenance studies. Over the past 15 years, the
design of monotherapy maintenance studies in bipolar disorder has evolved
significantly, but recent study designs continue to differ in important ways.
SCOPE: We reviewed the design of recent controlled bipolar maintenance studies,
using PubMed, from August 2006 to August 2009, examining the strengths and
weaknesses of different study design features. FINDINGS: Design differences are
sufficiently important that the disparate results across maintenance studies may
reflect either true differences in medication efficacy or the effects of these
design differences on outcome. Design elements such as recent episode polarity,
stabilization criteria, using enriched versus nonenriched samples, length of
stabilization before randomization, length of experimental phase, and recurrence
outcome criteria are critical factors that differ widely across studies and likely
play a role in study outcome. CONCLUSIONS: As consensus for trial designs for
bipolar maintenance therapy is developed, it will be easier to develop algorithms
for maintenance treatment based on results from studies as opposed to clinical
opinions.

Glerup, S., et al. (2016). "SorCS2 is required for BDNF-dependent plasticity in the
hippocampus." Mol Psychiatry 21(12): 1740-1751.
SorCS2 is a member of the Vps10p-domain receptor gene family receptors with
critical roles in the control of neuronal viability and function. Several genetic
studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and
attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-
d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-
deficient mice. This defect was traced to the ability of SorCS2 to form complexes
with the neurotrophin receptor p75NTR, required for pro-brain-derived neurotrophic
factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine
kinase TrkB to elicit long-term potentiation. Although the interaction with p75NTR
was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its
translocation to postsynaptic densities for synaptic tagging and maintenance of
synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB
autophosphorylation, and activation of downstream signaling cascades, impacting
neurite outgrowth and spine formation. Accordingly, Sorcs2-/- mice displayed
impaired formation of long-term memory, increased risk taking and stimulus seeking
behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our
results identify SorCS2 as an indispensable coreceptor for p75NTR and TrkB in
hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling
and mental disorders.

Goi, P. D., et al. (2015). "Pharmacological treatment and staging in bipolar

disorder: evidence from clinical practice." Rev Bras Psiquiatr 37(2): 121-125.
OBJECTIVES: Staging models for medical diseases are widely used to guide
treatment and prognosis. Bipolar disorder (BD) is a chronic condition and it is
among the most disabling disorders in medicine. The staging model proposed by
Kapczinski in 2009 presents four progressive clinical stages of BD. Our aim was to
evaluate pharmacological maintenance treatment across these stages in patients with
BD. METHODS: One hundred and twenty-nine subjects who met DSM-IV criteria for BD
were recruited from the Bipolar Disorders Program at Hospital de Clinicas de Porto
Alegre, Brazil. All patients were in remission. The subjects were classified
according to the staging model: 31 subjects were classified as stage I, 44 as stage
II, 31 as stage III, and 23 as stage IV. RESULTS: Patterns of pharmacological
treatment differed among the four stages (p = 0.001). Monotherapy was more frequent
in stage I, and two-drug combinations in stage II. Patients at stages III and IV
needed three or more medications or clozapine. Impairment in functional status
(Functioning Assessment Short Test [FAST] scale scores) correlated positively with
the number of medications prescribed. CONCLUSIONS: This study demonstrated
differences in pharmacological treatment in patients with stable BD depending on
disease stage. Treatment response can change with progression of BD. Clinical
guidelines could consider the staging model to guide treatment effectiveness.

Goldstein, B. I., et al. (2012). "Pharmacologic treatment of bipolar disorder in

children and adolescents." Child Adolesc Psychiatr Clin N Am 21(4): 911-939.
This review focuses mainly on published articles regarding the treatment of
school-aged children and adolescents with pediatric bipolar disorder. In light of
systematic reviews, large randomized controlled trial data are emphasized wherever
possible. This review addresses the treatment of acute manic/mixed episodes,
including combination treatment, the preliminary literature regarding bipolar
depression among youth, treatment in the face of comorbid conditions, and
maintenance treatment. Suggestions regarding future directions are offered. A
clinical vignette describing a teen with bipolar disorder is presented and bipolar
medications, dosing, efficacy, side effects, contraindications, and succinct
comments on each medication are summarized.

Gonzalez-Pinto, A., et al. (2010). "Assessment of medication adherence in a cohort

of patients with bipolar disorder." Pharmacopsychiatry 43(7): 263-270.
INTRODUCTION: This study aimed to identify factors associated with medication
adherence in bipolar disorder (BPD) patients. METHODS: EMBLEM is a 2-year,
prospective, observational study on the outcomes of BPD patients initiating or
changing treatment for a manic/mixed episode. Data were collected at baseline,
during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-
up (maintenance phase). Adherence was assessed by investigators at every visit.
Repeated measures logistic regression analyses identified variables associated with
adherence. RESULTS: Of 1,831 patients included in the analysis, 76.6% were adherent
and 23.4% were non-adherent with their BPD medication during the maintenance phase.
Patients were more likely to be adherent if they had insight into their illness at
week 12. Patients were less likely to be adherent if they had cannabis
abuse/dependence during the acute phase, work impairment or higher CGI
hallucinations/delusions at baseline DISCUSSION: Psychotic symptoms, poor insight,
cannabis abuse/dependence and work impairment are negatively related to medication
adherence during maintenance therapy of bipolar disorder. Patients with these
characteristics may need a different therapeutic approach.
Gonzalez-Pinto, A., et al. (2011). "Effectiveness of olanzapine monotherapy and
olanzapine combination treatment in the long term following acute mania--results of
a two year observational study in bipolar disorder (EMBLEM)." J Affect Disord
131(1-3): 320-329.
BACKGROUND: This study compared the 2-year outcomes of patients with a
manic/mixed episode of bipolar disorder taking olanzapine monotherapy or olanzapine
in combination with other agents. METHODS: EMBLEM (European Mania in Bipolar
Longitudinal Evaluation of Medication) is a 2-year, prospective, observational
study of clinical and functional outcomes of bipolar patients with an index
manic/mixed episode. The study consisted of two phases: acute (12 weeks) and
maintenance (follow-up over 2 years). The longitudinal outcome measure was the
Clinical Global Impression-Bipolar Disorder scale. Cox regression models compared
outcomes of both therapy groups using intention-to-treat and switching medication
analysis. Treatment-emergent adverse events were also assessed. RESULTS: 1076
patients were included in this analysis. 29% took olanzapine as monotherapy (n =
313) and 71% as combination (n = 763) at 12-weeks post-baseline (end of study acute
phase). After adjusting for patient characteristics using switching medication
analysis, only relapse rates differed (p = 0.01) in favour of monotherapy-treated
patients. There was no significant difference in rates of improvement, remission,
and recovery. Patients treated with combination therapy reported more tremor (OR
2.37, 95%CI 1.44-3.89) and polyuria (OR 3.08, 95%CI 1.45-6.54) treatment-emergent
events than monotherapy, although weight change was greater in the monotherapy
group. LIMITATIONS: Unknown confounding and potential selection bias may
differentially impact treatment outcomes. CONCLUSIONS: EMBLEM patients benefitted
from the selected therapy to a similar extent. Differences in patient
characteristics between those prescribed monotherapy and combination therapy appear
to be clinically relevant in the treatment decision. Physicians must balance the
benefits and risks when determining appropriate treatment for individual patients.

Goodwin, F. K., et al. (2011). "Maintenance treatment study designs in bipolar

disorder: do they demonstrate that atypical neuroleptics (antipsychotics) are mood
stabilizers?" CNS Drugs 25(10): 819-827.
In this conceptual review we argue that by certifying some of the atypical
neuroleptics (or, if one prefers, antipsychotics) as indicated for the
'maintenance' treatment of bipolar disorder, the US FDA has created confusion in
the field. These maintenance indications are based on studies using a 'relapse
prevention' design, a design that does not address whether the agents tested can
prevent new episodes of illness, i.e. recurrence prevention or true prophylaxis. We
found that the relapse prevention design fails to prove that these agents are mood
stabilizers because patients are pre-selected to respond to the study drug for an
acute mood episode (mania) and when they relapse, they do so into an episode of the
same polarity (i.e. mania). We believe that this represents withdrawal into the
same mood episode that patients experienced before the maintenance study began,
rather than prevention of a new mood episode, as research into the natural history
of bipolar disorder indicates that such new episodes typically are of the opposite
polarity. Thus, the inability of neuroleptics to prevent depression in such
maintenance studies reflects the general inability to prevent any new mood episode
recurrence (which we believe should be defined as 6 months or longer after the
index episode). If one defines a mood stabilizer, as we do, as a drug that prevents
new episodes of mania and depression in monotherapy, then these studies do not show
that atypical neuroleptics are mood stabilizers. Future maintenance research
studies in bipolar disorder should use the prophylaxis design (i.e. without pre-
selection of drug responders), rather than the relapse prevention design.

Goracci, A., et al. (2016). "Development, acceptability and efficacy of a

standardized healthy lifestyle intervention in recurrent depression." J Affect
Disord 196: 20-31.
BACKGROUND: Research evidence on the effects of integrated multifaceted
lifestyle interventions for depression is scanty. The aim of the present study is
to report on the development, acceptability and efficacy of a standardized healthy
lifestyle intervention, including exercise, eating habits, sleep hygiene and
smoking cessation in preventing relapses. METHODS: One hundred-sixty outpatients
with recurrent unipolar depression or bipolar disorder were recruited after
achieving full remission or recovery from the most recent depressive episode.
Patients were randomized to 3-months of usual care or to an intervention aimed at
promoting a healthy lifestyle (HLI), as an augmentation of pharmacological
maintenance treatment. Usual care consisted of clinical management visits. At the
end of the intervention, follow-up visits were scheduled at 3,6,9 and 12 months.
RESULTS: During the intervention phase, 1 relapse occurred in the HLI group and 4
in the control group. Over the 12 months of follow-up, relapses were 5 in the HLI
group and 16 in control group. Using an intent-to-treat approach, the overall
percentage of relapses was 6/81 (7.4%) in the HLI group vs. 20/79 (25.3%) in the
control group.. In a Kaplan-Meier survival analysis the risk of relapse was
significantly lower in patients receiving the HLI intervention (log-rank test,
p=0.003) over the 60 weeks of observation. The majority of patients assigned to HLI
adhered to the program, and were highly motivated throughout the intervention.
LIMITATIONS: The retention rate was low because patients were recruited during the
maintenance phase and the 1-year follow-up was relatively short to detect a long-
term effect of HLI. CONCLUSIONS: The HLI program proved to be efficacious in
preventing relapses. Given the absence of contraindications and its cost-
effectiveness in routine practice, the use of HLI should be encouraged to promote
the well-being of patients with recurrent depression.

Grande, I., et al. (2014). "Antipsychotic switching in bipolar disorders: a

systematic review." Int J Neuropsychopharmacol 17(3): 497-507.
With the increasingly widespread use of antipsychotics in bipolar disorder
(BD), switching among these agents and between antipsychotics and mood stabilizers
has become more common, in particular, since the introduction of the novel atypical
antipsychotics with mood stabilizer properties. This systematic review aims to
provide a comprehensive update of the current literature in BD about the switching
of antipsychotics, among them and between them and mood stabilizers, in acute and
maintenance treatment. We conducted a comprehensive, computerized literature search
using terms related to antipsychotic switching in BD in the PubMed/Medline,
PsycINFO, CINAHL database; the Cochrane Library and; the Clinicaltrials.gov web up
to January 9th, 2013 according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement. The search returned 4160 articles.
After excluding duplications, reviews, case reports and studies that did not fulfil
the selection criteria, 8 studies were included. Not only have few articles on
antipsychotic switching been published but also recruitment in most studies
included mixed samples of patients. In general, antipsychotic switching, regardless
of the route of drug administration, was well tolerated and no interference was
shown in antipsychotic effectiveness during the interchange of drugs. Metabolic
improvement was perceived when the switch involved antipsychotics with a low
metabolic risk profile. The evidence-base for antipsychotic switching in BD is
scant, and little controlled data is available. Switch from quetiapine to lithium
and from risperidone to olanzapine has proven successful. Switching to
antipsychotics with low metabolic risk had some positive impact on several safety
measures. In stabilized patients, the plateau cross-taper switch may be preferred.

Grande, I., et al. (2013). "Patterns of pharmacological maintenance treatment in a

community mental health services bipolar disorder cohort study (SIN-DEPRES)." Int J
Neuropsychopharmacol 16(3): 513-523.
Maintenance therapy in bipolar disorder (BD) is usually required to prevent
relapses and improve residual symptoms. Therefore, in this study, we describe
patterns of pharmacological maintenance treatment and identify associated clinical
features. This prospective multicentre epidemiological study recruited a cohort of
739 consecutive out-patients with clinically stable BD. Clinical stability was
assessed at baseline with the Clinical Global Impression scale for BD and
depressive symptoms with the Hamilton Depression Rating Scale. Psychotropic
medications were classified and analysed according to their mechanism as well as
use. Logistic regression models were used to examine the associations between
pharmacological strategies and clinical features. Longer time since last episode
[odds ratio (OR) 1.002, p < 0.0001] and family history of psychiatric disorders (OR
1.911, p = 0.028) were associated with lithium in monotherapy; manic polarity of
the most recent episode (OR 3.300, p = 0.006) and longer duration of clinical
stability (OR 1.009, p = 0.034) with antipsychotic in monotherapy; depressive
polarity of the most recent episode (OR 2.567, p = 0.003) and bipolar II disorder
diagnosis (OR 2.278, p = 0.008) with antidepressant combination; no ongoing
psychiatric co-morbidity (OR 0.230, p = 0.004) with lithium and anticonvulsant;
manic polarity of the most recent episode (OR 3.774, p < 0.0001) with lithium and
antipsychotic; manic polarity of the most recent episode (OR 2.907, p = 0.028) with
lithium, anticonvulsant and antipsychotic. The pharmacological patterns followed
published recommendations, except for the excessive use of antidepressants. This
study reveals clinical factors closely related to prescription patterns.

Grayson, D. R. and A. Guidotti (2013). "The dynamics of DNA methylation in

schizophrenia and related psychiatric disorders." Neuropsychopharmacology 38(1):
138-166.
Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder
(BP) with psychosis (BP+) express a complex symptomatology characterized by
positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies
of human SZ and BP+ brains show considerable alterations in the transcriptome of a
variety of cortical structures, including multiple mRNAs that are downregulated in
both inhibitory GABAergic and excitatory pyramidal neurons compared with non-
psychiatric subjects (NPS). Several reports show increased expression of DNA
methyltransferases in telencephalic GABAergic neurons. Accumulating evidence
suggests a critical role for altered DNA methylation processes in the pathogenesis
of SZ and related psychiatric disorders. The establishment and maintenance of CpG
site methylation is essential during central nervous system differentiation and
this methylation has been implicated in synaptic plasticity, learning, and memory.
Atypical hypermethylation of candidate gene promoters expressed in GABAergic
neurons is associated with transcriptional downregulation of the corresponding
mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent
reports indicate that the methylation status of promoter proximal CpG dinucleotides
is in a dynamic balance between DNA methylation and DNA hydroxymethylation.
Hydroxymethylation and subsequent DNA demethylation is more complex and involves
additional proteins downstream of 5-hydroxymethylcytosine, including members of the
base excision repair (BER) pathway. Recent advances in our understanding of altered
CpG methylation, hydroxymethylation, and active DNA demethylation provide a
framework for the identification of new targets, which may be exploited for the
pharmacological intervention of the psychosis associated with SZ and possibly BP+.

Gruber, J., et al. (2011). "Hooked on a feeling: rumination about positive and
negative emotion in inter-episode bipolar disorder." J Abnorm Psychol 120(4): 956-
961.
Rumination has been consistently implicated in the onset and maintenance of
depression. Less work has examined rumination in the context of bipolar disorder,
especially rumination about positive emotion. The present study examined rumination
about negative and positive emotion in interepisode bipolar disorder (BD; n = 39)
and healthy controls (CTL; n = 34). Trait rumination about positive and negative
emotion, as well as experiential and physiological responses to a rumination
induction, was measured. Illness course was also assessed for the BD group. Results
indicated that the BD group reported greater trait rumination about positive and
negative emotion compared with the CTL group, though no group differences emerged
during the rumination induction. For the BD group, trait rumination about positive
and negative emotion, as well as increased cardiovascular arousal (i.e., heart
rate), was associated with greater lifetime depression frequency; trait rumination
about positive emotion was associated with greater lifetime mania frequency. These
findings suggest that interepisode BD is associated with greater rumination about
positive and negative emotion, which in turn is associated with illness course.

Gruber, J., et al. (2013). "Letting go of the bad: deficit in maintaining negative,
but not positive, emotion in bipolar disorder." Emotion 13(1): 168-175.
Bipolar disorder is a disorder of emotion regulation. Less is known, however,
about the specific processes that foster the maintenance of such prolonged and
intense emotions-particularly positive-over time in this disorder. We investigated
group-related differences in the ability to maintain positive and negative emotion
representations over time using a previously validated emotion working memory task
(Mikels et al., 2005, 2008) among individuals with bipolar I disorder (BD; n = 29)
compared with both major depressive disorder (MDD; n = 29) and healthy control (n =
30) groups. Results revealed that the BD group exhibited a selective deficit in
maintaining negative-but not positive-emotions compared to both the MDD and the
control groups. The MDD and control groups did not differ significantly. These
findings suggest that the heightened magnitude and duration of positive emotion
observed in BD may, in part, be accounted for by difficulties maintaining negative
emotions.

Grunze, H. and J. M. Azorin (2014). "Clinical decision making in the treatment of

mixed states." World J Biol Psychiatry 15(5): 355-368.
OBJECTIVES: We reviewed the treatment of bipolar mixed states using efficacy
data of licensed and non-licensed physical or pharmacological treatments. METHODS:
We conducted a literature search to identify published studies reporting data on
mixed states. Grading was done using an in-house level of evidence and we compared
the efficacy with treatment recommendations of mixed states in current bipolar
disorder guidelines. RESULTS: A total of 133 studies reported data on mixed states,
and seven guidelines differentiate the acute treatment of mixed states from pure
states. The strongest evidence in treating co-occurring manic and depressive
symptoms was for monotherapy with aripiprazole, asenapine, extended release
carbamazepine, valproate, olanzapine, and ziprasidone. Aripiprazole was recommended
in three guidelines, asenapine in one, and carbamazepine and ziprasidone in two. As
adjunctive treatment, the strongest evidence of efficacy was for olanzapine plus
lithium or valproate. For maintenance, there is evidence for the efficacy of
monotherapy with valproate, olanzapine, and quetiapine. In the six guidelines
valproate or olanzapine are first line monotherapy options; one recommends
quetiapine. Recommended add-on treatments are lithium or valproate plus quetiapine.
CONCLUSIONS: There is a lack of studies designed to address the efficacy of
medications in mixed affective symptoms. Guidelines do not fully reflect the
current evidences.

Grunze, H., et al. (2013). "[Differential diagnosis of and pharmacotherapy for

bipolar disorder]." Fortschr Neurol Psychiatr 81 Suppl 1: S3-8.
Bipolar disorders constitute a group of frequent, chronic psychiatric
illnesses with a most severe impact on the patient's life. The course can be very
individual and heterogeneous, the best known and most frequent manifestations
include the classical bipolar I and bipolar II disorders. However, in Germany even
typical bipolar I disorders are underdiagnosed and, consequently, undertreated.
This is true despite the fact that the number of pharmacological treatment options
has rapidly increased during recent years, both in the field of anticonvulsants and
atypical antipsychotics. This supplies us today with new therapeutic strategies,
not only for acute mania, but also for bipolar depression and maintenance
treatment, and it is feasible to assume that there will be more options available
within the next few years.

Grunze, H., et al. (2013). "The World Federation of Societies of Biological

Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders:
update 2012 on the long-term treatment of bipolar disorder." World J Biol
Psychiatry 14(3): 154-219.
OBJECTIVES: These guidelines are based on a first edition that was published
in 2004, and have been edited and updated with the available scientific evidence up
to October 2012. Their purpose is to supply a systematic overview of all scientific
evidence pertaining to the long-term treatment of bipolar disorder in adults.
METHODS: Material used for these guidelines are based on a systematic literature
search using various data bases. Their scientific rigor was categorised into six
levels of evidence (A-F) and different grades of recommendation to ensure
practicability were assigned. RESULTS: Maintenance trial designs are complex and
changed fundamentally over time; thus, it is not possible to give an overall
recommendation for long-term treatment. Different scenarios have to be examined
separately: Prevention of mania, depression, or an episode of any polarity, both in
acute responders and in patients treated de novo. Treatment might differ in Bipolar
II patients or Rapid cyclers, as well as in special subpopulations. We identified
several medications preventive against new manic episodes, whereas the current
state of research into the prevention of new depressive episodes is less
satisfactory. Lithium continues to be the substance with the broadest base of
evidence across treatment scenarios. CONCLUSIONS: Although major advances have been
made since the first edition of this guideline in 2004, there are still areas of
uncertainty, especially the prevention of depressive episodes and optimal long-term
treatment of Bipolar II patients.

Guilmatre, A., et al. (2014). "The emerging role of SHANK genes in neuropsychiatric
disorders." Dev Neurobiol 74(2): 113-122.
The genetic heterogeneity of neuropsychiatric disorders is high, but some
pathways emerged, notably synaptic functioning. A large number of mutations have
been described in genes such as neuroligins, neurexins, and SHANK that play a role
in the formation and the maintenance of synapses. This review focuses on the
disorders associated with mutations in SHANK3 and the other members of its family,
SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of
glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome
(PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to
moderate to severe intellectual disability (ID) and poor language. The evolution of
patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has
been identified in patients with ASD with mild to severe ID. SHANK1 has been
associated with high-functioning autism in male patients, while carrier females
only display anxiety and shyness. Finally, based on neuropathological findings in
animal models and patients, a possible role of SHANK in Alzheimer's disease is
discussed. Altogether, this review describes the clinical trajectories associated
with different mutations of the SHANK genes and provides information to further
investigate the role of the SHANK genes in neuropsychiatric disorders.

Gurevich, M. I. and C. L. Robinson (2015). "Medication-free Alternatives for Long-

term Maintenance of Bipolar Disorder: A Case Series." Glob Adv Health Med 4(2): 53-
60.
Psychopharmacological treatment has been the mainstay in long-term
maintenance of bipolar disorder (BD) patients for the last 60 years. Conventionally
accepted treatment options are primarily based on expert opinion rather than on
well-executed, independently funded research. Investigation of maintaining patients
without medications using treatment alternatives has been neglected. This clinical
case series examines the outcomes of 7 BD patients who experienced a poor response
or significant side effects with conventional treatment modalities. Patients were
gradually and safely withdrawn from all medications. Treatment strategies were
based on an individualized holistic approach using herbs, nutritional supplements,
vitamins, amino acids, acupuncture, dietary recommendations, and behavioral
modifications. Multiple treatment modalities were combined addressing the
etiological causes for BD symptoms. Upon withdrawal from psychotropic medications,
patients were free of medication-induced side effects and obtained psychiatric
stability for at least 10 months. Further research is needed to investigate the
long-term outcomes of BD treatment modalities based on well-defined successful
outcome criteria, such as reduction in symptoms, improvement in quality of life,
overall health outcomes, and cost effectiveness.

Hadley, D., et al. (2011). "Safety, tolerability, and effectiveness of high doses
of adjunctive daily left prefrontal repetitive transcranial magnetic stimulation
for treatment-resistant depression in a clinical setting." J ECT 27(1): 18-25.
OBJECTIVE: Daily left prefrontal repetitive transcranial magnetic stimulation
(rTMS) recently received Food and Drug Administration (FDA) approval for the
treatment of depression and offers an alternative to traditional approaches. This
approval was based on a study using 3000 stimuli per day (15,000 stimuli per week)
in adults with unipolar depression not taking antidepressant medications. Several
meta-analyses suggest a dose-response relationship with TMS. This study was carried
out before US FDA approval to test the safety, tolerability, and effectiveness of
adjunctive high-dose left prefrontal rTMS in a clinical setting with particular
attention to safety of higher doses and potential interactions with antidepressant
medications, speed of response, and effects on suicidality. METHOD: We enrolled 19
patients who were in a current major depressive episode with treatment-resistant
unipolar or bipolar depression and treated them in their acute episode and in a
maintenance fashion for 18 months. The patients received daily left prefrontal rTMS
at 120% resting motor threshold, 10 Hz, 5 seconds on, and 10 seconds off and for a
mean of 6800 stimuli per session (34,000 stimuli per week), more than twice the
dose delivered in the pivotal FDA trial. All patients continued antidepressant
medication throughout the rTMS treatment; thus rTMS was an adjunctive treatment. We
measured adverse effects, depression, quality of life, suicidal ideation, and
social and physical functioning. RESULTS: These higher rTMS doses were well
tolerated without significant adverse effects or adverse events. All measured
dimensions showed improvement, with many showing improvement in 1 to 2 weeks. Of
perhaps most importance, suicidal ideation diminished in 67% of the patients after
just 1 week. CONCLUSIONS: These uncontrolled data suggest that higher doses of
daily left prefrontal rTMS may safely be used in outpatients with major depressive
episode even as an adjunctive treatment.

Hao, H., et al. (2015). "T2D and Depression Risk Gene Proteasome Modulator 9 is
Linked to Insomnia." Sci Rep 5: 12032.
Insomnia increases type-2 diabetes (T2D) risk. The 12q24 locus is linked to
T2D, depression, bipolar disorder and anxiety. At the 12q24 locus, the Proteasome-
Modulator 9 (PSMD9) single nucleotide polymorphisms (SNPs) rs74421874 [intervening
sequence (IVS) 3+nt460-G>A], rs3825172 (IVS3+nt437-C>T) and rs14259 (E197G-A>G) are
linked to: T2D, depression, anxiety, maturity-onset-diabetes-of the young 3/MODY3,
obesity, waist circumference, hypertension, hypercholesterolemia, T2D-macrovascular
disease, T2D-microvascular disease, T2D-neuropathy, T2D-carpal-tunnel syndrome,
T2D-nephropathy, T2D-retinopathy and non-diabetic retinopathy. PSMD9 SNP
rs1043307/rs14259 (E197G-A>G) plays a role in anti-depressant therapy response,
depression and schizophrenia. We aimed at determining PSMD9
rs74421874/rs3825172/rs14259 SNPs potential linkage to primary insomnia and sleep
hours in T2D families. We recruited 200 Italian T2D families phenotyping them for
primary insomnia and sleep hours per night. PSMD9-T2D-risk SNPs
rs74421874/rs3825172 and rs1043307/rs14259 were tested for linkage with insomnia
and sleep hours. Non-parametric-linkage analysis, linkage-disequilibrium-model
analysis, single-SNP analysis, cluster-based-parametric analysis, quantitative-
trait and variant-component analysis were performed using Merlin software. To
validate data, 1000 replicates were executed for the significant non-parametric
data. PSMD9 rs74421874 (IVS3+nt460-G>A), rs3825172 (IVS3+nt437-C>T) and
rs1043307/rs14259 (E197G-A>G) SNPs are linked to insomnia in our Italian families.

Hardeland, R. (2016). "Melatonin and Synthetic Melatoninergic Agonists in

Psychiatric and Age-associated Disorders: Successful and Unsuccessful Approaches."
Curr Pharm Des 22(8): 1086-1101.
 Melatonin and the following approved or investigational synthetic
melatoninergic agonists are compared with regard to half-life, receptor affinity,
metabolism and additional properties: TIK-301, piromelatine, GG-012, AH-001, AH-
017, agomelatine, ramelteon, GR 196429, MA-2, tasimelteon, UCM765, and UCM924.
Apart from restrictions from the respective approvals, theoretical limits of
treatment are outlined as they result from chronobiological, genetic, epigenetic,
degenerative or toxicological considerations. Melatoninergic agonists have been
shown to reliably entrain circadian rhythms, if chronobiological phase response
rules are followed. This allows the treatment of dysphased rhythms, circadian
rhythm sleep disorders, and forms of depression with an etiology of circadian
dysfunction, such as bipolar disorder and seasonal affective disorders. Entrainment
and induction of sleep onset requires only short actions, with low doses of
immediate-release melatonin likely to be sufficient. However, sleep maintenance is
poorly supported by any of the agonists, despite statistically demonstrable
effects. The combinations of melatoninergic properties with the inhibition of 5-
HT2C receptors, as in agomelatine and TIK-30, may result in moderate direct
antidepressive actions. Other limits of a successful treatment can arise from
genetic or epigenetic silencing of melatonin receptor genes, perhaps also from
imbalances between parallel signaling pathways in receptor mutants, and from
neurodegeneration, especially in the suprachiasmatic nucleus. Variants of circadian
clock genes cause rhythm deviations that may be corrected by melatoninergic
treatment, provided that the spontaneous oscillation period is not beyond the
entrainment range. Caveats concerning melatonin's roles as an immune modulator and
in certain pathologies, such as Parkinson's disease, as well as toxicological
considerations for agonists and their metabolites are also addressed.

Haroutunian, V., et al. (2014). "Myelination, oligodendrocytes, and serious mental

illness." Glia 62(11): 1856-1877.
Historically, the human brain has been conceptually segregated from the
periphery and further dichotomized into gray matter (GM) and white matter (WM)
based on the whitish appearance of the exceptionally high lipid content of the
myelin sheaths encasing neuronal axons. These simplistic dichotomies were
unfortunately extended to conceptually segregate neurons from glia, cognition from
behavior, and have been codified in the separation of clinical and scientific
fields into medicine, psychiatry, neurology, pathology, etc. The discrete
classifications have helped obscure the importance of continual dynamic
communication between all brain cell types (neurons, astrocytes, microglia,
oligodendrocytes, and precursor (NG2) cells) as well as between brain and periphery
through multiple signaling systems. The signaling systems range from
neurotransmitters to insulin, angiotensin, and multiple kinases such a glycogen
synthase kinase 3 (GSK-3) that together help integrate metabolism, inflammation,
and myelination processes and orchestrate the development, plasticity, maintenance,
and repair that continually optimize function of neural networks. A more
comprehensive, evolution-based, systems biology approach that integrates brain,
body, and environmental interactions may ultimately prove more fruitful in
elucidating the complexities of human brain function. The historic focus on
neurons/GM is rebalanced herein by highlighting the importance of a systems-level
understanding of the interdependent age-related shifts in both central and
peripheral homeostatic mechanisms that can lead to remarkably prevalent and
devastating neuropsychiatric diseases. Herein we highlight the role of glia,
especially the most recently evolved oligodendrocytes and the myelin they produce,
in achieving and maintaining optimal brain function. The human brain undergoes
exceptionally protracted and pervasive myelination (even throughout its GM) and can
thus achieve and maintain the rapid conduction and synchronous timing of neural
networks on which optimal function depends. The continuum of increasing myelin
vulnerability resulting from the human brain's protracted myelination underlies
underappreciated communalities between different disease phenotypes ranging from
developmental ones such as schizophrenia (SZ) and bipolar disorder (BD) to
degenerative ones such as Alzheimer's disease (AD). These shared vulnerabilities
also expose significant yet underexplored opportunities for novel treatment and
prevention approaches that have the potential to considerably reduce the tremendous
burden of neuropsychiatric disease.

Hartono, B., et al. (2012). "A novel finding of the atrial substrate properties and
long-term results of catheter ablation in chronic atrial fibrillation patients with
left atrial spontaneous echo contrast." J Cardiovasc Electrophysiol 23(3): 239-246.
BACKGROUND: The atrial substrate in chronic atrial fibrillation (AF) patients
with a left atrial spontaneous echo contrast (LASEC) has not been previously
reported. The aim of this study was to investigate the atrial substrate properties
and long-term follow-up results in the patients who received catheter ablation of
chronic AF. METHODS: Of 36 consecutive patients with chronic AF who received a
stepwise ablation approach, 18 patients with an LASEC (group I) were compared with
18 age-gender-left atrial volume matched patients without an LASEC (group II). The
atrial substrate properties including the weighted peak-to-peak voltage, total
activation time during sinus rhythm (SR), dominant frequency (DF), and complex
fractionated electrograms (CFEs) during AF in the bi-atria were evaluated. RESULT:
The left atrial weighted bipolar peak-to-peak voltage (1.0 +/- 0.6 vs 1.6 +/- 0.7
mV, P = 0.04), total activation time (119 +/- 20 vs 103 +/- 13 ms, P < 0.001) and
DF (7.3 +/- 1.3 vs 6.6 +/- 0.7 Hz, P < 0.001) differed between group I and group
II, respectively. Those parameters did not differ in the right atrium. The bi-
atrial CFEs (left atrium: 89 +/- 24 vs 92 +/- 25, P = 0.8; right atrium: 92 +/- 25
vs 102 +/- 3, P = 0.9) did not differ between group I and group II, respectively.
After a mean follow-up of 30 +/- 13 month, there were significant differences in
the antiarrhythmic drugs (1.1 +/- 0.3 vs 0.7 +/- 0.5, P = 0.02) needed after
ablation, and recurrence as persistent AF (92% vs 50%, P = 0.03) between group I
and group II, respectively. After multiple procedures, there were more group II
patients that remained in SR, when compared with group I (78% vs 44%, P = 0.04).
CONCLUSION: There was a poorer atrial substrate, lesser SR maintenance after
catheter ablation and need for more antiarrhythmic drugs in the chronic AF patients
with an LASEC when compared with those without an LASEC.

Harvey, A. G. (2011). "Sleep and circadian functioning: critical mechanisms in the

mood disorders?" Annu Rev Clin Psychol 7: 297-319.
Evidence for the importance of sleep in the mood disorders has mushroomed
over the past decade. Among adolescents and adults with a mood disorder, sleep
disturbance is a risk factor for episodes, can contribute to relapse, has an
adverse impact on emotion regulation, is critical for cognitive functioning,
compromises health, and may contribute to substance use comorbidity and
suicidality. This evidence has triggered a shift away from viewing sleep
disturbance as an epiphenomenon, toward viewing sleep disturbance as an important
but under-recognized mechanism in the multifactorial cause and maintenance of the
mood disorders. Because the biology underpinning the sleep and circadian system is
an open system, readily influenced by inputs from the environment, sleep in the
mood disorders represents a unique and exciting domain for interdisciplinary
research across behavioral, social, cognitive, and neurobiological levels of
explanation. Together, the accumulated evidence has informed a range of novel,
powerful, simple, and inexpensive treatments with potential for massive
improvements to public health, including improving quality of life, reducing length
and severity of episodes, and reducing the risk of subsequent episodes in the large
number of individuals who suffer from mood disorders.

Harvey, A. G., et al. (2015). "Treating insomnia improves mood state, sleep, and
functioning in bipolar disorder: a pilot randomized controlled trial." J Consult
Clin Psychol 83(3): 564-577.
OBJECTIVE: To determine if a treatment for interepisode bipolar disorder I
patients with insomnia improves mood state, sleep, and functioning. METHOD:
Alongside psychiatric care, interepisode bipolar disorder I participants with
insomnia were randomly allocated to a bipolar disorder-specific modification of
cognitive behavior therapy for insomnia (CBTI-BP; n = 30) or psychoeducation (PE; n
= 28) as a comparison condition. Outcomes were assessed at baseline, the end of 8
sessions of treatment, and 6 months later. This pilot was conducted to determine
initial feasibility and generate effect size estimates. RESULTS: During the 6-month
follow-up, the CBTI-BP group had fewer days in a bipolar episode relative to the PE
group (3.3 days vs. 25.5 days). The CBTI-BP group also experienced a significantly
lower hypomania/mania relapse rate (4.6% vs. 31.6%) and a marginally lower overall
mood episode relapse rate (13.6% vs. 42.1%) compared with the PE group. Relative to
PE, CBTI-BP reduced insomnia severity and led to higher rates of insomnia remission
at posttreatment and marginally higher rates at 6 months. Both CBTI-BP and PE
showed statistically significant improvement on selected sleep and functional
impairment measures. The effects of treatment were well sustained through follow-up
for most outcomes, although some decline on secondary sleep benefits was observed.
CONCLUSIONS: CBTI-BP was associated with reduced risk of mood episode relapse and
improved sleep and functioning on certain outcomes in bipolar disorder. Hence,
sleep disturbance appears to be an important pathway contributing to bipolar
disorder. The need to develop bipolar disorder-specific sleep diary scoring
standards is highlighted.

Haskett, R. F. and C. Loo (2010). "Adjunctive psychotropic medications during

electroconvulsive therapy in the treatment of depression, mania, and
schizophrenia." J ECT 26(3): 196-201.
Current guidelines regarding concomitant antidepressants during
electroconvulsive therapy (ECT) are inconsistent. Although the American Psychiatric
Association Task Force on ECT discouraged combination antidepressant treatment,
owing to the minimal evidence for enhanced efficacy and concern about increased
adverse effects, combination treatment is recommended and considered routine for
many practitioners in the United States and other parts of the world. Considering
the increasing levels of treatment resistance among patients referred for ECT and
the high relapse rate after acute ECT, the role of concomitant antidepressant
pharmacotherapy during ECT should be reevaluated. More research, however, is needed
to explore the impact of administering specific antidepressants during acute and
maintenance ECT (M-ECT), on antidepressant efficacy and cognitive adverse effects.
This will require appropriately controlled studies of ECT medication combinations
that include attention to a range of cognitive function measures and clinical
response. In addition, the role of combination ECT and psychotropic medication in
the treatment of mania and schizophrenia continues to receive attention,
particularly in those patients who have shown inadequate responses to psychotropic
medication alone. Although there is insufficient evidence to support the routine
addition of antipsychotic medications to ECT during the treatment of acute mania,
the literature suggests that it is unnecessary to discontinue antipsychotic
medication when ECT is added to the treatment of a manic patient that has been
unresponsive to pharmacological treatment. Despite the lack of well-controlled
studies, the existing literature suggests that combination ECT and antipsychotic
treatment is a useful option for patients with schizophrenia who are unresponsive
to pharmacological interventions alone, and its adverse effect profile does not
seem different from that seen with ECT alone.

Haslemo, T., et al. (2012). "UGT1A4*3 encodes significantly increased

glucuronidation of olanzapine in patients on maintenance treatment and in
recombinant systems." Clin Pharmacol Ther 92(2): 221-227.
Olanzapine, a world leader in antipsychotic drugs, is used in the treatment
of schizophrenia and bipolar disorder. There is considerable interpatient
variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by
uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated
retrospectively in patient samples taken for routine therapeutic drug monitoring
(TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed
that patients who were heterozygous as well as those who were homozygous for the
UGT1A4*3 allelic variant had significantly higher concentrations of the major
metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P <
0.001), respectively). This finding was in line with the significant increases in
glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48)
as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast,
serum concentrations of the parent drug were not significantly influenced by UGT1A4
genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a
major contributor to interpatient variability in olanzapine levels. However, with
respect to other drugs for which UGT1A4 has a dominant role in clearance, increased
glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug
exposure.

Hawke, L. D., et al. (2014). "Reducing stigma toward people with bipolar disorder:
impact of a filmed theatrical intervention based on a personal narrative." Int J
Soc Psychiatry 60(8): 741-750.
BACKGROUND: Stigma toward people with bipolar disorder (BD) is pervasive and
can have many negative repercussions. Common approaches to stigma reduction include
education and intergroup contact. From this perspective, the Collaborative RESearch
Team to study psychosocial issues in Bipolar Disorder (CREST.BD) and Canadian
Network for Mood and Anxiety Treatments (CANMAT) partnered to develop an
intervention to combat stigma. The result is a personal narrative intervention that
combines contact, education and drama to educate audiences and dispel the myths
that drive stigma. AIM: This study reports on the impact of the CREST.BD-CANMAT
stigma-reduction intervention in filmed format. METHODS: A sample of 137
participants was recruited to view the film, including health-care service
providers, university students in a health-care-related course, people with BD and
their friends and family members and the general public. Participants were
evaluated for stigmatizing attitudes and the desire for social distance before and
after the intervention and 1 month later. RESULTS: For health-care service
providers, the intervention was associated with statistically significant
improvements in several categories of stigmatizing attitudes, with maintenance 1
month later. The impact was more modest for the other subsamples. Students
demonstrated progressive, significant improvements in the desire for (less) social
distance. Some improvements were observed among members of the BD community and the
general public, but these were limited and eroded over time. CONCLUSION: This study
demonstrated that a filmed dramatic intervention based on the lived experience of
BD has statistically significant, sustainable stigma-reduction impacts for health-
care service providers and more limited impacts for other target groups. This
intervention can be considered an effective tool for use in stigma-reduction
campaigns specifically targeting members of the health-care sector. Results are
discussed in the context of multi-component stigma-reduction campaigns and the
potential needs of target groups.

Hayes, J. F., et al. (2016). "Adverse Renal, Endocrine, Hepatic, and Metabolic
Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A
Population-Based Cohort Study." PLoS Med 13(8): e1002058.
BACKGROUND: There is limited, poorly characterized information about adverse
events occurring during maintenance treatment of bipolar disorder. We aimed to
determine adverse event rates during treatment with lithium, valproate, olanzapine,
and quetiapine. METHODS AND FINDINGS: We conducted a propensity score adjusted
cohort study using nationally representative United Kingdom electronic health
records from January 1, 1995, until December 31, 2013. We included patients who had
a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate
(n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood
stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid
disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus,
cardiovascular disease, and hepatotoxicity. The propensity score included important
demographic, physical health, and mental health predictors of drug treatment
allocation. The median duration of drug treatment was 1.48 y (interquartile range
0.64-3.43). Compared to patients prescribed lithium, those taking valproate,
olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or
more severe, following adjustment for propensity score, age, and calendar year, and
accounting for clustering by primary care practice (valproate hazard ratio [HR]
0.56; 95% confidence interval [CI] 0.45-0.69; p < 0.001, olanzapine HR 0.57; 95% CI
0.45-0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47-0.80; p < 0.001).
Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40-0.89; p
= 0.012) and olanzapine (HR 0.48; 95% CI 0.29-0.77; p = 0.003), compared to those
taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09-
0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13-0.73; p = 0.007) and hypercalcemia
(valproate HR 0.25; 95% CI 0.10-0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14-
0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07-0.73; p = 0.013) were also reduced
relative to lithium. However, rates of greater than 15% weight gain on valproate,
olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31-2.01; p <
0.001, olanzapine HR 1.84; 95% CI 1.47-2.30; p < 0.001, quetiapine HR 1.67; 95% CI
1.24-2.20; p < 0.001) than in individuals prescribed lithium, as were rates of
hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06-1.87; p =
0.017). We found no significant difference in rates of chronic kidney disease stage
4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or
hepatotoxicity. Despite estimates being robust following sensitivity analyses,
limitations include the potential for residual confounding and ascertainment bias
and an inability to examine dosage effects. CONCLUSIONS: Lithium use is associated
with more renal and endocrine adverse events but less weight gain than commonly
used alternative mood stabilizers. Risks need to be offset with the effectiveness
and anti-suicidal benefits of lithium and the potential metabolic side effects of
alternative treatment options.

Hayes, J. F., et al. (2016). "Lithium vs. valproate vs. olanzapine vs. quetiapine
as maintenance monotherapy for bipolar disorder: a population-based UK cohort study
using electronic health records." World Psychiatry 15(1): 53-58.
It is unclear which maintenance treatment for bipolar disorder is superior in
clinical practice. Randomized controlled head-to-head trials of available drugs
either do not exist or are inconclusive. We aimed to compare rates of monotherapy
treatment failure in individuals prescribed lithium, valproate, olanzapine or
quetiapine by a population-based cohort study using electronic health records.
5,089 patients with bipolar disorder were prescribed lithium (N=1,505), valproate
(N=1,173) olanzapine (N=1,366) or quetiapine (N=1,075) as monotherapy. Treatment
failure was defined as time to stopping medication or add-on of another mood
stabilizer, antipsychotic, antidepressant or benzodiazepine. In unadjusted
analyses, the duration of successful monotherapy was longest in individuals treated
with lithium. Treatment failure had occurred in 75% of those prescribed lithium by
2.05 years (95% CI: 1.63-2.51), compared to 0.76 years (95% CI: 0.64-0.84) for
those prescribed quetiapine, 0.98 years (95% CI: 0.84-1.18) for those prescribed
valproate, and 1.13 years for those prescribed olanzapine (95% CI: 1.00-1.31).
Lithium's superiority remained in a propensity score matched analysis; when
treatment failure was defined as stopping medication or add-on of a mood stabilizer
or antipsychotic; and when treatment failure was restricted to more than three
months after commencing the study drug. Lithium appears to be more successful as
monotherapy maintenance treatment than valproate, olanzapine or quetiapine. Lithium
is often avoided because of its side effect profile, but alternative treatments may
reduce the time to being prescribed more than one drug, with potential additive
side effects of these treatments.

Hayes, J. F., et al. (2016). "Self-harm, Unintentional Injury, and Suicide in

Bipolar Disorder During Maintenance Mood Stabilizer Treatment: A UK Population-
Based Electronic Health Records Study." JAMA Psychiatry 73(6): 630-637.
IMPORTANCE: Self-harm is a prominent cause of morbidity in patients with
bipolar disorder and is strongly associated with suicide. There is evolving
evidence that lithium use may reduce suicidal behavior, in addition to concerns
that the use of anticonvulsants may increase self-harm. Information is limited
about the effects of antipsychotics when used as mood stabilizer treatment. Rates
of unintentional injury are poorly defined in bipolar disorder, and understanding
drug associations with this outcome may shed light on mechanisms for lithium's
potential antisuicidal properties through reduction in impulsive aggression.
OBJECTIVE: To compare rates of self-harm, unintentional injury, and suicide in
patients with bipolar disorder who were prescribed lithium, valproate sodium,
olanzapine, or quetiapine fumarate. DESIGN, SETTING, AND PARTICIPANTS: This
investigation was a propensity score (PS)-adjusted and PS-matched longitudinal
cohort study in a nationally representative UK sample using electronic health
records data collected between January 1, 1995, and December 31, 2013. Participants
included all patients diagnosed as having bipolar disorder who were prescribed
lithium, valproate, olanzapine, or quetiapine as maintenance mood stabilizer
treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was any form of self-
harm. Secondary outcomes were unintentional injury and suicide. RESULTS: Of the
14396 individuals with a diagnosis of BPD, 6671 were included in the cohort, with
2148 prescribed lithium, 1670 prescribed valproate, 1477 prescribed olanzapine, and
1376 prescribed quetiapine as maintenance mood stabilizer treatment. Self-harm
rates were lower in patients prescribed lithium (205; 95% CI, 175-241 per 10000
person-years at risk [PYAR]) compared with those prescribed valproate (392; 95% CI,
334-460 per 10000 PYAR), olanzapine (409; 95% CI, 345-483 per 10000 PYAR), or
quetiapine (582; 95% CI, 489-692 per 10000 PYAR). This association was maintained
after PS adjustment (hazard ratio [HR], 1.40; 95% CI, 1.12-1.74 for valproate,
olanzapine, or quetiapine vs lithium) and PS matching (HR, 1.51; 95% CI, 1.21-
1.88). After PS adjustment, unintentional injury rates were lower for lithium
compared with valproate (HR, 1.32; 95% CI, 1.10-1.58) and quetiapine (HR, 1.34; 95%
CI, 1.07-1.69) but not olanzapine. The suicide rate in the cohort was 14 (95% CI,
9-21) per 10000 PYAR. Although this rate was lower in the lithium group than for
other treatments, there were too few events to allow accurate estimates.
CONCLUSIONS AND RELEVANCE: Patients taking lithium had reduced self-harm and
unintentional injury rates. This finding augments limited trial and smaller
observational study results. It supports the hypothesis that lithium use reduces
impulsive aggression in addition to stabilizing mood.

Heeren, O., et al. (2011). "[Psychopharmacological treatment of bipolar disorder in

Latin American]." Rev Psiquiatr Salud Ment 4(4): 205-211.
OBJECTIVE: This study assessed the treatment preferences among Latin-American
psychiatrists for their bipolar disorder patients and if these preferences reflect
the current guidelines. METHODS: We designed a survey comprised of fourteen
questions. All the questions were aimed at the treatment of bipolar I patients
only. We distributed the survey by hand or e-mail to psychiatrists in eight
different countries: Argentina, Brasil, Colombia, Costa Rica, Ecuador, Mexico, Peru
and Venezuela. Between May 2008 and June 2009, we were able to gather 1143 surveys.
RESULTS: As the initial choice of treatment for a bipolar patient who debuts with
mania, 61.3% choose a combination of an atypical antipsychotic and a mood
stabilizer. Lithium Carbonate (50%) was the first choice for a mood stabilizer in a
manic episode. Olanzapine (55.4%) was the initial antipsychotic of choice for the
treatment of acute mania. For the treatment of acute bipolar depression, 27% choose
Lamotrigineas their first choice. Most of the psychiatrists (74.8%) prescribe
antidepressants for the treatment of bipolar depression. For maintenance treatment
of bipolar depression most psychiatrists first choice would be Lamotrigine (50.3%).
Most of the psychiatrists (89.1%) prescribed two or more psychotropic drugs for the
maintenance treatment of their bipolar patients. CONCLUSIONS: There were some
similarities with the studies previously done in the US. It seems that for the most
part the Latin-American psychiatrists don't strictly follow the literature
guidelines that are published, but rather adapt the treatment to the specific case.
More longitudinal studies of prescribing patterns in bipolar disorder are needed to
corroborate these findings.

Heffner, J. L., et al. (2012). "Cigarette smoking and impulsivity in bipolar

disorder." Bipolar Disord 14(7): 735-742.
OBJECTIVES: There is a high prevalence of smoking among individuals with
bipolar disorder, yet there have been few efforts to identify potential
contributing factors as a means of improving prevention and treatment approaches.
The goal of this study was to examine the association between impulsivity and the
initiation or maintenance of smoking in bipolar disorder. METHODS: Participants
comprised 97 adolescents and adults, ages 16-50, with bipolar I disorder who were
experiencing a mixed or manic episode at the time of study enrollment. Participants
completed the Barratt Impulsiveness Scale-11 (BIS-11) as a self-report indicator of
trait impulsivity, and the Logan Stop-Signal Task (SST), Delayed Reward Task (DRT),
and Degraded Stimulus Continuous Performance Task (DSCPT) as behavioral measures of
impulsivity. RESULTS: Current smokers (34%) and former smokers (23%) generally
reported higher trait impulsivity on the BIS-11 than never smokers (43%), with
minimal evidence for differences among the two ever-smoking groups. No differences
in impulsivity by smoking status emerged on the behavioral measures. CONCLUSIONS:
Trait impulsivity is associated with the initiation, but not necessarily the
maintenance, of cigarette smoking in adolescents and adults with bipolar disorder.
Our findings provide no evidence that smoking is associated with impulsive
responding on cognitive tasks during a symptomatic period during which impulsivity
is elevated.

Hello, M., et al. (2010). "Use of thalidomide for severe recurrent aphthous
stomatitis: a multicenter cohort analysis." Medicine (Baltimore) 89(3): 176-182.
Severe recurrent aphthous stomatitis (SRAS) is a rare, disabling disorder of
unknown etiology. Thalidomide is an effective second-line therapy for SRAS, but is
suppressive rather than curative, and adverse events limit its use. Few reports
describe the efficacy, tolerance, and safety of thalidomide, and how it is actually
used as long-term (maintenance) therapy for SRAS. Therefore, we conducted this
study to describe thalidomide use in the real-life management of a cohort of
patients with SRAS. This multicenter retrospective cohort study covered a period of
5 years and 5 months (January 2003-May 2008). Patients who had started thalidomide
monotherapy for SRAS during the 2003-2006 period were eligible. Data were collected
from patients' medical charts and supplemented by patients' responses during a
targeted telephone interview. Ninety-two patients followed at 14 centers were
included: 76 had oral or bipolar aphthosis, and 16 had Behcet disease. Thalidomide
was rapidly effective: 85% (78/92) entered complete remission (CR) within a median
of 14 days. Response time was independent of the initial thalidomide dose (r =
0.04). Thalidomide was continued for > or =3 months (maintenance therapy) by 77/92
(84%) of the patients on 1 of 2 maintenance regimens: continuous therapy with
regular intake (60/77) or intermittent therapy in response to attacks (17/77).
Although intermittent therapy was less restrictive than continuous therapy, medical
supervision under the former was less rigorous. The median maintenance dose was 100
mg/week, and did not reflect the initial dose (r = 0.18). The intermittent-
treatment group's median dose was significantly lower and its median duration of
thalidomide intake significantly longer than for patients on continuous therapy (19
vs. 150 mg/wk; p < 0.0001, and 32 vs. 19 mo; p = 0.002, respectively). Adverse
events were reported by 84% (77/92) of patients. They were mostly mild (78% of
patients), but sometimes severe (21%). Nevertheless, after 40 months of follow-up,
60% of patients were still receiving continuous or intermittent maintenance therapy
with favorable efficacy/tolerance ratios. Despite its retrospective nature, this
detailed study provides novel information on the different ways thalidomide is used
as SRAS maintenance therapy in a large and unselected cohort of patients. Low-dose
maintenance regimens appear to be widely used, effective, and relatively well
tolerated. These observations suggest the value of undertaking a randomized trial
to assess various maintenance regimens.

Henry, J. M. and M. A. Fuller (2011). "Asenapine: a new antipsychotic option." J

Pharm Pract 24(5): 447-451.
Asenapine is a new psychopharmacologic agent approved for the acute and
maintenance treatment of schizophrenia and the acute and maintenance treatment of
manic and mixed episodes associated with bipolar I disorder. The efficacy of
asenapine in treating schizophrenia was evaluated in four 6-week studies in which
placebo and active controls (risperidone, olanzapine, and haloperidol) were used.
Two 3-week placebo-controlled trials examined the efficacy of asenapine and active
control (olanzapine) in the treatment of bipolar I disorder. Asenapine demonstrated
efficacy in relation to placebo for 2 of the acute schizophrenia trials and both
trials examining the acute treatment of bipolar I disorder. Several factors should
be examined when considering asenapine therapy in relation to other antipsychotics
including efficacy, atypicality of receptor binding, obstacles to administration
and compliance, and finally cost. No efficacy advantage is evident with asenapine
over other antipsychotic agents. Barriers to achieving compliance with asenapine
include the recommendations of twice daily dosing, the need to avoid food and
liquids for at least 10 minutes postadministration, the need for patient
cooperation with sublingual administration, and the low bioavailability of the
tablet if swallowed. Finally, no cost advantage is evident for using asenapine in
comparison to the already available generic risperidone or other soon-to-be generic
atypical antipsychotics.

Hermes, E. D., et al. (2013). "Use of second-generation antipsychotic agents for

sleep and sedation: a provider survey." Sleep 36(4): 597-600.
OBJECTIVES: Anecdotal evidence suggests that second-generation antipsychotic
agents are increasingly used to treat sleep problems. This study sought to quantify
the proportion of new prescriptions for second-generation antipsychotic agents
started for sleep/sedation and the correlates of such use. DESIGN: A cross-
sectional survey of provider decision making at the time second-generation
antipsychotic agents were prescribed, documenting the reasons for the medication,
patient demographics, psychiatric and medical diagnoses, patient health
characteristics, and provider background. SETTING: A single Veterans Affairs
Medical Center over a 20-month period. PARTICIPANTS: Prescribers of second-
generation antipsychotic agents. INTERVENTIONS: N/A. RESULTS: Seven hundred seven
(32.2%) of 2,613 surveys indicated sleep/sedation was at least one reason for using
a second-generation anti-psychotic agent, whereas for 266 (12.1%) it was the only
reason. Quetiapine was most frequently prescribed overall as well as for
sleep/sedation (47.0% and 73.6% respectively). Second-generation antipsychotic
agent use for sleep/sedation was unrelated to sociodemographic characteristics,
least likely in patients with schizophrenia or bipolar disorder, and most likely as
a newly started second-generation antipsychotic agent. CONCLUSION: Sleep/sedation
is a common reason given for new prescriptions of second-generation antipsychotic
agents. Quetiapine is most frequently used for this purpose. A greater
understanding of why providers use second-generation antipsychotic agents rather
than safer and less costly alternatives for sleep problems may advance the
development of interventions to reduce adverse effects.

Hill, S. K., et al. (2015). "Regressing to Prior Response Preference After Set
Switching Implicates Striatal Dysfunction Across Psychotic Disorders: Findings From
the B-SNIP Study." Schizophr Bull 41(4): 940-950.
Difficulty switching behavioral response sets is established in psychotic
disorders. In rodent models, prefrontal lesions cause difficulty initially
switching to new response sets (perseverative errors) while striatal lesions cause
difficulty suppressing responses to previous choice preferences (regressive
errors). Studies of psychotic disorders have not previously assessed these 2 error
types. Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP)
participants included probands with schizophrenia (N = 212), psychotic bipolar (N =
192), and schizoaffective disorder (N = 131), their first-degree relatives (N =
267,226,165 respectively), and healthy controls (N = 258). Participants completed
the Penn Conditional Exclusion Test (PCET) to assess cognitive set switching and
the Brief Assessment of Cognition in Schizophrenia (BACS) to assess generalized
neuropsychological dysfunction. All proband groups displayed elevated rates of
perseverative and regressive errors compared to controls. After correcting for
generalized cognitive deficits to identify specific deficits in set shifting and
maintenance, there were no significant group differences for perseverative errors,
while the increased rate of regressive errors remained significant. Level of
regressive errors was similar across proband groups with minimal correlations with
antipsychotic medication dose, clinical ratings, and demographic characteristics.
Relatives of schizophrenia patients showed increased rates of regressive errors,
but familiality of this trait was significant only in bipolar pedigrees. Regressive
errors were partially independent of generalized cognitive deficits, suggesting a
potentially informative and specific cognitive deficit across psychotic disorders.
Preclinical data indicate that this deficit could be related to altered function in
a neural system that may include the dorsal striatum or other elements of
frontostriatal systems.

Hirschowitz, J., et al. (2010). "The pharmacological treatment of bipolar disorder:

the question of modern advances." Harv Rev Psychiatry 18(5): 266-278.
INTRODUCTION: Lithium has been the mainstay of treatment for patients with
bipolar disorder in the United States since 1970. Major treatment guidelines
recommend lithium as a first-line treatment for mania and maintenance treatment of
bipolar disorder, yet lithium has fallen out of favor while other agents have grown
in popularity. The purpose of this review is to examine the evidence for treatments
that were available in 1970 and to determine if the field has made any significant
advance in the treatment of mania, bipolar depression, and maintenance. METHODS: We
conducted a MEDLINE search through 2009, and examined only English-language,
randomized/controlled, placebo, or comparison studies. Tolerability as a factor was
not considered for this review. RESULTS: Lithium, valproate, benzodiazepines, and
antipsychotics have been reported effective for mania-which was essentially the
state of the field in 1970. Despite an FDA indication for the use of lamotrigine
for depression and depression maintenance, the supporting evidence is conflicting.
For bipolar maintenance, the evidence is overwhelming in support of lithium and
very thin for valproate and carbamazepine. There is emerging evidence that several
atypical antipsychotics may have efficacy in prevention. DISCUSSION: The gold
standard for treating bipolar disorder in 1970 was lithium, and the gold standard
in 2009 remains lithium. Newer agents may increase our armamentarium to some
extent, but it is not clear if they represent a major advance in treatment. They
still need to be tested against the gold standard.

Hong, C. C., et al. (2015). "Amisulpride monotherapy may be a choice of maintenance

treatment for patients with both bipolar I disorder and metabolic syndrome." Aust N
Z J Psychiatry 49(8): 757-758.

Hong, J., et al. (2010). "The cost of relapse for patients with a manic/mixed
episode of bipolar disorder in the EMBLEM study." Pharmacoeconomics 28(7): 555-566.
BACKGROUND: Bipolar disorder (BD) is characterized by episodes of mania and
depression. The debilitating symptoms during an acute episode require intensive
treatment, frequently leading to inpatient psychiatric care, which places
significant demands on health and social care systems and incurs substantial costs.
However, no study to date has estimated the economic impact of relapse. OBJECTIVES:
To estimate the direct costs associated with relapse in the treatment of BD
following an acute manic or mixed episode over a 21-month follow-up period in
routine clinical practice in Europe, using data from a large, prospective,
observational study. METHODS: EMBLEM was a prospective, observational study on the
outcomes of patients with a manic/mixed episode of BD conducted in 14 European
countries. Patients eligible for analysis were those enrolled in the 21-month
maintenance phase of the study, following the 3-month acute phase. Relapse was
defined as achieving any one of the following criteria: (i) at least a one-point
increase in Clinical Global Impression - Bipolar Disorder (CGI-BP) overall score
from the previous visit, with a final rating of > or =4; (ii) inpatient admission
for an acute episode of BD; or (iii) psychiatrists' confirmation of relapse. Data
on healthcare resource use were recorded retrospectively for the four respective
periods (3-6, 6-12, 12-18 and 18-24 month visits). Multivariate analyses were
performed to compare the cost of resource use (inpatient stay, day care,
psychiatrist visits and medication) for those who relapsed during the 21-month
maintenance phase and those who never relapsed. A sensitivity analysis was also
conducted to examine the 6-month costs during relapse. The analyses were adjusted
for patient characteristics and took account of non-Normality of the cost data by
using a log link function. UK unit costs were applied to resource use. The analysis
was repeated after multiple imputation for missing data. All costs were presented
as year 2007/08 values. RESULTS: A total of 1379 patients completed all visits
during the maintenance phase and were eligible for inclusion in the present
analysis. Of these, over half (54.3%) experienced relapse during this period. A
total of 792 patients without any missing data were eventually included in the
final cost model. Costs incurred by patients who relapsed during the 21-month
maintenance phase were approximately double those incurred by patients who never
relapsed (pounds sterling 9140 vs pounds sterling 4457; p < 0.05). Of the cost
difference, 80.3% was accounted for by inpatient stay. Estimates on the economic
impact were higher (pounds sterling 11,781 vs pounds sterling 4789; p < 0.05) in
the additional analysis with imputed missing data. The impact of relapse was even
greater in the 6-month cost comparison. The average 6-month costs for patients who
relapsed were found to be about three times higher than for those who did not
relapse (pounds sterling 4083 vs pounds sterling 1298; p < 0.05). CONCLUSIONS: Our
findings confirm the significant economic impact of relapse in BD patients after an
acute manic or mixed episode, even when considering direct costs only. Such costs
were dominated by inpatient stay. Nevertheless, the use of UK unit costs requires
caution when interpreting this costing in the context of a specific country, as
resource use and the associated costs will differ by country.

Hu, C., et al. (2017). "Trajectories of body mass index change in first episode of
mania: 3-year data from the Systematic Treatment Optimization Program for Early
Mania (STOP-EM)." J Affect Disord 208: 291-297.
BACKGROUND: Overweight/obesity is common in patients with bipolar disorder
(BD). However, little is known about longitudinal trends in body mass index (BMI)
in patients with BD. Furthermore, most studies on the association between BMI and
clinical outcomes are restricted by retrospective and cross-sectional designs. This
study uses prospectively-gathered data from a first episode mania (FEM) cohort to
examine the trajectories of BMI change and analyze their association with clinical
outcomes during a 3-year period. METHODS: A total of 110 FEM patients receiving
maintenance treatment and 57 healthy subjects were included. The comparisons of BMI
trajectories were examined using linear mixed-effects models. The effects of BMI on
time to any mood episode were assessed by Cox proportional-hazards models. RESULTS:
The estimated mean BMI in FEM patients significantly increased from 24.0kg/m2 to
25.4kg/m2 within 6 months. FEM patients had a significant BMI increase trend over
the entire 3 years follow-up, which was not observed in the control group. No
significant difference in BMI trajectory between patient subgroups (baseline
normal-weight vs. overweight/obese; male vs. female) was observed. BMI increase
predicted an increased risk of recurrence during follow-up visits (HR=1.50, 95% CI:
1.06-2.13; p=0.02). LIMITATIONS: Naturalistic design does not allow the accurate
assessments of the impact of pharmacologic treatments on BMI. CONCLUSIONS: FEM
patients showed a significantly increased BMI trajectory compared to healthy
subjects. Furthermore, BMI increase is independently associated with an increased
risk of recurrence to a new mood episode during 3-year follow-up. Thus, weight
control prevention is needed in the early course of BD.

Husain, M. I., et al. (2017). "Pilot study of a culturally adapted psychoeducation

(CaPE) intervention for bipolar disorder in Pakistan." Int J Bipolar Disord 5(1):
3.
BACKGROUND: Despite the use of maintenance medication, recurrence rates in
bipolar affective disorder (BPAD) are high. To date, there are no clinical trials
that have investigated the use of psychological interventions in bipolar disorder
in Pakistan. AIM: The purpose of the study was to assess the feasibility and
acceptability of a culturally adapted bipolar psychoeducation programme (CaPE) in
Pakistan. METHODS: Thirty-four euthymic bipolar I and II outpatients were
randomized to either 12 weekly sessions of individual psychoeducation plus
Treatment As Usual (Intervention) or Treatment As Usual (TAU) (Control). Outcomes
were assessed using the Young Mania Rating Scale (YMRS), Beck Depression Inventory
(BDI), EuroQoL (EQ-5D), Bipolar Knowledge and Attitudes and Questionnaire (BKAQ),
and a self-reported measure of medication adherence (Morisky Medication Adherence
Scale-4 items, MMAS-4). Effect sizes were derived from baseline adjusted
standardized regression coefficients. RESULTS: Retention in the study was good, 80%
of patients in the TAU follow-up assessment and 100% of patients in the CaPE group
attended all 12 sessions. Patient satisfaction was higher in the CaPE group
relative to control (ES = 1.41). Further, there were large effect sizes shown for
CaPE versus TAU for medication adherence (MMAS-4: ES = 0.81), knowledge and
attitudes towards bipolar (BKAQ: ES = 0.68), mania (YMRS: ES = 1.18), depression
(BDI: ES = 1.17) and quality of life measures (EQ-5D: ES --> 0.88). CONCLUSIONS:
Culturally adapted psychoeducation intervention is acceptable and feasible, and can
be effective in improving mood symptoms and knowledge and attitudes to BPAD when
compared with TAU. Larger scale studies are needed to confirm our findings. TRIAL
REGISTRATION: Clinicaltrials.gov identifier NCT02210390.

Huuhka, K., et al. (2012). "One-year follow-up after discontinuing maintenance

electroconvulsive therapy." J ECT 28(4): 225-228.
OBJECTIVES: Electroconvulsive therapy (ECT) has been established as an
effective method in the treatment of severe depressive or psychotic disorders. Its
efficacy is greatest in severe major depressive disorder (MDD) with or without
psychotic symptoms. However, maintaining remission after a successful course of
short-term ECT is often difficult owing to resistance to medication in these
patients. Therefore, the relapse rate after short-term ECT is high; 40% to 60% of
patients relapse even with adequate antidepressant continuation therapy. The risk
of relapse is greatest during the first months after discontinuation of short-term
ECT. Continuation/maintenance (c/m) ECT is an option in maintaining remission, but
systematic data and clinical guidelines are lacking. The point at which to
discontinue this treatment has not been adequately established. METHODS: Altogether
45 consecutive patients treated with c/mECT after short-term ECT to prevent relapse
were followed up 1 year after discontinuation of this treatment. RESULTS: Twenty
(44%) of 45 patients relapsed during follow-up, all within the first 8 months.
Patients having a diagnosis other than MDD (bipolar disorder, depressive episode
type I, schizophrenia, and schizoaffective disorder) were more likely to relapse
than MDD patients. CONCLUSIONS: Almost half of the patients relapsed in 1 year
after discontinuation of c/mECT, most of these within the first 3 months and all
within the first 8 months. The risk of relapse is greater in the patients with
diagnoses other than MDD. When discontinuing c/mECT, patients should be carefully
followed up; and for those at risk of relapse, even permanent mECT should be
considered. To the best of our knowledge, the present study is the first to report
the prognosis of patients after discontinuing c/mECT.

Inal-Emiroglu, F. N., et al. (2015). "Correlations between amygdala volumes and

serum levels of BDNF and NGF as a neurobiological markerin adolescents with bipolar
disorder." J Affect Disord 182: 50-56.
BACKGROUND: The amygdala is repeatedly implicated as a critical component of
the neurocircuitry regulating emotional valence. Studies have frequently reported
reduced amygdala volumes in children and adolescents with bipolar disorder (BD).
Brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) play
critical roles in growth, differentiation, maintenance, and synaptic plasticity of
neuronal systems in adolescent brain development. The aim of the present study was
to assess amygdala volumesand its correlation with serum levels of NGF and BDNF in
euthymic adolescents with BD and healthy controls. METHODS: Using structural MRI,
we compared the amygdala volumes of 30 euthymic subjects with BD with 23 healthy
control subjects aged between 13 and 19 years during a naturalistic clinical
follow-up. The boundaries of the amygdala were outlined manually. Serum BDNF and
NGF levels were measured using sandwich-ELISA and compared between the study
groups. RESULTS: The right or left amygdala volume did not differ between the study
groups.The right and left amygdala volumes were highly correlated with levels of
BDNF in the combined BD group and the valproate-treated group.Both R and L amygdala
volumes were correlated with BDNF levels in healthy controls. The left amygdala
volumes were correlated with BDNF levels in the lithium-treated group. LIMITATIONS:
This cross-sectional study cannot inform longitudinal changes in brain structure.
Further studies with larger sample sizes are needed to improve reliability.
CONCLUSIONS: The correlations between amygdala volumes and BDNF levels might be an
early neuromarker for diagnosis and/or treatment response in adolescents with BD.

Iszaj, F. and Z. Demetrovics (2011). ""Unborn selves"--literature as self-therapy

in Virginia Woolf's work." Psychiatr Hung 26(1): 26-35.
The connection between mental disorders and creativity in writers, poets, and
other artists has been the subject of scientific interest for a long time. The aim
of the present study is to examine the relationship between Virginia Woolf's
bipolar disorder and her literary creativity. The authors summarize Virginia
Woolf's life, family background, and the course of her illness and examine their
influence on her work and creation. The authors try to present the complex process
in the course of which the work of art is born with the help of the unconscious and
conscious. In addition, the authors consider the effect of the development of her
illness on her creativity and the way in which she integrated her experiences,
anxieties, misconceptions, and hallucinations into art during decompensated
depression. Based on these, the authors would like to give an insight into the
writer's life and work, which can help us understand better Virginia Woolf's
personality, both from artistic and psychiatric point of view.

Ittasakul, P., et al. (2012). "Effectiveness of quetiapine plus lamotrigine

maintenance therapy in challenging bipolar disorder patients." J Affect Disord
137(1-3): 139-145.
OBJECTIVE: Assess quetiapine plus lamotrigine (QTP+LTG) combination
maintenance therapy effectiveness in challenging bipolar disorder (BD). METHOD:
Outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar
Disorder (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD
Clinical Monitoring Form were naturalistically prescribed QTP+LTG. RESULTS: Fifty-
four outpatients with challenging BD, taking in addition to QTP+LTG, a mean+/-SD of
2.1+/-1.6 (in 63.0% at least 2) other psychotropic and 2.3+/-1.9 non-psychotropic
prescription medications, had QTP+LTG maintenance trials. Median(mean+/-SD) QTP+LTG
duration was 401(730+/-756) days. Final QTP and LTG doses were 87.5(188+/-211) and
300(287+/-108) mg/day, respectively. Half (27/54) of patients discontinued QTP (in
19), LTG (in 6), or QTP+LTG (in 2), after 294(415+/-414) days - due to side-effects
in 10, inefficacy in seven, non-adherence in five, and other reasons in five.
42.6%(23/54) had additional pharmacotherapy intervention for emergent mood
symptoms, after 175(261+/-237) days, with at least one psychotropic added (in
16/54) or substantively (by >/=50%) increased (in 7/54). 55.6%(30/54) had recurrent
mood episodes, after 126(187+/-158) days, most often depressive (in 35.2%),
although 64.8%(35/54) were euthymic at final visit taking QTP+LTG. Sedation
increased significantly during treatment among those with side-effect
discontinuations, and 19.2%(10/52, all having QTP added to LTG) had clinically
significant (>/=7%) weight gain. LIMITATIONS: No placebo comparison group. Small
sample of predominantly female Caucasian insured outpatients taking complex
concurrent medication regimens. CONCLUSION: Additional studies are warranted to
confirm our preliminary observation that QTP+LTG maintenance may be effective in
patients with challenging BD.

Ivleva, E. I., et al. (2014). "Smooth pursuit eye movement, prepulse inhibition,
and auditory paired stimuli processing endophenotypes across the schizophrenia-
bipolar disorder psychosis dimension." Schizophr Bull 40(3): 642-652.
BACKGROUND: This study examined smooth pursuit eye movement (SPEM), prepulse
inhibition (PPI), and auditory event-related potentials (ERP) to paired stimuli as
putative endophenotypes of psychosis across the schizophrenia-bipolar disorder
dimension. METHODS: Sixty-four schizophrenia probands (SZP), 40 psychotic bipolar I
disorder probands (BDP), 31 relatives of SZP (SZR), 26 relatives of BDP (BDR), and
53 healthy controls (HC) were tested. Standard clinical characterization, SPEM,
PPI, and ERP measures were administered. RESULTS: There were no differences between
either SZP and BDP or SZR and BDR on any of the SPEM, PPI, or ERP measure. Compared
with HC, SZP and BDP had lower SPEM maintenance and predictive pursuit gain and ERP
theta/alpha and beta magnitudes to the initial stimulus. PPI did not differ between
the psychosis probands and HC. Compared with HC, SZR and BDR had lower predictive
pursuit gain and ERP theta/alpha and beta magnitudes to the first stimulus with
differences ranging from a significant to a trend level. Neither active symptoms
severity nor concomitant medications were associated with neurophysiological
outcomes. SPEM, PPI, and ERP scores had low intercorrelations. CONCLUSION: These
findings support SPEM predictive pursuit and lower frequency auditory ERP activity
in a paired stimuli paradigm as putative endophenotypes of psychosis common to SZ
and BD probands and relatives. PPI did not differ between the psychosis probands
and HC. Future studies in larger scale psychosis family samples targeting putative
psychosis endophenotypes and underlying molecular and genetic mediators may aid in
the development of biology-based diagnostic definitions.

Jager, M., et al. (2013). "[How sustainable is supported employment? A follow-up

investigation]." Neuropsychiatr 27(4): 196-201.
SUBJECT: The largest European multicenter randomized controlled trial to date
on the effectiveness of supported employment (EQOLISE) was conducted in six
European centres until 2005. It revealed that the intervention "individual
placement and support" was more effective than conventional prevocational training
services. The aim of this investigation was to assess the Zurich sample
(individuals with schizophrenic, schizoaffective or bipolar disorders) 24 months
after termination of the EQOLISE trial in terms of working situation, income, and
hospital admissions. More favorable outcomes concerning these parameters were
assumed for the intervention group. METHODS: Assessment of the working situation
and psychiatric hospitalizations since the end as well as the development of
salaries since the start of EQOLISE. Comparisons between groups and illustration of
incomes using a random coefficient model were conducted. RESULTS: 50% of the
original sample could be assessed. All subjects who worked in competitive
workplaces at the end of EQOLISE were met in a different situation. No differences
were found concerning hospital admissions. The mean monthly income considerably
increased during EQOLISE and decreased during the third year. At the time of
follow-up it was approximately at the same level as the slightly increased control
group. CONCLUSIONS: This investigation points at limited sustainability of
supported employment among individuals with severe mental disorders in terms of
maintenance of employment and income if the job coaching is not continued.

Jairam, R., et al. (2012). "Do we really know how to treat a child with bipolar
disorder or one with severe mood dysregulation? Is there a magic bullet?" Depress
Res Treat 2012: 967302.
Background. Despite controversy, bipolar disorder (BD) is being increasingly
diagnosed in under 18s. There is scant information regarding its treatment and
uncertainty regarding the status of "severe mood dysregulation (SMD)" and how it
overlaps with BD. This article collates available research on treatment of BD in
under 18s and explores the status of SMD. Methods. Literature on treatment of BD in
under 18s and on SMD were identified using major search engines; these were then
collated and reviewed. Results. Some markers have been proposed to differentiate BD
from disruptive behaviour disorders (DBD) in children. Pharmacotherapy restricted
to short-term trials of mood-stabilizers and atypical-antipsychotics show mixed
results. Data on maintenance treatment and non-pharmacological interventions are
scant. It is unclear whether SMD is an independent disorder or an early
manifestation of another disorder. Conclusions. Valproate, lithium, risperidone,
olanzapine, aripiprazole and quetiapine remain first line treatments for acute
episodes in the under 18s with BD. Their efficacy in maintenance treatment remains
unclear. There is no validated treatment for SMD. It is likely that some children
who are currently diagnosed with BD and DBD and possibly most children currently
diagnosed with SMD will be subsumed under the proposed category in the DSM V of
disruptive mood dysregulation disorder with dysphoria.

Janicak, P. G. and J. T. Rado (2011). "Quetiapine monotherapy for bipolar

depression." Expert Opin Pharmacother 12(10): 1643-1651.
INTRODUCTION: Depression, in the context of bipolar disorder, is more
prevalent than hypomania or mania and accounts for most of the disability.
Furthermore, the treatment of bipolar depression is more complicated than the
treatment of unipolar major depression. Finally, the evidence base for
pharmacotherapy of bipolar depression is much smaller than for unipolar depression
or hypomania/mania. AREAS COVERED: The article examines the mechanism of action and
pharmacokinetics of quetiapine, its evidence base as a treatment for bipolar
depression and related issues of safety and tolerability. EXPERT OPINION: In the
context of bipolar disorder, quetiapine is the only monotherapy approved for the
treatment of hypomania/mania, depression and as an adjunctive maintenance therapy.
In addition to its antipsychotic properties, this broad mood stabilizing potential
may uniquely benefit and simplify the management of some bipolar patients who can
tolerate this agent.

Janicak, P. G. and J. T. Rado (2012). "Quetiapine for the treatment of acute

bipolar mania, mixed episodes and maintenance therapy." Expert Opin Pharmacother
13(11): 1645-1652.
INTRODUCTION: Bipolar disorder is characterized by mood instability, which
can be challenging to manage. First-line pharmacological approaches usually involve
lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several
second-generation antipsychotics have demonstrated benefits for various phases of
this disorder. AREAS COVERED: This article examines the pharmacodynamics and
pharmacokinetics of quetiapine ; its evidence base as an acute and maintenance
monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also
discussed, along with the related issues of its safety and tolerability. EXPERT
OPINION: In the context of bipolar disorder, quetiapine is the only agent approved
as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and
adolescents; as a monotherapy for acute depressive episodes in adults; and as an
adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition
to its antipsychotic properties, this broad mood-stabilizing potential may simplify
the management of select patients.

Jeong, J. H., et al. (2015). "Korean Medication Algorithm for Bipolar Disorder
2014: comparisons with other treatment guidelines." Neuropsychiatr Dis Treat 11:
1561-1571.
Our goal was to compare the recommendations of the Korean Medication
Algorithm Project for Bipolar Disorder 2014 (KMAP-BP 2014) with other recently
published guidelines for the treatment of bipolar disorder. We reviewed a total of
four recently published global treatment guidelines and compared each treatment
recommendation of the KMAP-BP 2014 with those in other guidelines. For the initial
treatment of mania, there were no significant differences across treatment
guidelines. All recommended mood stabilizer (MS) or atypical antipsychotic (AAP)
monotherapy or the combination of an MS with an AAP as a first-line treatment
strategy for mania. However, the KMAP-BP 2014 did not prefer monotherapy with MS or
AAP for dysphoric/psychotic mania. Aripiprazole, olanzapine, quetiapine, and
risperidone were the first-line AAPs in nearly all of the phases of bipolar
disorder across the guidelines. Most guidelines advocated newer AAPs as first-line
treatment options in all phases, and lamotrigine in depressive and maintenance
phases. Lithium and valproic acid were commonly used as MSs in all phases of
bipolar disorder. As research evidence accumulated over time, recommendations of
newer AAPs - such as asenapine, paliperidone, lurasidone, and long-acting
injectable risperidone - became prominent. This comparison identifies that the
treatment recommendations of the KMAP-BP 2014 are similar to those of other
treatment guidelines and reflect current changes in prescription patterns for
bipolar disorder based on accumulated research data. Further studies are needed to
address several issues identified in our review.

Jiang, Z., et al. (2015). "Effect of novel modified bipolar radiofrequency ablation
for preoperative atrial fibrillation combined with off-pump coronary artery bypass
grafting surgery." Heart Vessels 30(6): 818-823.
We described a novel modified bipolar radiofrequency (RF) ablation for
preoperative atrial fibrillation (AF) combined with off-pump coronary artery bypass
grafting (OPCABG) for patients with AF and coronary artery disease (CAD). The aim
of this study was to assess the effect of this novel procedure and to determine
whether it can eliminate AF for CAD patients. From January 2007 to June 2013, 45
patients (26 male patients) with AF (9 paroxysmal, 17 persistent, and 19 long-
standing persistent) and CAD underwent the novel modified bipolar RF ablation
combined with OPCABG in our department. After median sternotomy, the modified
bipolar RF ablation and OPCABG were performed on beating heart without
cardiopulmonary bypass. Pulmonary vein isolation and left atrium ablation were
achieved using a bipolar RF champ. Mitral annular lesion and ganglionic plexus were
ablated with a bipolar RF pen. The left atrial appendage was excluded using a
surgical stapler. 24 h holter monitoring and echocardiography were performed at
discharge and 3, 6, 12 months postoperatively as well as every year thereafter. The
modified bipolar RF ablation and OPCABG were performed successfully in all
patients. Mean AF ablation time was 33.6 +/- 4.2 min, and mean OPCABG time was 87.6
+/- 13.3 min. Mean postoperative hospital stay was 12.6 +/- 5.5 days. The
maintenance of sinus rhythm was 95.6 % (43/45) at discharge. There was no early
death and permanent pacemaker implantation in perioperation. At a mean follow-up of
29.8 +/- 10.2 months, 38 of 45 (84.4 %) patients were in sinus rhythm. Follow-up
TTE at 6 months postoperatively showed that left atrial diameter was significantly
reduced and left ventricular ejection fraction was significantly increased. The
novel modified bipolar RF ablation procedure was safe, feasible and effective. It
may be useful in selecting the best ablation approaches for patients with AF and
CAD.

Joas, E., et al. (2017). "Pharmacological treatment and risk of psychiatric

hospital admission in bipolar disorder." Br J Psychiatry.
BACKGROUND: Clinical trials have examined the efficacy of drugs to prevent
relapse in patients with bipolar disorder, however, their design often limits
generalisation to routine clinical practice. AIMS: To estimate the effectiveness of
drugs used for maintenance treatment in bipolar disorder. METHOD: We used national
registers to identify 35 022 individuals diagnosed with bipolar disorder and
information on lithium, valproate, carbamazepine, lamotrigine, quetiapine and
olanzapine treatment from 2006 to 2009. The main outcome was psychiatric hospital
admissions. We used stratified cox regression to compare periods on and off
medication within the same individual. RESULTS: Medication with lithium, valproate,
lamotrigine, olanzapine and quetiapine was associated with reduced rates of
admission to hospital. Lithium was more effective than quetiapine and olanzapine.
The effects of specific drugs depended on the polarity of the mood episode.
CONCLUSIONS: Our findings complement results from randomised controlled trails, but
suggest that lithium is more effective than both quetiapine and olanzapine in
routine clinical practice.

Jones, L., et al. (2015). "Gambling problems in bipolar disorder in the UK:
prevalence and distribution." Br J Psychiatry 207(4): 328-333.
 BACKGROUND: North American studies show bipolar disorder is associated with
elevated rates of problem gambling; however, little is known about rates in the
different presentations of bipolar illness. AIMS: To determine the prevalence and
distribution of problem gambling in people with bipolar disorder in the UK. METHOD:
The Problem Gambling Severity Index was used to measure gambling problems in 635
participants with bipolar disorder. RESULTS: Moderate to severe gambling problems
were four times higher in people with bipolar disorder than in the general
population, and were associated with type 2 disorder (OR = 1.74, P = 0.036),
history of suicidal ideation or attempt (OR = 3.44, P = 0.02) and rapid cycling (OR
= 2.63, P = 0.008). CONCLUSIONS: Approximately 1 in 10 patients with bipolar
disorder may be at moderate to severe risk of problem gambling, possibly associated
with suicidal behaviour and a rapid cycling course. Elevated rates of gambling
problems in type 2 disorder highlight the probable significance of modest but
unstable mood disturbance in the development and maintenance of such problems.

Jornada, L. K., et al. (2010). "Effects of mood stabilizers on hippocampus and

amygdala BDNF levels in an animal model of mania induced by ouabain." J Psychiatr
Res 44(8): 506-510.
There is a body of evidence suggesting that BDNF is involved in bipolar
disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain
(OUA), a specific Na(+)/K(+) ATPase inhibitor, induces hyperlocomotion in rats, and
has been used as an animal model of mania. The present study aims to investigate
the effects of the lithium (Li) and valproate (VPT) in an animal model of mania
induced by ouabain. In the reversal model, animals received a single ICV injection
of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the
rats were treated for 6 days with intraperitoneal (IP) injections of saline (SAL),
Li or VPT twice a day. In the maintenance treatment (prevention model), the rats
received IP injections of Li, VPT, or SAL twice a day for 12 days. In the 7th day
of treatment the animals received a single ICV injection of either OUA or aCSF.
After the ICV injection, the treatment with the mood stabilizers continued for more
6 days. Locomotor activity was measured using the open-field test and BDNF levels
were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT
reversed OUA-related hyperactive behavior in the open-field test in both
experiments. OUA decreased BDNF levels in first and second experiments in
hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the
impairment in BDNF expression after OUA administration in these cerebral areas. Our
results suggest that the present model fulfills adequate face, construct and
predictive validity as an animal model of mania.

Jun, C., et al. (2014). "Disturbance of the glutamatergic system in mood

disorders." Exp Neurobiol 23(1): 28-35.
The role of glutamatergic system in the neurobiology of mood disorders draws
increasing attention, as disturbance of this system is consistently implicated in
mood disorders including major depressive disorder and bipolar disorder. Thus, the
glutamate hypothesis of mood disorders is expected to complement and improve the
prevailing monoamine hypothesis, and may indicate novel therapeutic targets. Since
the contribution of astrocytes is found to be crucial not only in the modulation of
the glutamatergic system but also in the maintenance of brain energy metabolism,
alterations in the astrocytic function and neuroenergetic environment are suggested
as the potential neurobiological underpinnings of mood disorders. In the present
review, the evidence of glutamatergic abnormalities in mood disorders based on
postmortem and magnetic resonance spectroscopy (MRS) studies is presented, and
disrupted energy metabolism involving astrocytic dysfunction is proposed as the
underlying mechanism linking altered energy metabolism, perturbations in the
glutamatergic system, and pathogenesis of mood disorders.

Kaliora, S. C., et al. (2013). "The practice of electroconvulsive therapy in

Greece." J ECT 29(3): 219-224.
OBJECTIVE: To describe the practice of electroconvulsive therapy (ECT) in
Greece. METHODS: A survey was conducted during the academic year 2008-2009.
Electroconvulsive therapy use was investigated for 2007. All civilian institutions
providing inpatient care were included. Centers that provided ECT completed a 57-
item questionnaire. Centers that did not offer ECT completed a 13-item
questionnaire. RESULTS: Fifty-five (82.1%) of 67 institutions responded.
Electroconvulsive therapy was offered in 18 hospitals. Only 2 of 10 university
hospitals offered ECT. Overall, 137 patients were treated with 1271 sessions in
2007. Only 1.47% discontinued treatment owing to adverse events. There were no
deaths. Schizophrenia was the most common diagnosis (41.3%) among those receiving
ECT, followed by major depression (28.9%), bipolar depression (9.1%), catatonia
(4.1%), suicidal ideation (3.3%), and schizoaffective disorder (2.5%). Physicians
considered major depression (93.8%), catatonia (86.5%), schizophrenia (56.3%), and
mania (50%) the most appropriate indications. Written informed consent was required
in 77.8% of the institutions, whereas the rest required verbal consent. Bilateral
ECT was the preferred electrode placement (88.9%). Modified ECT was used
exclusively. Propofol was the preferred anesthetic (44.4%), followed by thiopental
(38.9%). Seven (38.9%) of 18 hospitals used a fixed stimulus dose at first
treatment. Five (27.8%) of 18 hospitals used the half-age method.
Continuation/maintenance ECT was used in 33.3% of the hospitals. Outpatient ECT was
seldom used. Lack of training, difficult access to anesthesiology, billing issues,
and stigma were cited as the main impediments to the practice of ECT. CONCLUSIONS:
Electroconvulsive therapy is practiced in moderate numbers in Greece and almost
exclusively on an inpatient basis. Lack of training and lack of availability of
anesthesiologists were cited as the most common obstacles to providing ECT.

Kalra, J., et al. (2015). "Cerebroprotective effects of RAS inhibitors: Beyond

their cardio-renal actions." J Renin Angiotensin Aldosterone Syst 16(3): 459-468.
Work on the brain renin-angiotensin system has been explored by various
researchers and has led to elucidation of its basic physiologies and behavior,
including its role in reabsorption and uptake of body fluid, blood pressure
maintenance with angiotensin II being its prominent effector. Currently, this
system has been implicated for its newly established effects, which are far beyond
its cardio-renal effects accounting for maintenance of cerebral blood flow and
cerebroprotection, seizure, in the etiology of Alzheimer's disease, Parkinson's
disease, multiple sclerosis, and bipolar disorder. In this review, we have
discussed the distribution of angiotensin receptor subtypes in the central nervous
system (CNS) together with enzymatic pathways leading to active angiotensin ligands
and its interaction with angiotensin receptor 2 (AT2) and Mas receptors. Secondly,
the use of angiotensin analogues (angiotensin converting enzyme inhibitors and AT1
and/or AT2 receptor blockers) in the treatment and management of the CNS disorders
mentioned above has been discussed.

Kamalinia, G., et al. (2013). "Serum levels of sodium valproate in patients

suffering from bipolar disorders: comparing acute and maintenance phases of mania."
Pharmacopsychiatry 46(3): 83-87.
OBJECTIVES: Bipolar disorders (BD) are characterized by episodes of mania and
depression. There is evidence that states of psychiatric disorders impact on
neurotransmitters, endocrine system and membrane transport and, therefore, it is
possible that specific phases of BD differentially influence the pharmacokinetics
of some drugs. The aim of the present study was to investigate the drug-disease
interaction between sodium valproate, one of the major drugs used in the treatment
of bipolar disorder, and acute versus maintenance states of manic episodes. METHOD:
37 patients (mean age +/- SD = 37.54 +/- 11.27 years; 23 males, 14 females)
suffering from bipolar disorder completed the study. Blood samples were taken
during both acute and maintenance states. RESULTS: Neither the trough concentration
(p = 0.567) nor the internal clearances (p = 0.729) of sodium valproate in the
acute phase of mania differed statistically or descriptively from those in the
maintenance phase. Marginally significant phase by gender interactions were
observed. CONCLUSION: No significant effect of the acute phase of mania was
observed in bipolar patients and no relationship could be found between drug
pharmacokinetics and disease phase. This may be explained by specific
pharmacokinetic features of the drug such as low extraction ratio values. However,
phase by gender interactions indicate possible gender-related issues.

Kanba, S. (2011). "[Introduction of treatment guideline for bipolar disorders made

by the Japanese Society of Mood Disorders]." Seishin Shinkeigaku Zasshi 113(9):
863-866.
Japanese Society of Mood Disorders published a treatment guideline for
bipolar disorders. In an annual symposium, the authors will talk about the details
of treatments for depression, mania and maintenance. In addition, some instructions
and cautions will be stated regarding appropriate use of guideline.

Kaplan, K. A. and A. G. Harvey (2013). "Behavioral treatment of insomnia in bipolar

disorder." Am J Psychiatry 170(7): 716-720.
Sleep disturbance is common in bipolar disorder. Stimulus control and sleep
restriction are powerful, clinically useful behavioral interventions for insomnia,
typically delivered as part of cognitive-behavioral therapy for insomnia (CBT-I).
Both involve short-term sleep deprivation. The potential for manic or hypomanic
symptoms to emerge after sleep deprivation in bipolar disorder raises questions
about the appropriateness of these methods for treating insomnia. In a series of
patients with bipolar disorder who underwent behavioral treatment for insomnia, the
authors found that regularizing bedtimes and rise times was often sufficient to
bring about improvements in sleep. Two patients in a total group of 15 patients
reported mild increases in hypomanic symptoms the week following instruction on
stimulus control. Total sleep time did not change for these individuals. Two of
five patients who underwent sleep restriction reported mild hypomania that was
unrelated to weekly sleep duration. Sleep restriction and stimulus control appear
to be safe and efficacious procedures for treating insomnia in patients with
bipolar disorder. Practitioners should encourage regularity in bedtimes and rise
times as a first step in treatment, and carefully monitor changes in mood and
daytime sleepiness throughout the intervention.

Kar, N., et al. (2014). "Thyrotoxicosis followed by hypothyroidism in a patient on

lithium." Ment Illn 6(2): 5415.
While hypothyroidism is common in lithium-treated patients, thyrotoxicosis is
rarely reported. We present a female patient on lithium for maintenance therapy of
bipolar affective disorder, who developed thyrotoxicosis for few months which was
followed by hypothyroidism which continued. There was no further thyrotoxicosis
episode during a five year follow up period. While she was treated for thyroid
dysfunction, lithium was continued. There was no clinical impact on the maintenance
of the bipolar affective disorder during the follow up period; she was maintained
well in the community.

Karanti, A., et al. (2014). "[Changes in prescription patterns to patients with

bipolar syndromes. Increased use of lamotrigine and decreased use of lithium]."
Lakartidningen 111(51-52): 2284-2286.
Lithium is a first line option in the maintenance treatment of bipolar
disorder, but several alternative treatment regimens have been introduced in recent
years, among them treatment with antiepileptic compounds and atypical antipsychotic
drugs. Little is known about if and how this has changed the prescription patterns
of mood stabilizers. We analysed trends in prescription of mood stabilisers in
Sweden using the national quality register for bipolar disorder (BipolaR), the
Prescribed Drug Register, and the Patient Register during the years 2007-2011. We
found that lithium use decreased while lamotrigine use increased in bipolar
patients. These changes could not be ex-plained by differences in bipolar subtypes;
lithium use decreased in both bipolar type I and type II, and the use of
lamotrigine increased in bipolar type II. Lithium use was more common in men,
whereas lamotrigine use was more common in women. The prescription of other mood
stabilisers did not change during these years.

Kaye, L., et al. (2014). "Gaze maintenance and autism spectrum disorder." J Dev
Behav Pediatr 35(9): 610-612.
CASE: Chase is a 5(1/2)-year-old boy whom you have followed in your primary
care practice since age 26 months. He was born full-term vaginal delivery weighing
6 pounds 15 ounces. His biological mother used heroin, tobacco, and cocaine during
pregnancy. From 8 weeks to 18 months, he spent time in a foster home where he was
provided limited attention and nurturing. At age 18 months, he entered a loving
foster home; at 26 months, he was adopted. There is maternal history of attention-
deficit hyperactivity disorder, learning disability, depression, bipolar disorder,
and substance abuse but no history of autism or cognitive disability. Chase
received early intervention before adoption. Specific concerns are unknown. At the
time of his adoption, he had delays in gross motor and fine motor skills, nonverbal
communication, and speech production. Familiar listeners find Chase to be 100%
intelligible but unfamiliar listeners understand about 70% of what Chase says. He
enjoys being with his adopted mother and imitating her. He has demonstrated
significant anxiety during his play therapy. He has difficulty in paying attention
to multistep directions. Chase can point and wave but has difficulty following
someone's eyes to see where another person is looking. Chase enjoys a variety of
interests but has a special fixation on Toy Story characters. Chase does initiate
social interactions but can be aggressive toward his siblings and oppositional
toward his parents. He is not aggressive at school. Teachers note hyperactivity and
impulsivity. Chase is bothered by bright lights and by others making loud noises
but has no difficulty with crowds. Chase is reported to have difficulty in
transitioning between activities. At his 5-year-old visit, you as well as his
mother and therapists note that he has trouble following with his eyes so he is
referred to a neuro-ophthalmologist. Evaluation showed Chase was able to fix on and
follow objects and light, his peripheral vision was normal, his pupils were equal
and reactive without afferent pupillary defect, and normal visual tracking as
assessed through pursuit and saccades. There were some head jerking motions
observed which were not thought to be part of Chase's attempts to view objects.
Gaze impersistence was noted, although it was not clear if this was due to a lack
of attention or a true inability to maintain a gaze in the direction instructed. On
review of the school's speech and language report, they state that he is >90%
intelligible. He has occasional lip trills. Testing with the Clinical Evaluation of
Language Fundamentals shows mild delays in receptive language, especially those
that require visual attention. Verbal Motor Production Assessment for Children
reveals focal oromotor control and sequencing skills that are below average, with
groping when asked to imitate single oromotor nonspeech movements and sequenced
double oromotor nonspeech movements. At 5(1/2) years, he returns for follow-up, and
he is outgoing and imaginative, eager to play and socialize. He makes eye contact
but does not always maintain it. He asks and responds to questions appropriately,
and he is able to follow verbal directions and verbal redirection. He is very
interested in Toy Story characters but willing to share them and plays with other
toys. Chase's speech has predictable, easy to decode sound substitutions. On
interview with him, you feel that he has borderline cognitive abilities. He also
demonstrates good eye contact but lack of visual gaze maintenance; this is the
opposite of the pattern you are accustomed to in patients with autism spectrum
disorder. What do you do next?

Keeley, P. W., et al. (2013). "Development and plasticity of outer retinal

circuitry following genetic removal of horizontal cells." J Neurosci 33(45): 17847-
17862.
The present study examined the consequences of eliminating horizontal cells
from the outer retina during embryogenesis upon the organization and assembly of
the outer plexiform layer (OPL). Retinal horizontal cells exhibit a migration
defect in Lim1-conditional knock-out (Lim1-CKO) mice and become mispositioned in
the inner retina before birth, redirecting their dendrites into the inner plexiform
layer. The resultant (mature) OPL, developing in the absence of horizontal cells,
shows a retraction of rod spherules into the outer nuclear layer and a sprouting of
rod bipolar cell dendrites to reach ectopic ribbon-protein puncta. Cone pedicles
and the dendrites of type 7 cone bipolar cells retain their characteristic
stratification and colocalization within the collapsed OPL, although both are
atrophic and the spatial distribution of the pedicles is disrupted. Developmental
analysis of Lim1-CKO retina reveals that components of the rod and cone pathways
initially co-assemble within their normal strata in the OPL, indicating that
horizontal cells are not required for the correct targeting of photoreceptor
terminals or bipolar cell dendrites. As the rod spherules begin to retract during
the second postnatal week, rod bipolar cells initially show no signs of ectopic
growth, sprouting only subsequently and continuing to do so well after the eighth
postnatal week. These results demonstrate the critical yet distinctive roles for
horizontal cells on the rod and cone pathways and highlight a unique and as-yet-
unrecognized maintenance function of an inhibitory interneuron that is not required
for the initial targeting and co-stratification of other components in the circuit.

Kemp, D. E., et al. (2010). "Metabolic syndrome in patients enrolled in a clinical

trial of aripiprazole in the maintenance treatment of bipolar I disorder: a post
hoc analysis of a randomized, double-blind, placebo-controlled trial." J Clin
Psychiatry 71(9): 1138-1144.
OBJECTIVE: To compare the effects of maintenance treatment with aripiprazole
or placebo on the incidence of metabolic syndrome in bipolar disorder. METHOD:
Patients with DSM-IV bipolar I disorder were stabilized on aripiprazole therapy for
6-18 weeks prior to double-blind random assignment to aripiprazole or placebo for
26 weeks. The rate of metabolic syndrome in each group was calculated at
maintenance phase baseline (randomization) and endpoint for evaluable patients
using a last-observation-carried-forward (LOCF) approach. Metabolic syndrome was
defined using the National Cholesterol Education Program Adult Treatment Panel III
criteria. The study was conducted from March 2000 to June 2003 at 76 centers in
Argentina, Mexico, and the United States. RESULTS: At entry into the maintenance
phase, 45/125 patients (36.0%) overall met criteria for metabolic syndrome. Mean
changes in the 5 components of metabolic syndrome (waist circumference,
triglyceride levels, high-density lipoprotein cholesterol level, blood pressure,
and glucose level) from baseline to week 26 were small except for a meaningful
reduction in triglycerides (placebo -18.9 mg/dL; aripiprazole -11.5 mg/dL). By the
end of the maintenance phase (endpoint, LOCF), 5/18 placebo-treated patients
(27.8%) and 4/14 aripiprazole-treated patients (28.6%) no longer met metabolic
syndrome criteria. The proportion of patients with metabolic syndrome was similar
in the placebo and aripiprazole groups at both baseline and week 26. There were no
significant changes in any of the individual components of metabolic syndrome
between aripiprazole- and placebo-treated patients during maintenance phase
treatment. CONCLUSIONS: The prevalence of metabolic syndrome in patients with
bipolar disorder is higher than that commonly reported in the general population.
The effect of 26 weeks of treatment with aripiprazole on the incidence of metabolic
syndrome and its components was similar to placebo. TRIAL REGISTRATION:
clinicaltrials.gov Identifier: NCT00036348.

Kemp, D. E., et al. (2012). "Ziprasidone with adjunctive mood stabilizer in the
maintenance treatment of bipolar I disorder: long-term changes in weight and
metabolic profiles." Eur Neuropsychopharmacol 22(2): 123-131.
This analysis was conducted to compare the effects of adjunctive ziprasidone
or placebo on metabolic parameters among patients receiving maintenance treatment
with lithium or valproate. We also tested whether metabolic syndrome (MetS) and
other risk factors were associated with baseline characteristics and treatment
response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV)
patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium
or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical
stability were subsequently randomized into Phase 2 to 6-months of double-blind
treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS
was found in 111 participants (23%). Participants with MetS (vs. non-MetS
participants) were more likely to be aged 40 years or older, had significantly more
severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in
abdominal obesity was associated with lower manic symptom improvement (p<0.05, as
assessed by MRS change score) during Phase 1, while symptom improvement differed
across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had
similar weight and metabolic profiles compared to the placebo+MS group across
visits. These results corroborate existing findings on ziprasidone which exhibits a
neutral weight and metabolic profile in the treatment of schizophrenia and bipolar
patients. Our findings suggest that MetS is highly prevalent in patients with
bipolar disorder, may be associated with greater manic symptom severity, and may
predict treatment outcomes.

Kesebir, S., et al. (2012). "Compulsive buying in bipolar disorder: is it a

comorbidity or a complication?" J Affect Disord 136(3): 797-802.
BACKGROUND: The objective of this study was to investigate the frequency of
compulsive buying in bipolar disorder (BD), to compare it with healthy controls,
and to search if there is a difference between bipolar cases with and without
compulsive buying in terms of sociodemographic qualities, temperament, clinical
characteristics and comorbid diagnoses. METHODS: One-hundred outpatient cases
diagnosed as BD according to DSM-IV were evaluated consecutively. Following the
diagnosis interview (SCID-I and II) the subjects completed the mood disorders
registry form, Compulsive Buying Scale and TEMPS-A. RESULTS: Compulsive buying
scores were higher in bipolar patients than healthy controls (p<0.001). Cases with
compulsive buying revealed higher cyclothymic and irritable temperament scores than
other bipolar patients (p=0.029 vs 0.045). Premenstrual syndrome and postpartum
onset were more frequent, while psychotic symptoms were less in compulsive buyer
bipolar patients (p=0.002, 0.009 vs 0.034). Severity of episode was lower (p=0.01),
number of episodes was higher (p=0.009). Acute onset and remission before and after
maintenance treatment were more frequent in patients with compulsive buying
(p=0.011 and p=0.011). Full remission between episodes was 100%. Cases with axis-1
and axis-2 comorbidities demonstrated higher compulsive buying scores (p=0.025 and
0.005). LIMITATIONS: Treatment regimen differences between patients are a
limitation of the study. CONCLUSIONS: This is the first study to relate compulsive
buying with the clinical characteristics of BD. Our results reveal that compulsive
buying in BD occurs together with mood episodes which are not very severe, but
frequent and with abrupt onset.

Kessing, L. V., et al. (2015). "Use of Lithium and Anticonvulsants and the Rate of
Chronic Kidney Disease: A Nationwide Population-Based Study." JAMA Psychiatry
72(12): 1182-1191.
IMPORTANCE: Lithium is the main mood stabilizing drug for bipolar disorder.
However, it is controversial whether long-term maintenance treatment with lithium
or other drugs for bipolar disorder causes chronic kidney disease (CKD). OBJECTIVE:
To compare rates of CKD and in particular rates of end-stage CKD among individuals
exposed to successive prescriptions of lithium, anticonvulsants, or other drugs
used for bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS: This is a Danish
nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly
selected sample of 1.5 million individuals among all persons who were registered in
Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode
or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10,591), and
all patients exposed to either lithium (n = 26,731) or anticonvulsants (n=420,959).
Cohort 2 included the subgroup of 10,591 patients diagnosed as having bipolar
disorder. MAIN OUTCOMES AND MEASURES: Possible CKD, definite CKD, and end-stage CKD
(defined as long-term dialysis or renal transplantation). RESULTS: A total of
14,727 (0.8%), 18,762 (1.0%), and 3407 (0.2%) in cohort 1 and 278 (2.6%), 319
(3.0%), and 62 (0.6%) in cohort 2 were diagnosed as having possible, definite, or
end-stage CKD, respectively. Based on the total sample and not considering
diagnoses, use of lithium was associated with an increased rate of definite CKD (0
prescriptions: hazard ratio [HR] = 1.09, 95% CI, 0.81-1.45; >/=60 prescriptions: HR
= 3.65, 95% CI, 2.64-5.05; P for trend < .001) and possible CKD (0 prescriptions:
HR = 1.01, 95% CI, 0.79-1.30; >/=60 prescriptions: HR = 2.88, 95% CI, 2.17-3.81; P
for trend < .001), whereas use of anticonvulsants, antipsychotics, or
antidepressants was not. Neither use of lithium nor use of any other drug class was
associated with increasing rates of end-stage CKD. In patients with bipolar
disorder, use of lithium was associated with an increased rate of definite CKD (1-2
prescriptions: HR = 0.89, 95% CI, 0.39-2.06; >/=60 prescriptions: HR = 2.54, 95%
CI, 1.81-3.57; P for trend < .001) or possible CKD (1-2 prescriptions: HR = 1.26,
95% CI, 0.65-2.43; >/=60 prescriptions, HR = 2.48, 95% CI, 1.80-3.42; P for trend <
.001), as was use of anticonvulsants (definite CKD, 1-2 prescriptions: HR = 1.23,
95% CI, 0.76-1.99; >/=60 prescriptions, HR = 2.30, 95% CI, 1.53-3.44; P for trend <
.001; possible CKD, 1-2 prescriptions: HR = 1.11, 95% CI, 0.70-1.76; >/=60
prescriptions: HR = 1.97, 95% CI, 1.34-2.90; P for trend < .001). There was no such
association with antipsychotics or antidepressants. Also in patients with bipolar
disorder, use of lithium was not significantly associated with an increased rate of
end-stage CKD, whereas use of anticonvulsants was (1-2 prescriptions, HR = 0 [95%
CI, 0.00-infinity]; 30-39 prescriptions: HR = 3.23, 95% CI, 1.26-8.27; >/=60
prescriptions: HR = 2.06, 95% CI, 0.82-5.16; P for trend = .002). CONCLUSIONS AND
RELEVANCE: Maintenance treatment with lithium or anticonvulsants as practiced in
modern care is associated with an increased rate of CKD. However, use of lithium is
not associated with an increased rate of end-stage CKD. The associations between
use of medication and CKD may at least partly be attributed to bias.

Ketter, T. A. (2010). "Nosology, diagnostic challenges, and unmet needs in managing

bipolar disorder." J Clin Psychiatry 71(10): e27.
The spectrum of bipolar disorders includes the subtypes of bipolar I
disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder not
otherwise specified (NOS). Because depression is the most pervasive symptom of
bipolar disorder, this condition is frequently misdiagnosed as unipolar major
depressive disorder. As a result, patients often experience substantive delays in
receiving the correct diagnosis and appropriate treatment. To help meet this
important diagnostic challenge, various markers have been identified that have
predictive value for a bipolar outcome, including early onset of depression, family
history of bipolar disorder, atypical depressive symptoms, and the presence of
psychosis. Unmet needs in the management of bipolar disorder include an enhanced
diagnostic process, more options for treating bipolar depressive episodes, and
safer, more tolerable medications for long-term maintenance treatment.

Ketter, T. A. (2014). "Acute and maintenance treatments for bipolar depression." J

Clin Psychiatry 75(4): e10.
Patients with bipolar disorder are symptomatic about half of the time,
experiencing depression more often than mania/hypomania. Because patients usually
seek treatment during a depressive episode (rather than a manic episode), bipolar
depression is commonly misdiagnosed as unipolar depression. Providing an accurate
and timely bipolar depression diagnosis is critical for the proper treatment of the
patient. Some FDA-approved treatments are helpful during acute and maintenance
phases of therapy, but there is a significant unmet need for effective bipolar
depression treatments with favorable side-effect profiles. Newer agents offer the
promise of improvements in tolerability, but additional research is needed to
actualize this promise into better treatments for patients struggling with bipolar
depression.

Ketter, T. A., et al. (2016). "Long-term safety and efficacy of armodafinil in

bipolar depression: A 6-month open-label extension study." J Affect Disord 197: 51-
57.
BACKGROUND: Safe/well-tolerated treatments for bipolar I depression remain
limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a
wakefulness-promoting agent evaluated in 3 acute, controlled efficacy studies with
variable efficacy results. METHODS: Completers of three 8-week, double-blind,
placebo-controlled adjunctive armodafinil studies (150-200 mg/day added to ongoing
stable maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I
depression could enter this 6-month, open-label extension study. Objectives
included evaluation of safety/tolerability (primary) and efficacy (secondary).
RESULTS: 867 patients enrolled; 863 received >/=1 dose of armodafinil and 506 (58%)
completed the 6-month study. Headache, insomnia, and anxiety were the most common
adverse events (AEs) reported, whereas akathisia, nausea, sedation/somnolence, and
weight increase were uncommon. Mean measures assessing emergence of mania, anxiety,
insomnia, or suicidality showed no worsening. Discontinuations due to AEs occurred
in 57 (7%) patients. Serious AEs occurred in 27 (3%) patients and were considered
treatment-related in 8 (1%) patients. Depressive symptoms improved over the 6
months, as did patient functioning. LIMITATIONS: Lack of placebo control.
CONCLUSIONS: Adjunctive armodafinil was generally safe and well tolerated over 6
months of open-label treatment at 150-200 mg/day when taken with protocol-defined
mood stabilizers for bipolar I depression. This 6-month open-label study suggested
that armodafinil augmentation of bipolar maintenance therapies may have a favorable
risk profile and may improve depressive symptoms in some patients with bipolar I
depression.

Ketter, T. A., et al. (2016). "Treatment of bipolar disorder: Review of evidence

regarding quetiapine and lithium." J Affect Disord 191: 256-273.
BACKGROUND: Lithium, the prototypical mood stabilizer, and quetiapine, a
second-generation antipsychotic, are widely used acute and maintenance
pharmacotherapies for bipolar disorder. The Clinical and Health Outcomes Initiative
in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study was the
first comparative effectiveness assessment of lithium versus quetiapine (in
combination with adjunctive personalized treatment), and found no overall
significant differences in efficacy and safety/tolerability outcomes between
lithium and quetiapine. Completion of Bipolar CHOICE offers a timely opportunity to
review the evidence regarding lithium and quetiapine for bipolar disorder. METHODS:
Controlled clinical trials and real-world observational studies that included
quetiapine and lithium as monotherapy or as combination therapy were identified by
literature search. Selected studies were reviewed in detail. RESULTS: Review of the
available trials suggested comparable efficacy of quetiapine and lithium in acute
mania, and possibly greater efficacy for quetiapine compared with lithium in acute
bipolar depression and in prevention of recurrent (particularly depressive)
episodes. Combination therapy including quetiapine and lithium was generally more
effective than either agent alone in acute mania and bipolar maintenance, although
adding lithium to quetiapine did not increase efficacy in acute bipolar depression.
Safety data for quetiapine and lithium were consistent with the established
profiles of the two treatments. LIMITATIONS: Limitations include those of the
available efficacy and effectiveness trial data. CONCLUSIONS: Quetiapine and
lithium have overlapping but distinctive roles in different phases of bipolar
disorder, and further studies of these agents (particularly in combination with one
another) are warranted.

Ketter, T. A., et al. (2015). "Adjunctive armodafinil for major depressive episodes
associated with bipolar I disorder." J Affect Disord 181: 87-91.
BACKGROUND: In a previous study, adjunctive armodafinil 150 mg/day
significantly improved depressive symptoms associated with bipolar I disorder.
METHODS: Multicenter, double-blind study of patients with a major depressive
episode despite bipolar I disorder maintenance therapy randomized to adjunctive
placebo or adjunctive armodafinil 150 or 200mg/day for 8 weeks; for logistical
reasons, assignment to armodafinil 200mg/day was discontinued early. Primary
efficacy was measured by change from baseline to week 8 in 30-Item Inventory of
Depressive Symptomatology-Clinician-Rated (IDS-C30) total score. RESULTS: Patients
were randomized to adjunctive placebo (n=230), adjunctive armodafinil 150 mg/day
(n=232), or adjunctive armodafinil 200mg/day (n=30; analyzed for safety only).
Least-square mean change in IDS-C30 total score was numerically superior for
adjunctive armodafinil 150 mg/day vs adjunctive placebo, but was not statistically
significant (p=0.13). Armodafinil was well-tolerated. Adverse events (AEs) observed
in >5% with adjunctive armodafinil 150 mg/day and more frequently than with
adjunctive placebo were headache (16% [38/231] vs 13% [30/229]) and nausea (7%
[17/231] vs 2% [5/229]). The most common AEs with adjunctive armodafinil 200mg/day
were diarrhea and dry mouth (17% [5/30] each vs 6% [13/229] and 1% [3/229],
respectively, with adjunctive placebo). LIMITATIONS: Early study discontinuation
for logistical reasons by the sponsor limited adjunctive armodafinil 200-mg/day
assessment. CONCLUSIONS: FDA-approved bipolar I depression treatments are limited.
Adjunctive armodafinil 150 mg/day reduced depressive symptoms associated with
bipolar I disorder to a greater extent than adjunctive placebo, although the
difference failed to reach statistical significance. Safety data indicate treatment
with adjunctive armodafinil was well-tolerated.

Khan, A., et al. (2013). "Comparative mortality risk in adult patients with
schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-
deficit/hyperactivity disorder participating in psychopharmacology clinical
trials." JAMA Psychiatry 70(10): 1091-1099.
IMPORTANCE: There is concern that increased mortality risk among patients
with psychiatric illness may be worsened by psychopharmacological agents.
OBJECTIVES: To assess mortality risk among adult patients with a diagnosis of
schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-
deficit/hyperactivity disorder participating in clinical trials conducted by
pharmaceutical companies for US Food and Drug Administration (FDA) approval to
market and to evaluate if psychopharmacological agents worsen this risk. DATA
SOURCES: The FDA Summary Basis of Approval (SBA) reports of new drug applications
and supplemental applications for 28 psychopharmacological agents approved between
1990 and 2011. STUDY SELECTION: The FDA SBA reports detailing exposure data from
acute placebo-controlled trials and safety extension studies including 92,542
patients from 47 adult drug approval programs for treatment of schizophrenia,
depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity
disorder and SBA reports on combination and maintenance therapy programs for
treatments of bipolar disorder. DATA EXTRACTION AND SYNTHESIS: We reviewed and
synthesized mortality data from SBA reports that combined mortality rates across
the clinical trials, including information on patient exposure years (PEY) for
active treatments and placebo for individual indications. MAIN OUTCOMES AND
MEASURES: Overall mortality rate per 100,000 PEY in relation to the psychiatric
diagnosis of the patients participating in psychopharmacology clinical trials.
Also, the overall mortality rates using PEY technique among patients assigned to
psychopharmacological agents or placebo were evaluated. RESULTS: Overall, mortality
risk was high and significantly associated with psychiatric diagnosis (chi(2)(4) =
1760; P < .001). Compared with the general adult population, patients with
schizophrenia had the highest mortality risk (3.8-fold increase), followed by
patients with depression (3.15-fold increase) and bipolar disorder (3.0-fold
increase). The mortality risk was not increased when patients were assigned to
psychotropic agents rather than placebo except for heterocyclic antidepressants.
Suicide accounted for 109 of all 265 deaths (41.1%). CONCLUSIONS AND RELEVANCE:
These data suggest that increased mortality rates reported in population studies
are detectable among adult patients with psychiatric illnesses participating in
psychopharmacological trials. Furthermore, 3- to 4-month exposure to modern
psychotropic agents, such as atypical antipsychotic agents, selective serotonin
reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors
does not worsen this risk. Given the inherent limitations of the FDA SBA reports,
further research is needed to support firm conclusions.

Khan, M. and R. S. El-Mallakh (2015). "Renal microcysts and lithium." Int J

Psychiatry Med 50(3): 290-298.
 OBJECTIVE: To review the relationship between lithium-related renal
dysfunction and microcysts. METHOD: Electronic databases (PubMed and Google
Scholar) were queried. RESULTS: From a total of 12,425 publications, 76 were
reviewed. DISCUSSION: Glomerular renal dysfunction occurs after an average of 20
years of continuous lithium treatment, and the severity is related to the total
lithium load as measured by dose and duration. Recently, several reports have
highlighted the relationship between renal microcyst formation and significant
reductions in glomerular filtration rate. Radiologically visible lithium-related
microcysts are usually 1-2 mm and occasionally 3 mm. Smaller cysts, which are
impossible to resolve, are probably more common than the visible cysts, based on
observations of renal needle biopsies. Increases in the number of microcysts and
the space they occupy within kidney volume appear to be related to both the
duration of lithium treatment and the reduction in kidney function. The proposed
mechanism of microcyst formation is related to the antiapoptotic effect of lithium.
Specifically, by preventing renal tubular epithelial cells from undergoing
apoptosis as part of the process of normal renal maintenance, lithium may be
allowing the inappropriate growth of the surface area of tubules to form
invaginations and ultimately cysts. It is proposed that the physical space occupied
by these cysts in the limited volume within the renal capsule compromises the
function of otherwise healthy renal tissue. Monitoring of kidneys utilizing
radiographic imaging may be more sensitive than monitoring laboratory values.
Additional research is required to optimize this new monitoring tool.

Kinnan, S., et al. (2011). "Zolpidem-induced mania in a patient with

schizoaffective disorder." Psychosomatics 52(5): 493-494.

Kittel-Schneider, S., et al. (2015). "Lithium-induced Clock Gene Expression in

Lymphoblastoid Cells of Bipolar Affective Patients." Pharmacopsychiatry 48(4-5):
145-149.
INTRODUCTION: Disturbances of circadian rhythms occur in all episodes of
bipolar disorder (BD). Lithium, as gold-standard in the maintenance treatment of
BD, is known to influence circadian processes. METHODS: In a pilot study
lymphoblastoid cell lines (LCLs) were generated from 8 BD patients and 6 healthy
controls. The LCLs were treated with lithiumchloride (LiCl) for 3 weeks. Cell
cycles were then synchronized and expressional analysis by quantitative Real Time
PCR was done. RESULTS: BD and controls differed in the period length regarding DBP
(albumin D-box binding protein) expression and DBP expression was also influenced
by lithium treatment. Furthermore, baseline DBP expression was significantly
different between non-treated BD and healthy controls. None of the other analyzed
circadian genes showed to be influenced by chronic lithium treatment or to be
differentially regulated due to the diagnosis. DISCUSSION: We here show that
chronic lithium treatment of LCLs leads to decreased expression of the clock gene
DBP, rendering DBP a lithium-regulated gene. We could confirm the role of the
circadian clock as well in lithium mode of action as in the pathomechanisms of BD
although future studies with a greater number of participants and cell lines are
needed.

Kleimann, A., et al. (2016). "Psychopharmacological treatment of 1650 in-patients

with acute mania-data from the AMSP study." J Affect Disord 191: 164-171.
BACKGROUND: Several studies have analyzed prescription patterns for bipolar
disorder, but few have for acute mania. Treatment strategies in this complex domain
change over time and do not always follow evidence-based guidelines. METHODS:
Prescription data of in-patients suffering from acute mania in the time period from
2005 to 2012 were obtained from the database of the Drug Safety Program in
Psychiatry (Institut fur Arzneimittelsicherheit in der Psychiatrie; AMSP). Data
were collected on two index dates per year. Changes over time were analyzed
comparing the time periods 2005/06 and 2011/12. RESULTS: Among 1650 patients (mean
+/-SD; age: 48.9+/-14.91 years; 53.1% females) 54.1% received anticonvulsants,
74.5% second-generation antipsychotics (SGAs), 17.8% first-generation
antipsychotics (FGAs), 29.1% lithium, 44.1% benzodiazepines and 14.5%
antidepressants. Prescription of SGAs increased from 70% to 79% (p=0.005), while
prescription of FGAs and anticonvulsants decreased from 19% to 13% (p<0.05) and 59%
to 46% (p<0.001), respectively. Only 30% of patients received monotherapy with one
mood stabilizer. We observed an impact of gender, age and psychotic symptoms on
treatment strategy. 36.8% of the women</=40 years received valproate. LIMITATIONS:
Follow-up data are missing and no differentiation between acute and maintenance
treatments could be made due to the cross-sectional design. Additionally, our
findings do not necessarily translate to outpatients or to other countries.
CONCLUSIONS: Combination therapies represent standard clinical practice. Though
many results reflect clinical necessity, the high number of antidepressant
prescriptions or valproate use in women of child-bearing age should be judged
critically. Further prospective studies should focus on real-world prescription
practice in acute mania to evaluate efficacy and safety of common practice. This
paper is dedicated to Prof. Dr. Hanns Hippius on the occasion of his 90th birthday.

Knebel, R. J., et al. (2010). "Lithium carbonate maintenance therapy in a

hemodialysis patient with end-stage renal disease." Am J Psychiatry 167(11): 1409-
1410.

Kodesh, A., et al. (2012). "Epidemiology and comorbidity of severe mental illnesses
in the community: findings from a computerized mental health registry in a large
Israeli health organization." Soc Psychiatry Psychiatr Epidemiol 47(11): 1775-1782.
PURPOSE: Maccabi Healthcare Services, a large health maintenance organization
(HMO) operating in Israel, has recently constructed a computerized registry of
patients with severe mental illnesses (SMI). In the present study, we aimed to use
this registry to investigate the epidemiology of schizophrenia and bipolar
affective disorder among adults, and to assess their comorbidity and mortality
compared to the general population. METHODS: In this historical cohort study, we
investigated the age- and sex-specific prevalence and incidence rates of HMO
members diagnosed with schizophrenia or bipolar affective disorder between 2003 and
2009. We compared their medical comorbidity and mortality to the general HMO
population. RESULTS: A total of 8,848 and 5,732 patients were diagnosed with
bipolar (crude prevalence rate of 5 per 1,000) and schizophrenia (3 per 1,000),
respectively. The annual incidence rates were 4.2 and 2.4 per 1,000 for
schizophrenia and bipolar disorder, respectively. On average, schizophrenic men
were diagnosed 4-5 years earlier than schizophrenic women. Compared to the general
population, schizophrenia and bipolar disorder patients had a 12- and 9-year
shorter life expectancy, respectively. They were also more likely to be diagnosed
with diabetes mellitus (odds ratio of 1.9 and 1.6, respectively). CONCLUSIONS: The
current study demonstrates the potential use of automated medical databases to
characterize the epidemiology of SMI in the community. The increased comorbidity
and mortality among these patients has important implication for health authorities
for prevention and delivery of health-care services.

Konstantakopoulos, G., et al. (2015). "Drugs under early investigation for the
treatment of bipolar disorder." Expert Opin Investig Drugs 24(4): 477-490.
INTRODUCTION: Despite the availability of several treatment options for
bipolar disorder (BD), patients suffer from chronic, subsyndromal symptoms, quite
frequent polarity shifts, cognitive impairment and poor community function.
Overall, the current treatment outcomes for BD highlight the need to develop
targeted, more effective and safe treatments. AREAS COVERED: This review focuses on
compounds currently under investigation for BD, covering compounds tested through
animal studies to those in Phase II clinical trials over the past 5 years. These
drugs concern all phases of BD treatment, that is, mania, depression, maintenance,
and cognitive dysfunction. EXPERT OPINION: Limitations exist in applying valid
preclinical bipolar models and study designs. Research emphasis is given mainly on
bipolar depression, with few compounds showing some evidence of efficacy. Non-
effectiveness in current studies of mania and maintenance treatment reflects the
need for novel compounds. Glycogen synthase kinase 3, casein kinase 1, inositol
monophosphatase inhibition, histone deacetylase inhibition pathways are known
targets that should proceed from preclinical to the clinical trial level.

Kontis, D., et al. (2013). "[Dementia and bipolar disorder on the borderline of old
age]." Psychiatriki 24(2): 132-144.
Dementia and bipolar disorder have been traditionally considered two separate
clinical entities. However, recent preclinical and clinical data in elderly people
suggest that they are in fact related. Several theories have been put forward to
interpret their relationship which could be summed up as follows: (1) Dementia
could increase the risk for the emergence of bipolar symptoms, or (2) conversely,
bipolar disorder might be associated with heightened risk for developing
pseudodementia or dementia. (3) Alternatively, dementia, other brain diseases or
drugs affecting brain function could lead to the combination of symptoms of
dementia and bipolar disorder in elderly individuals. The two disorders demonstrate
similarities with respect to their clinical expression (agitation, psychotic, mood
and cognitive symptoms) and structural brain neuroimaging (enlarged lateral
ventricles and white matter hyperintensities using magnetic resonance imaging-MRI).
Despite the above similarities, the two disorders also have important differences.
As expected, cognitive symptoms prevail in dementia and mood symptoms in bipolar
disorder. In dementia but not in bipolar disorder there is evidence that brain
structural abnormalities are diffuse and hippocampal volumes are smaller. Dementia
and bipolar disorder present different abnormalities in functional brain
neuroimaging. The pattern of "ventral" hyperactivity and "dorsal" hypoactivity in
brain emotional circuits at rest is revealed in bipolar disorder but not dementia.
With respect to their treatment, acetylcholinesterase inhibitors and memantine are
indicated against cognitive symptoms in dementia and also improve behavioural and
psychological symptoms appearing during the course of dementia. Lithium,
anticonvulsants, antipsychotics and antidepressants are effective in the management
of the acute episodes of bipolar disorder of younger adults, but there are not yet
evidence-based data in elderly bipolar patients. It is likely that the efficacy of
anticonvulsants and antipsychotics is superior during acute bipolar episodes in
elderly individuals, although both drug categories have been associated with
important adverse effects. Current data suggest that the best option during the
maintenance phase of the elderly bipolar disorder is the continuation of agents
which have been shown effective in the management of acute episodes. The
appropriate treatment of cognitive symptoms in elderly bipolar patients has not
been thoroughly investigated. In addition, the therapeutic value of psychotropics
except cholinesterase inhibitors and memantine in dementia is still controversial,
due to their association with side effects. Recent studies which have focused on
the role of lithium in dementia could help clarify the relationship of dementia and
elderly bipolar disorder. Although there are promising findings with respect to the
value of lithium treatment in the prevention of dementia, the existing clinical
studies do not support any beneficial effect of lithium administration on enhancing
cognitive functioning of people with dementia. The specific role of lithium in
dementia and the preventive value of interventions against vascular risk factors in
both disorders remain to be evaluated in future prospective studies.

Koruth, J. S., et al. (2012). "Bipolar irrigated radiofrequency ablation: a

therapeutic option for refractory intramural atrial and ventricular tachycardia
circuits." Heart Rhythm 9(12): 1932-1941.
BACKGROUND: Irrigated radiofrequency (RF) ablation can be insufficient to
eliminate intramurally located septal atrial flutter (AFL) and ventricular
tachycardia (VT) circuits. Bipolar ablation between 2 ablation catheters may be
considered for such circuits. OBJECTIVE: To evaluate the utility of bipolar
irrigated ablation to terminate arrhythmias resistant to unipolar ablation.
METHODS: In vitro: Bipolar and sequential unipolar RF ablation lesions were placed
on porcine ventricular tissue in a saline bath to assess for lesion transmurality.
Clinical: 3 patients with atypical septal flutter (AFL), 4 patients with septal VT,
and 2 with left ventricle free-wall VT, all of whom failed sequential unipolar RF
ablation, underwent bipolar RF ablation using irrigated catheters placed on either
surface of the interatria/interventricular septum and left ventricle free-wall,
respectively. RESULTS: In vitro: Bipolar RF was found to be more likely to achieve
transmural lesions (82% vs 33%; P = .001) and could do so in tissues with
thicknesses of up to 25 mm. Clinical: All 5 AFLs (3 patients) were successfully
terminated with bipolar RF. In follow-up, AFL recurred in 2 of the 3 patients and
atrial fibrillation and AFL recurred in 1 of the 3. All 3 thereafter underwent
repeat procedures with successful maintenance of sinus rhythm in 2 of the 3
patients (6-month follow-up). In the VT subgroup, 5 of 6 septal VTs and 2 of 3
free-wall VTs were terminated successfully during ablation. In follow-up (12
months), 2 of the 4 patients in the septal bipolar group and 1 of the 2 patients in
the free-wall group remained free of VT. CONCLUSIONS: Bipolar RF can be used to
terminate arrhythmias in select patients with tachyarrhythmias.

Kovacs, G. (2010). "[Long-term (prophylactic) therapy of bipolar patients with

aripiprazole]." Neuropsychopharmacol Hung 12(2): 369-372.
This case report presents two female bipolar patients, suffering from their
disorders for several years, who are now on prophylactic aripiprazole therapy.
Previously given drugs were ineffective and/or caused side effects, so the therapy
had to be changed. The patients are now on aripiprazole for two years without any
affective episodes, their functioning is appropriate and there has been no need for
hospitalization. The condition of the first patient has been balanced by
aripiprazole-venlafaxine combination therapy. The second patient was first
prescribed aripiprazole and lithium, but because of its side effect
(hypothyreosis), lithium has been stopped after six months, so she is on
aripiprazole monotherapy for one and a half year. The initial dose of aripiprazole
was 15 and 30 mg for the two patients, which caused extrapyramidal side effects,
disappearing after changing to a maintenance dose of 7.5 mg. Unfortunately at
present no specific clinical or biological markers are available for clinicians to
guide their choice of medications. The two cases presented raises attention not
only to the success of aripiprazole prophylactic treatment, but also to several
factors which in the future may aide the clinician in choosing the adequate
pharmacological agent (gender, bipolar I disorder, psychotic mixed episodes,
partial remission during interepisodes, effectiveness of low dose aripiprazole).

Kozicky, J. M., et al. (2012). "Comparison of neuropsychological effects of

adjunctive risperidone or quetiapine in euthymic patients with bipolar I disorder."
Int Clin Psychopharmacol 27(2): 91-99.
Although associations between antipsychotic use and neuropsychological
impairment in bipolar I disorder have been observed, there is a lack of studies
comparing the effects of specific agents used in this population. We compared
performance between patients receiving maintenance treatment with mood stabilizer
monotherapy (n=15), adjunctive risperidone (n=15) or quetiapine (n=17), and a group
of demographically matched healthy controls (n=28) on tests of executive function
(working memory, set shifting, and inhibition) and verbal learning. Despite having
a similar clinical profile, patients being treated with risperidone showed
significantly impaired working memory, set-shifting, and verbal learning (P<0.05)
compared with those either on mood stabilizer monotherapy or adjunctive quetiapine.
Although randomized controlled trials are required to confirm the cognitive side
effects of medications prescribed for maintenance treatment of bipolar I disorder,
preliminary results indicate that addition of risperidone to a mood stabilizer has
a negative impact on executive function and verbal learning, an effect not shared
with quetiapine.

Kraemer, S., et al. (2013). "Comparably high retention and low relapse rates in
different subpopulations of bipolar patients in a German non-interventional study."
BMC Psychiatry 13: 193.
BACKGROUND: Although a range of pharmacotherapeutical options are available
for the treatment of bipolar disorder, patient non-adherence to prescribed
treatment regimens and early treatment discontinuation remain among the primary
obstacles to effective treatment. Therefore, this observational study assessed time
on mood stabilizing medication and retention rates in patients with bipolar
disorder (BD). METHODS: In an 18-month, prospective, multicenter, non-
interventional study conducted in Germany 761 outpatients (>/=18 years) with BD and
on maintenance therapy were documented. For analysis, patients were stratified by
baseline medication: monotherapy olanzapine (OM, N = 186), lithium (LM, N = 152),
anticonvulsants (N = 216), other mood stabilizing medication (OMS, N = 44);
combination therapy olanzapine/lithium (N = 47), olanzapine/anticonvulsant (N =
68), other combinations (OC, N = 48). Continuation on medication was assessed as
retention rates with 95% confidence intervals. Time to discontinuation and relapse-
free time were calculated by Kaplan-Meier analysis. A relapse was defined as
increase to CGI-BP >3, worsening of CGI-BP by >/=2 points, hospitalization or death
related to BD. A Cox regression was calculated for the discontinuation of mood
stabilizing therapy (reference: OM). Logistic regression models with stepwise
forward selection were used to explore possible predictors of maintenance of
treatment and relapse. RESULTS: After 540 days (18 months), the overall retention
rate of baseline medication was 87.7%, without notable differences between the
cohorts. The overall mean time on mood stabilizing treatment was 444.7 days, with a
range of 377.5 (OMS) to 481 (LM) by cohort. 74.0% of all patients were without
relapse, with rates between the cohorts ranging from 58.4% (OC) to 80.2% (LM).
CONCLUSIONS: Retention rates exceeded controlled trial results in all treatment
cohorts, in addition to other explanations possibly reflecting that the physicians
were expertly adapting treatment regimens to the individual patient's disease
characteristics and special needs.

Kutzelnigg, A., et al. (2014). "Compliance as a stable function in the treatment

course of bipolar disorder in patients stabilized on olanzapine: results from a 24-
month observational study." Int J Bipolar Disord 2(1): 13.
Compliance is a key factor in the maintenance treatment of bipolar disorder.
This noninterventional study was conducted to explore factors associated with
higher levels of compliance in bipolar patients, all treated in routine clinical
settings. Bipolar outpatients (Clinical Global Impression of Severity score </=3)
who had been stabilized with olanzapine mono- or combination therapy for >/=4 weeks
were enrolled in the study. Compliance to medication was assessed at baseline and
after 3, 6, 9, 12, 18, and 24 months by a physician-rated, 4-point categorical
scale using the following classification: noncompliant (patients being compliant to
treatment schedule less than 20% of the time) and low (20% to 59% of the time),
moderate (60% to 79% of the time), and high (>/=80% of the time) levels of
compliance. Both baseline and post-baseline factors were used in a generalized
estimating equations (GEE) model to predict the likelihood of high compliance. Of
891 eligible patients, 657 patients completed the 24-month observation period. High
levels of compliance (>/=80%) were observed in 67% of patients at baseline,
increasing to 80% in study completers. High compliance at baseline was identified
as a strong predictor of compliance during study participation (odds ratio (OR) =
6.9, 95% confidence interval (CI) = 5.0 to 9.5, p < 0.001). Factors associated with
high compliance during the study (GEE model) included greater life satisfaction (p
= 0.002), better insight into illness (p < 0.001), less work impairment (p =
0.007), and fewer days of inpatient care (p = 0.002). Compliance ratings varied by
country (p < 0.001) and duration of post-baseline treatment (p = 0.014). In
conclusion, a number of clinical, functional, and social factors were identified as
predictors of compliance in patients with bipolar disorder. As compliance is
crucial for the long-term management of these patients, more attention should be
directed towards compliance itself and factors associated with compliance levels in
everyday treatment settings.

Landersdorfer, C. B., et al. (2017). "Lithium in Paediatric Patients with Bipolar

Disorder: Implications for Selection of Dosage Regimens via Population
Pharmacokinetics/Pharmacodynamics." Clin Pharmacokinet 56(1): 77-90.
BACKGROUND: Lithium is a well-established treatment for bipolar I disorder in
adults. However, there is a paucity of information on its
pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop
the first lithium dosage regimens based on population
pharmacokinetics/pharmacodynamics for paediatric patients. METHODS: Lithium
concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-
Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients
with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-
modelled. Concentrations and clinical effects following several dosage regimens
were predicted by Monte Carlo simulations. RESULTS: The pharmacokinetics were well
characterised by a two compartment model with linear elimination. Including the
effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume
of distribution decreased the unexplained inter-individual variability by up to 12
%. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg
LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The
average lithium concentration over a dosing interval required for a 50 % reduction
in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium
carbonate in two daily doses was predicted to achieve a >/=50 % reduction in YMRS
in 74 % of patients, while ~8 % of patients would be expected to have trough
concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore,
therapeutic drug monitoring will still be required even with these dosing
strategies. CONCLUSIONS: When accounting for body size, the pharmacokinetic
parameters in paediatric patients were within the range of estimates from adults.
Pharmacokinetic/pharmacodynamic modelling supported development of practical
scientifically-based dosage regimens for paediatric patients.

Lee, J. Y. and A. G. Harvey (2015). "Memory for therapy in bipolar disorder and
comorbid insomnia." J Consult Clin Psychol 83(1): 92-102.
OBJECTIVE: To examine the extent to which patients recall the contents of
therapy from 1 session to the next and to determine whether recall is associated
with treatment outcome. METHOD: Thirty interepisode individuals with bipolar
disorder and comorbid insomnia (ages 21-62 years, 56.7% women, 56.7% Caucasian)
participated in a randomized controlled trial of psychotherapies. Patients received
either cognitive behavior therapy for insomnia (CBTI-BP; n = 17) or psychoeducation
(PE; n = 13). At the beginning of each weekly session, patients freely recalled as
many therapy points (i.e., distinct ideas, principles, and experiences) as they
could from their previous session. After each session, therapists recorded a list
of all therapy points delivered. Treatment outcome was measured via the Insomnia
Severity Index (ISI), Pittsburgh Sleep Quality Index, Patient-Reported Outcome
Measurement Info System-Sleep, and Quality of Life-Sleep (QOL-Sleep), administered
pre- and posttreatment, and treatment evaluation questions administered
posttreatment. RESULTS: Patients recalled 19.6% to 36.9% of therapy points listed
by therapists. Raw numbers of therapy points recalled were positively correlated
with reductions in ISI scores and gains in QOL-Sleep and with most treatment
evaluation questions. Percentages of therapy points recalled were positively
correlated with gains in QOL-Sleep but with no other sleep outcome measures or any
of the treatment evaluation questions. Patients in CBTI-BP recalled more therapy
points than did those in PE but did not differ in the percentages of points
recalled. CONCLUSIONS: Memory for therapy is poor. The amount of content recalled
is positively associated with treatment outcome. Enhancing memory for therapy might
play a key role in improving treatment outcome.

Lemaire, M., et al. (2015). "Increased affective reactivity to neutral stimuli and
decreased maintenance of affective responses in bipolar disorder." Eur Psychiatry
30(7): 852-860.
BACKGROUND: Affective dysregulation is a core feature of bipolar disorder
(BD) and a significant predictor of clinical and functional outcome. Affective
dysregulation can arise from abnormalities in multiple processes. This study
addresses the knowledge gap regarding the precise nature of the processes that may
be dysregulated in BD and their relationship to the clinical expression of the
disorder. METHODS: Patients with BD (n=45) who were either in remission or in a
depressive or manic state and healthy individuals (n=101) were compared in terms of
the intensity, duration and physiological response (measured using inter-beat
intervals and skin conductance) to affective and neutral pictures during passive
viewing and during experiential suppression. RESULTS: Compared to healthy
individuals, patients with BD evidenced increased affective reactivity to neutral
pictures and reduced maintenance of subjective affective responses to all pictures.
This pattern was present irrespective of clinical state but was more pronounced in
symptomatic patients, regardless of polarity. Patients, regardless of symptomatic
status, were comparable to healthy individuals in terms of physiological arousal
and voluntary control of affective responses. CONCLUSION: Our study demonstrates
that increased affective reactivity to neutral stimuli and decreased maintenance of
affective responses are key dimensions of affective dysregulation in BD.

Lencer, R., et al. (2010). "Sensorimotor transformation deficits for smooth pursuit
in first-episode affective psychoses and schizophrenia." Biol Psychiatry 67(3):
217-223.
BACKGROUND: Smooth pursuit deficits are an intermediate phenotype for
schizophrenia that may result from disturbances in visual motion perception,
sensorimotor transformation, predictive mechanisms, or alterations in basic
oculomotor control. Which of these components are the primary causes of smooth
pursuit impairments and whether they are impaired similarly across psychotic
disorders remain to be established. METHODS: First-episode psychotic patients with
bipolar disorder (n = 34), unipolar depression (n = 24), or schizophrenia (n = 77)
and matched healthy participants (n = 130) performed three smooth pursuit tasks
designed to evaluate different components of pursuit tracking. RESULTS: On ramp
tasks, maintenance pursuit velocity was reduced in all three patients groups with
psychotic bipolar patients exhibiting the most severe impairments. Open loop
pursuit velocity was reduced in psychotic bipolar and schizophrenia patients.
Motion perception during pursuit initiation, as indicated by the accuracy of
saccades to moving targets, was not impaired in any patient group. Analyses in 138
participants followed for 6 weeks, during which patients were treated and psychotic
symptom severity decreased, and no significant change in performance in any group
was revealed. CONCLUSIONS: Sensorimotor transformation deficits in all patient
groups suggest a common alteration in frontostriatal networks that dynamically
regulate gain control of pursuit responses using sensory input and feedback about
performance. Predictive mechanisms appear to be sufficiently intact to compensate
for this deficit across psychotic disorders. The absence of significant changes
after acute treatment and symptom reduction suggests that these deficits appear to
be stable over time.

Leombruni, P. and F. Gastaldi (2010). "Oxcarbazepine for the treatment of

trichotillomania." Clin Neuropharmacol 33(2): 107-108.
OBJECTIVE: There is no pharmacological treatment of trichotillomania that has
consistently demonstrated efficacy, although good results have been obtained with
antidepressants and other drugs such as atypical antipsychotics, bupropion,
lithium, and topiramate. The anticonvulsant oxcarbazepine has also been used as
mood stabilizer and has been tested for treating binge eating, but there is no
report on oxcarbazepine in trichotillomania. CASE: We report the case of an obese
43-year-old woman with a diagnosis of trichotillomania in comorbidity with binge
eating disorder who was treated with a flexible dose of the anticonvulsant
oxcarbazepine. RESULT: We administered oxcarbazepine at a dosage of 1200 mg/d, and
this subject improved both in hair pulling and in eating behaviors with no relapse
after 9 months. CONCLUSIONS: Further studies with a wide sample of patients are
needed to prove the efficacy of oxcarbazepine and the long-term maintenance of
these benefits. Relationships of trichotillomania with bipolar spectrum should also
be investigated.
Leon, A. C., et al. (2011). "Antidepressants and risks of suicide and suicide
attempts: a 27-year observational study." J Clin Psychiatry 72(5): 580-586.
OBJECTIVE: The 2007 revision of the black box warning for suicidality with
antidepressants states that patients of all ages who initiate antidepressants
should be monitored for clinical worsening or suicidality. The objective of this
study was to examine the association of antidepressants with suicide attempts and
with suicide deaths. METHOD: A longitudinal, observational study of mood disorders
with prospective assessments for up to 27 years was conducted at 5 US academic
medical centers. The study sample included 757 participants who enrolled from 1979
to 1981 during an episode of mania, depression, or schizoaffective disorder, each
based on Research Diagnostic Criteria. Unlike randomized controlled clinical trials
of antidepressants, the analyses included participants with psychiatric and other
medical comorbidity and those receiving acute or maintenance therapy, polypharmacy,
or no psychopharmacologic treatment at all. Over follow-up, these participants had
6,716 time periods that were classified as either exposed to an antidepressant or
not exposed. Propensity score-adjusted mixed-effects survival analyses were used to
examine risk of suicide attempt or suicide, the primary outcome. RESULTS: The
propensity model showed that antidepressant therapy was significantly more likely
when participants' symptom severity was greater (odds ratio [OR] = 1.16; 95% CI,
1.12-1.21; z = 8.22; P < .001) or when it was worsening (OR = 1.69; 95% CI, 1.50-
1.89; z = 9.02; P < .001). Quintile-stratified, propensity-adjusted safety analyses
using mixed-effects grouped-time survival models indicate that the risk of suicide
attempts or suicides was reduced by 20% among participants taking antidepressants
(hazard ratio, 0.80; 95% CI, 0.68-0.95; z = -2.54; P = .011). CONCLUSIONS: This
longitudinal study of a broadly generalizable cohort found that, although those
with more severe affective syndromes were more likely to initiate treatment,
antidepressants were associated with a significant reduction in the risk of
suicidal behavior. Nonetheless, we believe that clinicians must closely monitor
patients when an antidepressant is initiated.

Li, Z., et al. (2017). "Valproate Attenuates Endoplasmic Reticulum Stress-Induced

Apoptosis in SH-SY5Y Cells via the AKT/GSK3beta Signaling Pathway." Int J Mol Sci
18(2).
Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role
in a range of neurological disorders, such as neurodegenerative diseases, spinal
cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic
drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently,
VPA has been reported to exert neurotrophic effects and promote neurite outgrowth,
but its molecular mechanism is still unclear. In the present study, we investigated
whether VPA inhibited ER stress and promoted neuroprotection and neuronal
restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively,
upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected
by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT)
assay, and the expression of ER stress-related apoptotic proteins such as
glucoseregulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved
caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence
assays. To explore the pathway involved in VPA-induced cell proliferation, we also
examined p-AKT, GSK3beta, p-JNK and MMP-9. Moreover, to detect the effect of VPA in
primary cortical neurons, immunofluorescence staining of beta-III tubulin and Anti-
NeuN was analyzed in primary cultured neurons exposed to TG. Our results
demonstrated that VPA administration improved cell viability in cells exposed to
TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the
levels of ATF6, XBP-1, GSK3beta, p-JNK and MMP-9. Furthermore, the levels of the ER
stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved
caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also
increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of
primary cortical neurons. Collectively, the neurotrophic effect of VPA is related
to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the
maintenance of neuronal growth. Collectively, our results suggested a new approach
for the therapeutic function of VPA in neurological disorders and neuroprotection.

Liauw, S. S. and R. S. McIntyre (2010). "Atypical antipsychotic tolerability and

switching strategies in bipolar disorder." Expert Opin Pharmacother 11(17): 2827-
2837.
IMPORTANCE TO THE FIELD: Atypical antipsychotics have unequivocally advanced
the pharmacotherapy of bipolar disorders. These broad-spectrum treatments offer
efficacy against core symptoms of acute mania, mixed state, depressed and
maintenance phases of the disorder. Atypical antipsychotics are not, however, a
panacea and are associated with several problematic tolerability and safety
concerns. For example, emerging evidence militates against the original notion that
atypical agents are without risk for extrapyramidal side effects and possibly
tardive dyskinesia when compared to their therapeutic predecessors, the
conventional antipsychotics. Although classified together, atypical antipsychotics
are heterogeneous in their tolerability and safety profile, an issue relevant to
individualizing treatment selection and switching antipsychotics for optimal
clinical management. AREAS COVERED IN THIS REVIEW: This article reviews relevant
adverse events attributable to the use of atypical antipsychotics and strategies
for switching these agents, with particular attention to the bipolar disorder
population. WHAT THE READER WILL GAIN: The reader will gain both a perspective of
treatment-emergent adverse events associated with atypical agents in the treatment
of bipolar disorder and a precise analysis of common adverse events that frequently
lead to treatment discontinuation and/or switching to a separate agent. TAKE HOME
MESSAGE: Atypical antipsychotics provide for a different array of treatment-
emergent adverse events than conventional agents. The therapeutic index of
treatment is a ratio of the relative benefit divided by the probability of harm
(i.e., side effects). Taken together, the atypical antipsychotics offer an improved
therapeutic index when compared to conventional agents in bipolar disorder.
Nevertheless, atypicals fall short of the ideal, necessitating frequent
discontinuation and switching.

Licht, R. W. (2012). "Lithium: still a major option in the management of bipolar

disorder." CNS Neurosci Ther 18(3): 219-226.
Still after more than 50 years, lithium is a major treatment of bipolar
disorder, even though it has not been promoted by the pharmaceutical industry over
the last decades. In recent years the evidence base on lithium for bipolar disorder
has substantially increased due to results from a number of trials. Therefore, a
review of this evidence is timely. The efficacy of lithium as an acute treatment
and as a maintenance treatment of bipolar disorder was evaluated through a review
of the evidence, focusing on modern, randomized, parallel-group designed trials.
Additionally, the evidence was sought translated into the proper use of lithium in
clinical practice. Lithium's antimanic efficacy has been convincingly demonstrated.
However, as blood monitoring due to the risk of toxicity is required and due to an
insufficient response in highly agitated patients, lithium monotherapy has a
limited place in the acute treatment of severe manic states. For acute bipolar
depression, results are conflicting. Recent maintenance trials have added
substantially to the documentation of lithium's long-term stabilizing properties in
bipolar disorder, and these properties have been demonstrated independently of any
acute response to lithium. Finally, it is now beyond doubt that not only does
lithium prevent mania, but also depression in bipolar disorder. Lithium is still to
be considered a major if not the most important mood- stabilizer, at least for
maintaining long-term stability in patients with bipolar disorder. The potential
risks of lithium should be weighed up against its benefits and the fact that
serious adverse effects are usually avoidable.

Licht, R. W., et al. (2010). "Lamotrigine versus lithium as maintenance treatment

in bipolar I disorder: an open, randomized effectiveness study mimicking clinical
practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6)."
Bipolar Disord 12(5): 483-493.
OBJECTIVES: In industry-generated pivotal studies, lamotrigine has been found
to be superior to placebo and comparable to lithium in the maintenance treatment of
bipolar I disorder. Here, we directly compared lamotrigine to lithium under
conditions similar to clinical routine conditions. METHODS: Adult bipolar I
disorder patients with at least two episodes within the last five years and an
index episode requiring treatment were randomized to lithium (n = 78; doses
adjusted to obtain serum levels of 0.5-1.0 mmol/L) or to lamotrigine (n = 77; up-
titrated to 400 mg/day) as maintenance treatments. Randomization took place when
clinically appropriate, and comedication was allowed within the first six months
after randomization. The patients were enrolled from March 2001 to December 2005,
and observations were censored December 2006, allowing a subgroup of patients to be
followed for more than five years. The primary outcome measure was time to
predefined endpoints indicating insufficient maintenance treatment, and the major
secondary outcome measure was time to any study endpoint. Data were analyzed
primarily by Cox proportional regression models. RESULTS: For the primary outcome
measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was
0.92 [95% confidence interval (CI): 0.60-1.40]. When the primary endpoints were
broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and
depression were, respectively, 1.91 (95% CI: 0.73-5.04) and 0.69 (95% CI: 0.41-
1.22). There was no between-group difference in terms of staying in study [HRR:
0.85 (95% CI: 0.61-1.19)]. Most treatment failures occurred within the first 1.5
years of treatment, and, among patients followed for at least five years,
practically no patients were maintained successfully on monotherapy with either of
the drugs. The lithium-treated patients reported diarrhea, tremor, polyuria, and
thirst more frequently. Two cases, probably lamotrigine-related, of benign rash
occurred. CONCLUSIONS: No differences in maintenance effectiveness between lithium
and lamotrigine could be demonstrated. Lamotrigine was better tolerated than
lithium, but apparently this did not influence the outcome.

Lin, C. C., et al. (2016). "Relapses and recurrences of catatonia: 30-case analysis
and literature review." Compr Psychiatry 66: 157-165.
OBJECTIVE: Relieving catatonia helps identify the underlying etiology and its
treatment. However, catatonia may reemerge after some time, but there are few data
on the relapses and recurrences of catatonia. We aimed to investigate the
characteristics of patients with relapses or recurrences of catatonia as well as
the efficacy of the lorazepam-diazepam protocol on them. METHODS: Patients with
catatonia who had more than one episode of catatonia and were treated with the
lorazepam-diazepam protocol were identified. Their medical charts were reviewed,
and interview was conducted. RESULTS: Thirty patients were identified. Nineteen
(63.3%) were diagnosed with schizophrenia, five (16.7%) with major depressive
disorder, two (6.7%) with bipolar disorder, and four (13.3%) with general medical
conditions. In the 68 relapses and relapses the lorazepam-diazepam protocol was
used, full response was reported in 54 (79.4%) of them. Twelve of 19 (63.2%)
patients with schizophrenia were treated with clozapine. Twenty (66.7%) out of 30
patients were maintained on oral lorazepam by the time of discharge. Literature
review showed similar prevalence of schizophrenia in patients with more than one
episode of catatonia, and a wide variety of treatment options. CONCLUSION: The
lorazepam-diazepam protocol was mostly effective in managing relapses and
recurrences of catatonia. Maintenance clozapine and oral lorazepam were beneficial
in a significant number of patients.

Lindenmayer, J. P. and A. Kaur (2016). "Antipsychotic Management of Schizoaffective

Disorder: A Review." Drugs 76(5): 589-604.
Schizoaffective disorder (SAD) is an incapacitating illness that presents
clinicians with challenges in terms of both its diagnosis and its
psychopharmacological management. Most studies conducted on the
psychopharmacological treatment of SAD also include patients with schizophrenia or
other psychotic illnesses, thereby providing an unspecific view to the clinician as
to the best way of treating patients with SAD. The objective of this article is to
review studies on evidence-based treatment of patients with SAD. We conducted a
systematic literature search in MEDLINE/PubMed for full-text studies in the English
language using the terms 'Schizoaffective and treatment' or 'antipsychotic
schizoaffective'. Our review found relatively few studies with either an active
comparator or placebo that examined the efficacy of antipsychotics for patients
with SAD without an admixture of patients with schizophrenia. Only oral
paliperidone extended release (ER), paliperidone long-acting injection (LAI), and
risperidone have been shown to be effective and safe in reducing psychotic as well
as affective components in acutely ill SAD patients in controlled studies.
Paliperidone ER and LAI have also been shown to be efficacious in the maintenance
treatment phase of SAD patients. While no supportive data exist, it is possible
that other atypical antipsychotics may have similar efficacy to the two mentioned
above. We conclude with a number of research recommendations for the study of
treatment options for patients with SAD. First, there is a need for studies with
patients specifically diagnosed with SAD for both the acute and the maintenance
phase. The sample size needs to be adequate to allow a primary analysis of efficacy
and to allow for analysis of the SAD subtypes: depressed and bipolar. Another
recommendation is the need for studies of patients with SAD stratified into
patients with and without mood stabilizers or antidepressants to allow the
examination of the adjunctive role of these psychotropic medications. A third
recommendation is to focus on specific co-morbid aspects of patients with SAD, such
as suicidality and substance use disorders. Data from such studies will fill the
gap of evidence-based treatment approaches and help clinicians in making important
treatment decisions for patients with this complex condition.

Lindstrom, L., et al. (2017). "Maintenance therapy with second generation

antipsychotics for bipolar disorder - A systematic review and meta-analysis." J
Affect Disord 213: 138-150.
BACKGROUND: Second generations antipsychotics (SGA) are frequently used for
maintenance treatment in bipolar disorder. We systematically reviewed the efficacy
and long-term effects of treatment with SGA, regardless of treatment strategy (SGA
administered either as monotherapy or as adjunctive therapy), in comparison to
placebo, lithium or valproate. Primary outcomes were relapses (mood episode
recurrence) and discontinuation. METHOD: Clinical studies were identified through
database searching in PubMed, Embase, PsychInfo and Cochrane Library and critically
appraised based on the Cochrane Handbook. Full data extraction of raw data was
performed and analyzed with meta-analyses, and level of evidence graded using
GRADE. Only randomized controlled studies (RCT) and observational studies were
included, with a minimum follow-up of 6 months. Comparators used were restricted to
placebo, lithium, valproate or other anti-epileptic drugs. RESULTS: We identified
15 RCTs on SGA in bipolar disorder with follow-up-time of 6 months up to 2 years,
and one observational study reporting long-term effects of up to 4 years. A total
of 6142 patients were included in the randomized trials. No long-term RCTs beyond 2
years follow-up was identified. All RCTs except for one included patients with
bipolar disorder type I only. All RCTs except for two included patients pre-
stabilized on the drug under investigation prior to randomization (enrichment
design). For SGA as adjunctive therapy to lithium or valproate, meta-analyses
showed that treatment with either aripiprazole (RR: 0.65, 95% CI 0.50-0.85),
quetiapine (RR: 0.38, 95% CI 0.32-0.46) or ziprasidone (RR: 0.62, 95% CI 0.40-0.96)
reduced the overall risk of relapses in patients that had responded during the
stabilization phase. Adjunctive therapy with quetiapine was the only drug that
reduced both manic and depressive episodes. For SGA as monotherapy, only quetiapine
was shown to be better than lithium/ valproate for both manic and depressive
relapses, but only for patients stabilized on quetiapine during the acute phase. As
monotherapy, olanzapine, quetiapine and risperidone were shown to be superior to
placebo in reducing the overall risk of relapses. LIMITATIONS: There were
considerable limitations to the evidence base of maintenance treatment with SGA in
bipolar disorder. Most studies used stabilized patients, i.e. enrichment design
(selection bias), had considerable dropout levels (attrition bias), and variable
degree of reporting bias. No long-term RCT data on efficacy is available beyond 2
years, and almost all studies are on bipolar disorder type I patients only. Despite
these limitations, we elucidate quantitative findings from meta-analyses conducted
on the randomized trials published on the topic.

Livianos, L., et al. (2012). "Is melatonin an adjunctive stabilizer?" Psychiatry

Clin Neurosci 66(1): 82-83.

Llorca, P. M., et al. (2013). "Guidelines for the use and management of long-acting
injectable antipsychotics in serious mental illness." BMC Psychiatry 13: 340.
BACKGROUND: Long-acting injectable (LAI) formulations are not widely used in
routine practice even though they offer advantages in terms of relapse prevention.
As part of a process to improve the quality of care, the French Association for
Biological Psychiatry and Neuropsychopharmacology (AFPBN) elaborated guidelines for
the use and management of antipsychotic depots in clinical practice. METHODS: Based
on a literature review, a written survey was prepared that asked about 539 options
in 32 specific clinical situations concerning 3 fields: target-population,
prescription and use, and specific populations. We contacted 53 national experts,
42 of whom (79%) completed the survey. The options were scored using a 9-point
scale derived from the Rand Corporation and the University of California in the
USA. According to the answers, a categorical rank (first-line/preferred choice,
second-line/alternate choice, third-line/usually inappropriate) was assigned to
each option. The first-line option was defined as a strategy rated as 7-9
(extremely appropriate) by at least 50% of the experts. The following results
summarize the key recommendations from the guidelines after data analysis and
interpretation of the results of the survey by the scientific committee. RESULTS:
LAI antipsychotics are indicated in patients with schizophrenia, schizoaffective
disorder, delusional disorder and bipolar disorder. LAI second-generation
antipsychotics are recommended as maintenance treatment after the first episode of
schizophrenia. LAI first-generation antipsychotics are not recommended in the early
course of schizophrenia and are not usually appropriate in bipolar disorder. LAI
antipsychotics have long been viewed as a treatment that should only be used for a
small subgroup of patients with non-compliance, frequent relapses or who pose a
risk to others. The panel considers that LAI antipsychotics should be considered
and systematically proposed to any patients for whom maintenance antipsychotic
treatment is indicated. Recommendations for medication management when switching
oral antipsychotics to LAI antipsychotics are proposed. Recommendations are also
given for the use of LAI in specific populations. CONCLUSION: In an evidence-based
clinical approach, psychiatrists, through shared decision-making, should be
systematically offering to most patients that require long-term antipsychotic
treatment an LAI antipsychotic as a first-line treatment.

Loftis, J. M., et al. (2013). "Effect of epigallocatechin gallate supplementation

in schizophrenia and bipolar disorder: an 8-week, randomized, double-blind,
placebo-controlled study." Ther Adv Psychopharmacol 3(1): 21-27.
OBJECTIVES: Strategies that focus on the reduction of oxidative stress and
inflammation may have therapeutic benefit for the treatment of schizophrenia. This
clinical trial sought to determine, in a double-blind study, whether
epigallocatechin gallate (EGCG), a green tea extract, is a useful adjunct to
maintenance antipsychotic medication. METHODS: Adults with schizophrenia,
schizoaffective disorder or bipolar disorder who were maintained on antipsychotic
and other psychotropic medications were randomized to supplemental EGCG or placebo.
Study participants completed clinical assessments and blood draws to evaluate
supplemental treatment effects on psychiatric symptoms and plasma inflammatory
markers. RESULTS: A total of 34 participants (17 EGCG, 17 placebo) were randomized
and 25 participants (14 EGCG, 11 placebo) completed the study. Both treatment
groups showed significant reductions in psychotic, depressive and anxiety symptoms
from baseline to end of treatment. However, EGCG did not significantly affect
psychiatric symptoms or inflammatory markers, as compared with placebo. Adverse
effects were mild and comparable between groups. CONCLUSION: There was no signal
for a therapeutic effect of the green tea extract EGCG on psychiatric symptoms in
this placebo-controlled pilot study.

Lolich, M., et al. (2010). "[First psychotic episode in bipolar disorder: clinical
differentiation and functional impact in an Argentinean national sample]." Vertex
21(94): 418-427.
BACKGROUND: Bipolar disorder in its early phase results in a diagnostic and
therapeutic challenge for the clinician. Individuals with bipolar disorder can be
grouped according with their different clinical features such as the presence or
absence of psychotic symptoms. Early illness detection and treatment is usually
associated with a better prognosis. OBJECTIVE: The main objective of this study was
to compare the clinical features, functionality and stigma of patients with bipolar
disorder with psychotic symptoms at onset. METHOD: A total sample of 175 bipolar
disorder outpatients completed clinical assessment (YMRS and HAM-D), functionality
(FAST), and stigma (ISE) scales. All patients were clinically stable for at least
three months and were following active maintenance treatment regimens. RESULTS: The
psychotic group consisted of 70 patients and the non-psychotic group 105 patients.
Statistical significant differences were found between patients with and without
psychotic features regarding sex, age at diagnosis, perceived stigma and functional
impairment. Bipolar patients with psychotic symptoms at onset received an early
treatment. DISCUSSION: Clinical differences found in both groups of bipolar
patients have therapeutic implications which may account for different outcomes.
Differential interventions could be designed according to each clinical group.
Special attention should be paid to bipolar first episode features.

Lorenz, B., et al. (2010). "Retinal blinding disorders and gene therapy--molecular
and clinical aspects." Curr Gene Ther 10(5): 350-370.
Retinal blinding disorders together have a prevalence of 1 in 2000 humans
world wide and represent a significant impact on the quality of life as well as the
possibility to attain personal achievements. Mutations in genes that are expressed
either in RPE cells, photoreceptors or bipolar cells can cause varying forms of
degenerative or stationary retinal disorders, as the presence of the encoded
proteins is crucial for normal function, maintenance and synaptic interaction. The
degree of damage caused by different mutations depends upon the type of mutation
within the gene, resulting in either total absence or the presence of a non-
functional or potentially toxic protein. Potential treatment strategies require the
identification of the cell type, in which the mutated gene is expressed for later
targeting by viral vector mediated gene transfer. In the first part of this review,
the authors present different cellular pathways that take place either in the RPE,
photoreceptors, or bipolar cells. Furthermore, the authors demonstrate why genetic
and molecular testing methods, which clearly identify the disease causing
mutations, are crucial for attaining the correct diagnosis in order to identify
patients suitable to be treated by upcoming new therapeutic methods. In the second
part, a short clinical classification of the most important forms of retinal
blinding disorders is given, together with clinical aspects concerning the problems
that arise when facing low residual visual perception and the enormous
heterogeneity of symptoms within these disorders.

Machino, A., et al. (2013). "The valproate serum level in maintenance therapy for
bipolar disorder in Japan." Hiroshima J Med Sci 62(1): 7-12.
The appropriate therapeutic serum valproate level in maintenance therapy for
bipolar disorder is not well known. We studied the serum valproate levels in
seventeen bipolar I and twenty-four bipolar II disorder outpatients who had been
treated with stable doses of valproate successfully for at least 12 months as
prophylactic therapy. The trough serum valproate levels were 52.2 +/- 20.4
microg/ml in bipolar I, and 41.0 +/- 18.3 microg/ml in bipolar II disorder
patients, respectively. A greater trend towards a higher trough level (p = 0.07)
was indicated in the bipolar I disorder group. We speculate that these valproate
levels may be an approximation to the appropriate valproate levels in maintenance
therapy and that there may be a correlation between the level of valproate required
for stabilization and the subtype of the bipolar disorder. However, when
interpreting these findings, certain limitations to this study? Need to be taken
into account as follows. The sample size was small. We could not look at a group on
valproate that had relapsed and a group that had dropped out of maintenance
therapy. Further studies are needed.

Mahgoub, N., et al. (2014). "Symptoms and observations: differences in time course
during electroconvulsive therapy in geriatric depressed patients." J ECT 30(1): e7-
8.
Electroconvulsive therapy is used for the management of severe and refractory
depression across the age spectrum. Treatment is guided by clinical response.
However, there may be differences between the time course of improvement in
clinical observations and patients' self-report of improvements. We report 4 cases
of depression in late life that illustrate this issue. We discuss the potential
significance of such differences and the need for research.

Mahowald, M. W., et al. (2010). "Insomnia: how tricky can it get?" Sleep Med 11(4):
335-336.

Malempati, R. N. (2015). "Aripiprazole adjunct treatment in bipolar I or II

disorder, depressed state: a 2-year clinical study." J Nerv Ment Dis 203(1): 58-64.
The symptomatic course of bipolar disorder (BPD) is chronic and dominated by
depression. As recurrence rates are high, maintenance therapy is required. Although
efficacious, mood stabilizers may be hampered by poor adherence, and second-
generation antipsychotic medications may be associated with weight gain and
metabolic abnormalities. There is evidence to suggest that aripiprazole is
beneficial in major depressive disorder and BPD with depression. We therefore
investigated 2-year clinical outcomes with aripiprazole adjunct therapy at 5 to 15
mg once daily alongside a mood stabilizer in 40 patients with BPD. All patients
experienced marked improvements in Montgomery-Asberg Depression Rating Scale scores
by 6 weeks and substantial reductions in Clinical Global Impressions Scale scores
by 6 months. All patients were able to return to optimal or premorbid functioning
by 6 months to 1 year. By 1 year, all patients made a complete functional recovery
on the Sheehan Disability Scale. Improvements were maintained on all measures up to
2 years. There were minimal adverse events, all of which decreased during therapy.
Our findings indicate that aripiprazole adjunct treatment is safe and effective as
an acute and maintenance therapy for BPD. However, the findings will need to be
replicated by larger studies.

Malhi, G. S., et al. (2010). "The pharmacological treatment of bipolar disorder in

primary care." Med J Aust 193(4 Suppl): S24-30.
OBJECTIVE: To provide a practical overview of the pharmacological management
of adults with bipolar disorder in primary care and the role of general
practitioners in the pharmacotherapy of this complex disorder. DATA SOURCES:
Published guidelines for the treatment of bipolar disorder, plus Cochrane reviews,
meta-analyses, review articles and reports from randomised controlled trials that
were published up to May 2009. STUDY SELECTION: Over 500 articles on the treatment
of bipolar disorder were reviewed, with an emphasis on meta-analyses and systematic
reviews of randomised controlled trials. Where evidence was more limited, open
trials and non-controlled data were also reviewed. DATA EXTRACTION: Key
recommendations relevant to GPs were synthesised and rated according to National
Health and Medical Research Council levels of evidence. DATA SYNTHESIS: Lithium,
valproate and atypical antipsychotics are first-line treatment options for acute
mania, and monotherapy is ideal if it produces an adequate response. For depressive
episodes, recommendations are less definitive and the use of antidepressants is
controversial. Most patients require maintenance treatment, during which
pharmacotherapy should be used to prevent relapse, and psychological and social
interventions should be considered. CONCLUSIONS: Bipolar disorder is a lifelong
episodic illness that affects 1%-2% of the population, many of whom are principally
managed by their GPs. Pharmacological treatment with mood-stabilising agents is the
primary form of management, although this is ideally provided in conjunction with
psychosocial interventions.

Malhi, G. S., et al. (2016). "Lithiumeter: Version 2.0." Bipolar Disord 18(8): 631-
641.
BACKGROUND: The Lithiumeter was developed as a visual and practical guide for
determining lithium levels in the management of bipolar disorder (BD). It appears
to have been well received, as evidenced by its increasing popularity amongst
doctors as a deskside clinical aide, and adoption and reproduction of the schematic
in clinical guidelines and texts. However, since its publication 5 years ago, key
basic neuroscience and clinical research developments pertaining to lithium have
significantly advanced our understanding, necessitating further refinement of
guidance concerning the practicalities of lithium therapy. METHODS: Literature
concerning the indications for, and therapeutic levels of, lithium and the
associated acute and chronic risks of therapy was scrutinized as part of updating
clinical practice guidelines. We have reviewed these updates and identified
significant areas of change with respect to the previous Lithiumeter (version 1.0).
RESULTS: Since 2011, updated clinical practice guidelines have narrowed the
indicated plasma lithium concentration for maintenance therapy, suggesting that
additional guidance is necessary for optimizing treatment. Relevant updated
clinical guidance was integrated to constitute the Lithiumeter 2.0, which provides
a more comprehensive overview of the practical aspects of lithium therapy while
maintaining a focus on optimization of lithium levels, such as differential
titration of lithium depending on the current mood state. CONCLUSIONS: The
Lithiumeter 2.0 is an update that clinicians will find useful for their practice.
By addressing some of the issues faced in clinical practice, translational clinical
research will continue to inform the Lithiumeter in future updates.

Malhi, G. S., et al. (2012). "Mania: diagnosis and treatment recommendations." Curr
Psychiatry Rep 14(6): 676-686.
This article provides recommendations for the diagnosis and treatment of
mania, which characterizes bipolar I disorder (BD I). Failure to detect mania leads
to misdiagnosis and suboptimal treatment. To diagnose mania, clinicians should
include a detailed mood history within their assessment of patients presenting with
depression, agitation, psychosis or insomnia. With regards to treatment, by
synthesizing the findings from recent treatment guidelines, and reviewing relevant
literature, this paper has distilled recommendations for both acute and long-term
management. Antimanic agents including atypical antipsychotics and traditional mood
stabilizers are employed to reduce acute manic symptoms, augmented by
benzodiazepines if needed, and in refractory or severe cases with behavioural
and/or psychotic disturbance, electroconvulsive therapy may occasionally be
necessary. Maintenance/prophylaxis therapy aims to reduce recurrences/relapse, for
which the combination of psychological interventions with pharmacotherapy is
beneficial as it ensures adherence and monitoring of tolerability.

Malhi, G. S., et al. (2013). "Potential mechanisms of action of lithium in bipolar

disorder. Current understanding." CNS Drugs 27(2): 135-153.
Lithium has been used for over half a century for the treatment of bipolar
disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence
supporting its efficacy in this role. Despite this, the specific mechanisms by
which lithium exerts its mood-stabilizing effects are not well understood. Given
the inherently complex nature of the pathophysiology of bipolar disorder, this
paper aims to capture what is known about the actions of lithium ranging from
macroscopic changes in mood, cognition and brain structure, to its effects at the
microscopic level on neurotransmission and intracellular and molecular pathways. A
comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO
was conducted using relevant keywords and the findings from the literature were
then reviewed and synthesized. Numerous studies report that lithium is effective in
the treatment of acute mania and for the long-term maintenance of mood and
prophylaxis; in comparison, evidence for its efficacy in depression is modest.
However, lithium possesses unique anti-suicidal properties that set it apart from
other agents. With respect to cognition, studies suggest that lithium may reduce
cognitive decline in patients; however, these findings require further
investigation using both neuropsychological and functional neuroimaging probes.
Interestingly, lithium appears to preserve or increase the volume of brain
structures involved in emotional regulation such as the prefrontal cortex,
hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a
neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases
inhibitory (GABA) neurotransmission; however, these broad effects are underpinned
by complex neurotransmitter systems that strive to achieve homeostasis by way of
compensatory changes. For example, at an intracellular and molecular level, lithium
targets second-messenger systems that further modulate neurotransmission. For
instance, the effects of lithium on the adenyl cyclase and phospho-inositide
pathways, as well as protein kinase C, may serve to dampen excessive excitatory
neurotransmission. In addition to these many putative mechanisms, it has also been
proposed that the neuroprotective effects of lithium are key to its therapeutic
actions. In this regard, lithium has been shown to reduce the oxidative stress that
occurs with multiple episodes of mania and depression. Further, it increases
protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma
2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3
and autophagy. Overall, it is clear that the processes which underpin the
therapeutic actions of lithium are sophisticated and most likely inter-related.

Malhi, G. S., et al. (2011). "The lithiumeter: a measured approach." Bipolar Disord
13(3): 219-226.
BACKGROUND: Lithium has long been recognised for its mood-stabilizing effects
in the management of bipolar disorder (BD) but in practice its use has been limited
because of real and 'imagined' concerns. This article addresses the need for
lithium to be measured with respect to its clinical and functional effects. It
introduces a visual scale, termed lithiumeter, which captures the optimal lithium
plasma levels for the treatment of BD. METHODS: Key words pertaining to lithium's
administration, dosing, and side effects as well as its efficacy in acute and long-
term treatment of BD were used to conduct an electronic search of the literature.
Relevant articles were identified by the authors and reviewed. RESULTS: This paper
outlines the considerations necessary prior to initiating lithium therapy and
provides a guide to monitoring lithium plasma levels. Current recommendations for
optimal plasma lithium levels in the management of BD are then discussed with
respect to indications for use in the acute phases of the illness and maintenance
therapy. The risks associated with lithium treatment are also discussed.
CONCLUSIONS: The lithiumeter provides a practical guide of optimal lithium levels
for the clinical management of BD.

Manchia, M., et al. (2013). "Assessment of Response to Lithium Maintenance

Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report."
PLoS One 8(6): e65636.
OBJECTIVE: The assessment of response to lithium maintenance treatment in
bipolar disorder (BD) is complicated by variable length of treatment, unpredictable
clinical course, and often inconsistent compliance. Prospective and retrospective
methods of assessment of lithium response have been proposed in the literature. In
this study we report the key phenotypic measures of the "Retrospective Criteria of
Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale
currently used in the Consortium on Lithium Genetics (ConLiGen) study. MATERIALS
AND METHODS: Twenty-nine ConLiGen sites took part in a two-stage case-vignette
rating procedure to examine inter-rater agreement [Kappa (kappa)] and reliability
[intra-class correlation coefficient (ICC)] of lithium response. Annotated first-
round vignettes and rating guidelines were circulated to expert research clinicians
for training purposes between the two stages. Further, we analyzed the
distributional properties of the treatment response scores available for 1,308
patients using mixture modeling. RESULTS: Substantial and moderate agreement was
shown across sites in the first and second sets of vignettes (kappa = 0.66 and
kappa = 0.54, respectively), without significant improvement from training.
However, definition of response using the A score as a quantitative trait and
selecting cases with B criteria of 4 or less showed an improvement between the two
stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score
distribution indicated three subpopulations (full responders, partial responders,
non responders). CONCLUSIONS: We identified two definitions of lithium response,
one dichotomous and the other continuous, with moderate to substantial inter-rater
agreement and reliability. Accurate phenotypic measurement of lithium response is
crucial for the ongoing ConLiGen pharmacogenomic study.

Mangiola, F., et al. (2016). "Gut microbiota in autism and mood disorders." World J
Gastroenterol 22(1): 361-368.
The hypothesis of an important role of gut microbiota in the maintenance of
physiological state into the gastrointestinal (GI) system is supported by several
studies that have shown a qualitative and quantitative alteration of the intestinal
flora in a number of gastrointestinal and extra-gastrointestinal diseases. In the
last few years, the importance of gut microbiota impairment in the etiopathogenesis
of pathology such as autism, dementia and mood disorder, has been raised. The
evidence of the inflammatory state alteration, highlighted in disorders such as
schizophrenia, major depressive disorder and bipolar disorder, strongly recalls the
microbiota alteration, highly suggesting an important role of the alteration of GI
system also in neuropsychiatric disorders. Up to now, available evidences display
that the impairment of gut microbiota plays a key role in the development of autism
and mood disorders. The application of therapeutic modulators of gut microbiota to
autism and mood disorders has been experienced only in experimental settings to
date, with few but promising results. A deeper assessment of the role of gut
microbiota in the development of autism spectrum disorder (ASD), as well as the
advancement of the therapeutic armamentarium for the modulation of gut microbiota
is warranted for a better management of ASD and mood disorders.

Manning, J. S. (2015). "Measuring patient outcomes and making the transition from
acute to maintenance treatment for bipolar depression." J Clin Psychiatry 76(12):
e1603.
Patients with bipolar disorder require diligent management involving
psychoeducation, a strong therapeutic alliance, and ongoing monitoring with rating
scales to achieve the best outcomes. Clinicians should monitor symptom response,
functioning, and quality of life to determine if treatment needs to be be adjusted.
Assessing adverse effects must be done regularly to improve treatment adherence.
Because effective acute phase treatments are often continued in maintenance
treatment, clinicians must find the right balance of efficacy and tolerability for
long-term success. The FDA has approved 7 agents for maintenance treatment of
bipolar disorder. Because of the high risk of recurrent depressive episodes,
clinicians should be aware of which agents are more effective for reducing manic or
depressive relapses.

Mantere, O., et al. (2011). "[Maintenance therapy in bipolar affective disorder]."

Duodecim 127(9): 891-898.
In bipolar affective disorder, the patients exhibit life-long susceptibility
to periodic episodes of depression, mania, hypomania, including mixed phases.
Maintenance therapy aims to prevent new episodes of affective disorder and
associated self-destructive behavior, to prevent milder symptoms occurring between
the actual episodes and to maintain functional capacity. Maintenance therapy is
always initiated upon the diagnosis of bipolar affective disorder. In a type II
disorder with mild symptoms, gradual termination of maintenance therapy can be
considered while monitoring the status of the patient. The drug is chosen on the
basis of individual benefit/risk ratio.

Marcus, R., et al. (2011). "Efficacy of aripiprazole adjunctive to lithium or

valproate in the long-term treatment of patients with bipolar I disorder with an
inadequate response to lithium or valproate monotherapy: a multicenter, double-
blind, randomized study." Bipolar Disord 13(2): 133-144.
OBJECTIVES: To evaluate the efficacy and safety of aripiprazole (ARI)
adjunctive to lithium (Li) or valproate (Val) (ARI+Li / Val) compared with placebo
(PLB) adjunctive to Li or Val (PLB+Li / Val) as maintenance therapy for patients
with bipolar I disorder who had an inadequate response to Li or Val monotherapy.
METHODS: Patients with a current manic/mixed episode received Li or Val for at
least 2 weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS)
total score >/= 16 and </= 35% decrease from baseline at 2 weeks] received
adjunctive single-blind ARI plus mood stabilizer. Patients who achieved stability
[YMRS and Montgomery-Asberg Depression Rating Scale (MADRS) score </= 12] for 12
consecutive weeks were randomized to double-blind ARI (10-30 mg/day) or PLB+Li /
Val. Relapse was monitored for 52 weeks. Adverse events (AEs) were also evaluated.
RESULTS: A total of 337 patients were randomized to ARI+ Li / Val (n=168) or PLB+Li
/ Val (n=169). The Kaplan-Meier relapse rate at 52 weeks was 17% with ARI+Li / Val
and 29% with PLB+Li / Val. ARI+Li / Val significantly delayed time to any relapse
compared with PLB+Li / Val; hazard ratio=0.54 (95% confidence interval: 0.33-0.89;
log-rank p=0.014). The most common AEs >/= 5%(ARI+Li / Val versus PLB+Li / Val)
were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor
(6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). CONCLUSIONS: Continuation of
ARI+Li / Val treatment increased the time to relapse to any mood episode compared
with Li or Val monotherapy, and was relatively well tolerated during the one-year
study. These findings suggest that there is a long-term benefit in continuing ARI
adjunctive to a mood stabilizer after sustained remission is achieved.

Maremmani, A. G., et al. (2013). "The long-term outcomes of heroin dependent-

treatment-resistant patients with bipolar 1 comorbidity after admission to enhanced
methadone maintenance." J Affect Disord 151(2): 582-589.
OBJECTIVE: The aim of this study was to compare the long-term outcomes of
treatment-resistant bipolar 1 heroin addicts with peers who were without DSM-IV
axis I psychiatric comorbidity (dual diagnosis). METHOD: 104 Heroin-dependent
patients (TRHD), who also met criteria for treatment resistance - 41 of them with
DSM-IV-R criteria for Bipolar 1 Disorder (BIP1-TRHD) and 63 without DSM-IV-R axis I
psychiatric comorbidity (NDD-TRHD) - were monitored prospectively (3 years on
average, min. 0.5, max. 8) along a Methadone Maintenance Treatment Programme
(MMTP). RESULTS: The rates for survival-in-treatment were 44% for NDD-TRHD patients
and 58% for BIP1-TRHD patients (p=0.062). After 3 years of treatment such rates
tended to become progressively more stable. BIP1-TRHD patients showed better
outcome results than NDD-TRHD patients regarding CGI severity (p<0.001) and DSM-IV
GAF (p<0.001). No differences were found regarding urinalyses for morphine between
groups during the observational period. Bipolar 1 patients needed a higher
methadone dosage in the stabilization phase, but this difference was not
statistically significant. LIMITATIONS: The observational nature of the protocol,
the impossibility of evaluating a follow-up in the case of the patients who dropped
out, and the multiple interference caused by interindividual variability, the
clinical setting and the temporary use of adjunctive medications. CONCLUSIONS:
Contrary to expectations, treatment-resistant patients with bipolar 1 disorder
psychiatric comorbidity showed a better long-term outcome than treatment-resistant
patients without psychiatric comorbidity.

Marienfeld, C. and R. A. Rosenheck (2015). "Psychiatric services and prescription

fills among veterans with serious mental illness in methadone maintenance
treatment." J Dual Diagn 11(2): 128-135.
 OBJECTIVE: Comorbidity and co-prescription patterns of people with serious
mental illness in methadone maintenance may complicate their treatment and have not
been studied. The goal of this study was to examine the care and characteristics of
people with serious mental illness in methadone maintenance treatment nationally in
the Veterans Health Administration (VHA). METHODS: Using national VHA data from
FY2012, bivariate and multiple logistic regression analyses were used to compare
veterans in methadone maintenance treatment wo had a serious mental illness
(schizophrenia, bipolar disorder, or major affective disorder) to patients in
methadone maintenance treatment without serious mental illness and patients with
serious mental illness who were not in methadone maintenance treatment. RESULTS:
Only a small fraction of patients with serious mental illness were receiving
methadone maintenance treatment (0.65%), but a relatively large proportion in
methadone maintenance treatment had a serious mental illness (33.2%). Compared to
patients without serious mental illness, patients with serious mental illness in
methadone maintenance treatment were more likely to have been homeless, to have had
a recent psychiatric hospitalization, to be over 50% disabled, and to have had more
fills for more classes of psychotropic drugs. Compared to other patients with
serious mental illness, patients with serious mental illness in methadone
maintenance treatment were more likely to have a drug abuse diagnosis and to reside
in large urban areas. CONCLUSIONS: One-third of patients in methadone maintenance
treatment have serious mental illness and more frequent psychiatric comorbidity,
and they are more likely to use psychiatric and general health services and fill
more types of psychiatric prescriptions. Further study and clinical awareness of
potential drug-drug interactions in this high medication and service using
population are needed.

Marino, J., et al. (2012). "The role of paliperidone extended release for the
treatment of bipolar disorder." Neuropsychiatr Dis Treat 8: 181-189.
BACKGROUND: Bipolar disorder (BD) is a chronic, relapsing, episodic mental
illness associated with other psychiatric comorbidities. There is a substantial
economic burden with BD, which makes it challenging to treat. The aim of this
review is to evaluate the pharmacology, clinical efficacy, and safety data related
to paliperidone extended release (ER) for the treatment of BD. METHODS: A
literature search was performed from January 1966 through January 2012 using
PreMEDLINE, MEDLINE, EMBASE, IPA, and ClinicalTrials.gov to identify articles in
English regarding the pharmacology, clinical efficacy, and safety of paliperidone
ER in acute mania or mixed episodes or in the maintenance treatment of BD I.
RESULTS: There are currently three published studies relating to the use of
paliperidone ER for the treatment of BD. Two of these evaluated paliperidone ER as
monotherapy for acute mania, while the other assessed its role as adjunct with a
mood stabilizer. CONCLUSION: According to the limited available evidence,
paliperidone at higher doses of ER 9-12 mg/day may be a safe and efficacious
treatment option for acute episodes of mania in BD. A once-daily dose formulation
may improve patient adherence to treatment; however, the cost of paliperidone ER,
which is higher than that of generically available second-generation antipsychotics
(such as olanzapine and risperidone), and a lack of alternative dosage forms (ie,
liquid, intramuscular) compared with other agents may limit its usefulness in the
treatment of BD. The role of paliperidone ER as an adjunctive agent or for long-
term use requires further investigation.

Marmura, M. J., et al. (2010). "Electronic medical records as a research tool:

evaluating topiramate use at a headache center." Headache 50(5): 769-778.
BACKGROUND: Electronic medical records (EMRs) are used in large healthcare
centers to increase efficiency and accuracy of documentation. These databases may
be utilized for clinical research or to describe clinical practices such as
medication usage. METHODS: We conducted a retrospective analysis of EMR data from a
headache clinic to evaluate clinician prescription use and dosing patterns of
topiramate. The study cohort comprised 4833 unique de-identified records, which
were used to determine topiramate dose and persistence of treatment. RESULTS:
Within the cohort, migraine was the most common headache diagnosis (n = 3753,
77.7%), followed by tension-type headache (n = 338, 7.0%) and cluster or trigeminal
autonomic cephalalgias (n = 287, 5.9%). Physicians prescribed topiramate more often
for subjects with migraine and idiopathic intracranial hypertension (P < .0001)
than for those with other conditions, and more often for subjects with coexisting
conditions including obesity, bipolar disorder, and depression. The most common
maintenance dose of topiramate was 100 mg/day; however, approximately 15% of
subjects received either less than 100 mg/day or more than 200 mg/day. More than a
third of subjects were prescribed topiramate for more than 1 year, and subjects
with a diagnosis of migraine were prescribed topiramate for a longer period of time
than those without migraine. CONCLUSIONS: Findings from our study using EMR
demonstrate that physicians use topiramate at many different doses and for many
off-label indications. This analysis provided important insight into our patient
populations and treatment patterns.

Mavranezouli, I. and J. Lokkerbol (2017). "A Systematic Review and Critical

Appraisal of Economic Evaluations of Pharmacological Interventions for People with
Bipolar Disorder." Pharmacoeconomics 35(3): 271-296.
BACKGROUND: Bipolar disorder (BD) is a chronic mood disorder that causes
substantial psychological and financial burden. Various pharmacological treatments
are effective in the management and prevention of acute episodes of BD. In an era
of tighter healthcare budgets and a need for more efficient use of resources,
several economic evaluations have evaluated the cost effectiveness of treatments
for BD. OBJECTIVE: The aim of this study was to systematically review and appraise
published economic evaluations of pharmacological interventions for BD. METHODS: A
systematic search combining search terms specific to BD with a health economics
search filter was conducted on six bibliographic databases (EMBASE, MEDLINE,
PsycINFO, HTA, NHS EED, CENTRAL) in order to identify trial- or model-based full
economic evaluations of pharmacological treatments of any phase of the disorder
that were published between 1 January 1990 and 18 December 2015. Studies that met
the inclusion criteria were critically appraised using the Quality of Health
Economic Studies (QHES) checklist, and synthesised in a narrative way. RESULTS: The
review included 19 economic studies, which varied with regard to the type and
number of interventions assessed, the study design, the phase of treatment (acute
or maintenance), the source of efficacy data and the method for evidence synthesis,
the outcome measures, the time horizon and the countries/settings in which the
studies were conducted. The study quality was variable but the majority of studies
were of high or fair quality. CONCLUSION: Pharmacological interventions are cost
effective, compared with no treatment, in the management of BD, both in the acute
and maintenance phases. However, it is difficult to draw safe conclusions on the
relative cost effectiveness between drugs due to differences across studies and
limitations characterising many of them. Future economic evaluations need to
consider the whole range of treatment options available for the management of BD
and adopt appropriate methods for evidence synthesis and economic modelling, to
explore more robustly the relative cost effectiveness of pharmacological
interventions for people with BD.

McCormick, U., et al. (2015). "Diagnosis and treatment of patients with bipolar
disorder: A review for advanced practice nurses." J Am Assoc Nurse Pract 27(9):
530-542.
PURPOSE: This review article provides an overview of the frequency, burden of
illness, diagnosis, and treatment of bipolar disorder (BD) from the perspective of
the advanced practice nurses (APNs). DATA SOURCES: PubMed searches were conducted
using the following keywords: "bipolar disorder and primary care," restricted to
dates 2000 to present; "bipolar disorder and nurse practitioner"; and "bipolar
disorder and clinical nurse specialist." Selected articles were relevant to adult
outpatient care in the United States, with a prioritization of articles written by
APNs or published in nursing journals. CONCLUSIONS: BD has a substantial lifetime
prevalence in the population at 4%. Because the manic or depressive symptoms of BD
tend to be severe and recurrent over a patient's lifetime, the condition is
associated with significant burden to the individual, caregivers, and society.
Clinician awareness that BD may be present increases the likelihood of successful
recognition and appropriate treatment. A number of pharmacological and
nonpharmacological treatments are available for acute and maintenance treatments,
with the prospect of achieving reduced symptom burden and increased functioning for
many patients. IMPLICATIONS FOR PRACTICE: Awareness of the disease burden,
diagnostic issues, and management choices in BD has the potential to enhance
outcome in substantial proportions of patients.

McElroy, S. L., et al. (2011). "A randomized, placebo-controlled study of

adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleep
disturbance." Int Clin Psychopharmacol 26(1): 48-53.
This study evaluated the efficacy and tolerability of ramelteon in ambulatory
bipolar I disorder with manic symptoms and insomnia. Twenty-one outpatients with
bipolar I disorder by Diagnostic and Statistical Manual of Mental Disorders, fourth
edition criteria with mild-to-moderate manic symptoms and sleep disturbance were
randomized to receive either ramelteon (N=10) or placebo (N=11) in an 8-week,
double-blind, fixed-dose (8 mg/day) study. Ramelteon and placebo had similar rates
of reduction in ratings of symptoms of insomnia, mania, and global severity of
illness. However, ramelteon was associated with improvement in a global rating of
depressive symptoms. It was also well tolerated and associated with no serious
adverse events. The small sample size may have limited the ability of the study to
detect potentially clinically important drug-placebo differences. Further studies
of ramelteon in subgroups of bipolar patients with sleep disturbance, including
those with depression or euthymia, seem indicated.

McGee-Lawrence, M. E. and J. J. Westendorf (2011). "Histone deacetylases in

skeletal development and bone mass maintenance." Gene 474(1-2): 1-11.
The skeleton is a multifunctional and regenerative organ. Dynamic activities
within the bone microenvironment necessitate and instigate rapid and temporal
changes in gene expression within the cells (osteoclasts, osteoblasts, and
osteocytes) responsible for skeletal maintenance. Regulation of gene expression is
controlled, in part, by histone deacetylases (Hdacs), which are intracellular
enzymes that directly affect chromatin structure and transcription factor activity.
Key roles for several Hdacs in bone development and biology have been elucidated
though in vitro and in vivo models. Recent findings suggest that clinical usage of
small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder,
cancer, and a multitude of other ailments may have unintended effects on bone cell
populations. Here we review the progress that has been made in the last decade in
understanding how Hdacs contribute to bone development and maintenance.

McGill, B. and M. L. Moulds (2014). "Characteristics of autobiographical memories

and prospective imagery across a spectrum of hypomanic personality traits." Memory
22(8): 1139-1148.
Evidence of a strong causal relationship between mental imagery and emotion
has informed psychological conceptualisations of disordered positive mood states
(i.e., mania). Holmes et al.'s cognitive model of bipolar disorder asserts a
prominent role for intrusive and affect-laden positive imagery of the past and the
future in the amplification and maintenance of positive mood and associated manic
behaviours. The aims of the current study were two-fold: (1) to test aspects of
this model in a non-clinical population sampled for hypomanic personality traits
and (2) to examine the phenomenological characteristics of positive
autobiographical memories and imagery of the future. Undergraduate students (N =
80) completed a battery of self-report questionnaires and rated their positive and
negative memories and images of the future on a number of dimensions. We found
significant positive correlations between hypomanic tendencies and the (1) everyday
experience and use of mental imagery, (2) experience of intrusive mental imagery of
future events, (3) emotional intensity and sensory detail of positive but not
negative autobiographical memories. Results are discussed in the context of their
theoretical and clinical implications, and directions for future research are
considered.

McGrane, I. R. and M. Stuhec (2016). "Comment on An Open Trial of Lurasidone as an

Acute and Maintenance Adjunctive Treatment for Outpatients With Treatment-Resistant
Bipolar Disorder." J Clin Psychopharmacol 36(5): 520-521.

McGuire, J. M., et al. (2016). "New-Onset Visual Hallucinations With Eszopiclone."

Prim Care Companion CNS Disord 18(2).

McIntyre, R. S. (2010). "Aripiprazole for the maintenance treatment of bipolar I

disorder: A review." Clin Ther 32 Suppl 1: S32-38.
BACKGROUND: Bipolar disorder is a chronic neuropsychiatric syndrome
associated with substantial rates of recurrence, interepisodic dysfunction,
comorbidity, and premature mortality. Metabolic comorbidity (eg, overweight,
obesity, metabolic syndrome) differentially affects individuals with bipolar
disorder and contributes to increased illness-associated morbidity and mortality
(ie, cardiovascular disease). Few pharmacologic agents have been approved by the US
Food and Drug Administration for the maintenance treatment of bipolar disorder.
OBJECTIVE: This paper discusses the metabolic profile of aripiprazole and reviews
pivotal registration trials of aripiprazole for the maintenance treatment of adults
with bipolar I disorder. METHODS: MEDLINE was searched for English-language
articles published between January 1995 and November 2009. The key search term was
aripiprazole, combined with bipolar disorder and maintenance treatment. The review
was limited to randomized, controlled registration trials, supplemented by poster
presentations involving the registration-trial data sets. RESULTS: Three studies of
the efficacy and tolerability of aripiprazole monotherapy in the maintenance
treatment of bipolar I disorder were identified by the literature search: a 26-
week, randomized, double-blind study and its 74-week extension phase (for a total
of 100 weeks of double-blind treatment), and a randomized, double-blind comparison
of aripiprazole with placebo and lithium (internal comparator) for up to 12 weeks.
After 100 weeks of double-blind treatment, aripiprazole had a minimal effect on
body composition and did not disrupt metabolic parameters compared with placebo.
The mean (SD) weight change was 0.4 (0.8) kg with aripiprazole and -1.9 (0.8) kg
with placebo (P = NS). A clinically significant (> or =7%) increase in weight
occurred in 20% of the aripiprazole group and 5% of the placebo group (P = 0.01).
Extrapyramidal symptoms were reported in 22% of the aripiprazole group and 15% of
the placebo group. The identified trials of aripiprazole primarily enrolled
patients during a manic state; no maintenance trials of combination therapy or
trials enrolling individuals presenting with an acute depressive episode were
identified. CONCLUSIONS: The available evidence supports the efficacy and
tolerability of aripiprazole in the maintenance treatment of bipolar disorder. The
placebo-subtracted differences in body composition and metabolic parameters suggest
utility for aripiprazole in the long-term treatment of bipolar disorder.

McIntyre, R. S. (2011). "Long-term treatment of bipolar disorder in adults." J Clin

Psychiatry 72(2): e06.
Bipolar disorder is a common, chronic, multidimensional syndrome that appears
to be a progressive illness, in that each episode substantially increases the risk
that another episode will occur and will be less responsive to treatment than
previous episodes. The biphasic and episodic nature of bipolar disorder
substantially contributes to its negative impact on patients' quality of life as
well as their physical, social, and occupational functioning. Patients with bipolar
disorder often have co-occurring conditions, particularly medical comorbidities,
and, unfortunately, several psychotropic medications prescribed to treat bipolar
disorder may increase the risk of developing certain medical illnesses. Although
the recommendation in psychiatric care is to regularly assess patients' physical
health, many clinicians are not yet implementing this strategy in their clinical
practice. When making evidence-based medication choices, clinicians can select from
several FDA-approved agents for the treatment of acute manic and depressive
episodes as well as for maintenance therapy. Additionally, psychotherapies are
effective when used in combination with pharmacotherapy.

McIntyre, R. S., et al. (2010). "Asenapine for long-term treatment of bipolar

disorder: a double-blind 40-week extension study." J Affect Disord 126(3): 358-365.
BACKGROUND: Asenapine is approved in the United States for acute treatment of
manic or mixed episodes of bipolar I disorder with or without psychotic features.
We report the results of long-term treatment with asenapine in patients with
bipolar I disorder. METHODS: Patients completing either of two 3-week efficacy
trials and a subsequent 9-week double-blind extension were eligible for this 40-
week double-blind extension. Patients in the 3-week trials were randomized to
flexible-dose asenapine (5 or 10mg BID), placebo, or olanzapine (5-20mg QD;
included for assay sensitivity only). Patients entering the extension phase
maintained their preestablished treatment; those originally randomized to placebo
received flexible-dose asenapine (placebo/asenapine). Safety and tolerability
endpoints included adverse events (AEs), extrapyramidal symptoms, laboratory
values, and anthropometric measures. Efficacy, a secondary assessment, was measured
as change in Young Mania Rating Scale (YMRS) total score from 3-week trial baseline
to week 52 with asenapine or olanzapine; the placebo/asenapine group was assessed
for safety only. RESULTS: Incidence of treatment-emergent AEs was 71.9%, 86.1%, and
79.4% with placebo/asenapine, asenapine, and olanzapine, respectively. The most
frequent treatment-emergent AEs were headache and somnolence with
placebo/asenapine; insomnia, sedation, and depression with asenapine; and weight
gain, somnolence, and sedation with olanzapine. Among observed cases, mean +/- SD
changes in YMRS total score at week 52 were -28.6 +/- 8.1 and -28.2 +/- 6.8 for
asenapine and olanzapine, respectively. LIMITATIONS: The study did not have a long-
term placebo group. CONCLUSIONS: In this 52-week extension in patients with bipolar
mania, asenapine was well tolerated and long-term maintenance of efficacy was
supported.

McIntyre, R. S., et al. (2011). "Aripiprazole for the maintenance treatment of

bipolar disorder: a review of available evidence." Neuropsychiatr Dis Treat 7: 319-
323.
We aimed to review and synthesize results reporting on the maintenance
efficacy of Aripiprazole in adults with bipolar I disorder. Aripiprazole is FDA
approved for the acute and maintenance treatment of bipolar I disorder.
Aripiprazole's efficacy during the long-term treatment of bipolar disorder is
supported by extension of acute phase studies and long-term (ie, 100-week) double-
blind placebo controlled recurrence prevention registration trials. Aripiprazole is
not established as efficacious in the acute or maintenance treatment of bipolar
depression. Moreover, aripiprazole's efficacy during the acute or maintenance phase
of bipolar II disorder has not been sufficiently studied. Aripiprazole has a
relatively lower hazard for metabolic disruption and change in body composition
when compared to other atypical agents (eg, olanzapine, quetiapine). Moreover,
aripiprazole has minimal propensity for sedation, somnolence and prolactin
elevation. Aripiprazole is associated with extrapyramidal side effects, notably
akathisia, which in most cases is not severe or treatment limiting. Future research
vistas are to explore aripiprazole's efficacy in bipolar subgroups; recurrence
prevention of bipolar depression; and in combination with other mood stabilizing
agents.

McKenna, B. S., et al. (2014). "Abnormalities of brain response during encoding

into verbal working memory among euthymic patients with bipolar disorder." Bipolar
Disord 16(3): 289-299.
OBJECTIVES: Individuals with bipolar disorder (BD) have trait-like deficits
in attention and working memory (WM). A fundamental dissociation for most verbal WM
theories involves the separation of sensory-perceptual encoding, reliant upon
attention, from the maintenance of this information in WM proper. The present study
examined if patients with BD demonstrate differential neural changes in encoding
and maintenance WM processes that underlie cognitive impairment. METHODS: Event-
related functional magnetic resonance imaging during a delayed match-to-sample WM
paradigm was employed in 23 inter-episode medicated patients with BD and 23
demographically similar healthy comparison participants. We examined brain regions
during encoding and maintenance task intervals to identify regions that
demonstrated differential effects between groups. Medication effects and functional
connectivity between prefrontal cortex and basal ganglia/thalamus were examined
during the encoding interval due to the importance of these regions and the
connection among them for encoding into WM. RESULTS: Patients with BD exhibited
deficits in task accuracy and attenuated brain response during the encoding
interval in areas of the prefrontal cortex, caudate, thalamus, and posterior visual
regions. In contrast, patients with BD exhibited hyperactivation in posterior
sensory regions during the maintenance interval. Among the BD group, those with
greater medication load exhibited the greatest brain response within the prefrontal
cortex. CONCLUSIONS: Reduction in activation during the encoding interval suggests
that attentional deficits underlie WM deficits in patients with BD. These deficits
appear to be trait-like in so far as they were observed during periods of euthymia
in patients with BD. Medication effects remain to be further explored as there was
evidence of prefrontal changes dependent on medication load.

Meduri, M., et al. (2016). "A meta-analysis of efficacy and safety of aripiprazole
in adult and pediatric bipolar disorder in randomized controlled trials and
observational studies." J Affect Disord 191: 187-208.
BACKGROUND: Aripiprazole (ARP) has been shown to be effective in the
treatment of bipolar disorder (BD). However, no prior investigation considered both
randomized clinical trials (RCTs) and non-RCTs. We here evaluated the efficacy and
safety of ARP compared with placebo (PCB) and other drugs at 3- and 12-weeks in
adult and pediatric population including, for the first time, both observational
and controlled studies. METHODS: All studies were systematically located by
searching electronic sources (EMBASE, MEDLINE, CINHAIL, PsychINFO, Cochrane Central
Register of Controlled Trials, Scopus and ClinicalTrials.gov) till June 30th, 2015.
The primary outcome was ARP efficacy (mean change from baseline in Young Mania
Rating Scale); secondary outcomes regarded acceptability and safety. Results
Sixteen RCTs and 6 non-RCTs met our inclusion criteria; 2505 and 2932 patients were
included in the analyses of acute and stabilization phase, respectively. In both
the acute and stabilization phases ARP efficacy was superior to PCB and comparable
to other drugs. The safety profile was similar to other drugs considering in
particular sedation, akathisia, weight gain, extrapyramidal and gastroenteric
symptoms, with a significant lower risk of hyperprolactinemia particularly at 12-
weeks. LIMITATIONS: Data on failed trials are generally limited. CONCLUSIONS: ARP
resulted to be an effective treatment in children and adults with BD at 3- and 12-
weeks both in a controlled experimental setting or in the real world clinical
practice, being poorly associated with hyperprolactinemia. Larger studies are
needed to confirm our results related to the maintenance phases and to the
pediatric bipolar population.

Melcher, T., et al. (2014). "Common and disease-specific dysfunctions of brain

systems underlying attentional and executive control in schizophrenia and bipolar
disorder." Eur Arch Psychiatry Clin Neurosci 264(6): 517-532.
Schizophrenia and bipolar disorder broadly overlap in multiple areas
involving clinical phenomenology, genetics, and neurobiology. Still, the
investigation into specific elementary (sub-)processes of executive functioning may
help to define clear points of distinction between these categorical diagnoses to
validate the nosological dichotomy and, indirectly, to further elucidate their
pathophysiological underpinnings. In the present behavioral study, we sought to
separate common from diagnosis-specific deficits in a series of specific elementary
sub-functions of executive processing in patients with schizophrenia and bipolar
disorder. For our purpose, we administered a modern and multi-purpose
neuropsychological task paradigm to equal-sized and matched groups of schizophrenia
patients, patients with bipolar disorder, and healthy control subjects. First,
schizophrenia patients compared to the bipolar group exhibited a more pronounced
deficit in general measures of task performance comprising both response speed and
accuracy. Additionally, bipolar patients showed increased advance task preparation,
i.e., were better able to compensate for response speed deficits when longer
preparation intervals were provided. Set-shifting, on the other hand, was impaired
to a similar degree in both patient groups. Finally, schizophrenia patients
exhibited a specific deficit in conflict processing (inhibitory control) and the
shielding of task-relevant processing from distraction (i.e., attentional
maintenance). The present investigation suggests that specific neuropsychological
measures of elementary executive functions may represent important points of
dissociation between schizophrenia and bipolar disorder, which may help to
differentiate the pathophysiological underpinnings of these major psychiatric
disorders. In this context, the present findings highlight the measures of
inhibitory control and attentional maintenance as promising candidates.

Meyer, T. D., et al. (2011). "Is risk for mania associated with increased
daydreaming as a form of mental imagery?" J Affect Disord 135(1-3): 380-383.
BACKGROUND: Bipolar disorder and risk for mania are associated with setting
high goals and dysregulated goal pursuit. One mechanism mediating between setting
high goals and manic symptoms could be daydreaming or more generally, mental
imagery. 'Daydreams' (as one form of mental imagery) are characterized by the fact
that the content is produced deliberately. Akiskal et al. (1995) reported that
daydreaming prospectively predicted a switch from unipolar depression to bipolar
disorder. We here hypothesized that risk for mania should also be associated with
increased daydreaming after controlling for depression. METHOD: N=249 participants
from a non-clinical, community sample completed several self-report measures
including the Hypomanic Personality scale and Daydreaming scale. RESULTS:
Hierarchical regression revealed that risk for mania predicted daydreaming after
controlling for current and former depression. LIMITATIONS: Only self-report
measures were used. The sample was a non-clinical, primarily White British sample,
which has implications for generalizability. CONCLUSIONS: Despite limitations our
results support the hypothesis that vulnerability for mania is associated with
daydreaming. Daydreaming was related to mania and depression which highlights that
it might be relevant for the etiology or maintenance of mood disorders.

Michopoulos, I., et al. (2010). "Quetiapine monotherapy in bipolar I disorder: a 1-

year stabilization in a woman having undergone bone marrow transplantation." World
J Biol Psychiatry 11(2 Pt 2): 519-521.
Queatiapine has been used in bipolar mania and most recently in bipolar
depression with good results; however, its use in maintenance treatment has not
been established yet. A case of a woman suffering from bipolar I disorder who
underwent bone marrow transplantation twice because of leukaemia is presented. The
use of quetiapine as a monotherapy was efficient and safe and proved to be a good
treatment in mood stabilization for 1 year.

Minichino, A., et al. (2014). "Prefronto-cerebellar transcranial direct current

stimulation improves sleep quality in euthymic bipolar patients: a brief report."
Behav Neurol 2014: 876521.
INTRODUCTION: Sleep problems are common in bipolar disorder (BD) and may
persist during the euthymic phase of the disease. The aim of the study was to
improve sleep quality of euthymic BD patients through the administration of
prefronto-cerebellar transcranial direct current stimulation (tDCS). METHODS: 25
euthymic outpatients with a diagnosis of BD Type I or II have been enrolled in the
study. tDCS montage was as follows: cathode on the right cerebellar cortex and
anode over the left dorsolateral prefrontal cortex (DLPFC); the intensity of
stimulation was set at 2 mA and delivered for 20 min/die for 3 consecutive weeks.
The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality at
baseline and after the tDCS treatment. RESULTS: PSQI total score and all PSQI
subdomains, with the exception of "sleep medication," significantly improved after
treatment. DISCUSSION: This is the first study where a positive effect of tDCS on
the quality of sleep in euthymic BD patients has been reported. As both prefrontal
cortex and cerebellum may play a role in regulating sleep processes, concomitant
cathodal (inhibitory) stimulation of cerebellum and anodal (excitatory) stimulation
of DLPFC may have the potential to modulate prefrontal-thalamic-cerebellar circuits
leading to improvements of sleep quality.

Minnai, G. P., et al. (2011). "Effectiveness of maintenance electroconvulsive

therapy in rapid-cycling bipolar disorder." J ECT 27(2): 123-126.
OBJECTIVES: : To evaluate the effectiveness of maintenance electroconvulsive
therapy (m-ECT) in rapid-cycling (RC) bipolar disorder (BPD) patients. METHODS: : A
population sample of 14 patients with BPD (type I or II) and an RC course were
treated with m-ECT. Patients had not responded to previous treatments. Sessions of
m-ECT were administered monthly and then gradually decreased in frequency upon
amelioration of the course. Response to treatment was evaluated as the difference
between days of illness before and after the treatment for the same 2 periods in a
2-year time frame. RESULTS: : We treated 14 patients with RC BPD (mean age, 46
years; 71% women; 64% with BPD type I). Mean treatment duration was 21 months. All
patients improved during treatment. Eight (58%) did not relapse during the 2-year
follow-up period, and 6 (42%) relapsed one time each year. Illness duration
decreased 13-fold from 304 to 24 days of illness per year, and illness-free
intervals increased from 52 to 334 d/yr (all P < 0.0001). A multivariate analysis
showed that the factors independently associated with improvement were male sex,
diagnosis of type II BPD, hyperthymic temperament, and younger age. CONCLUSIONS: :
Despite patients' clinical severity, we recorded a highly significant reduction of
illness morbidity. The m-ECT had a real, long-term prophylactic effect in treating
a severe clinical course such as that with rapid cycles. Notwithstanding, our study
has to be considered preliminary and carries some limitations, such as its
naturalistic design and relatively low number of patients recruited.

Missio, G., et al. (2013). "The ARIQUELI study: potentiation of quetiapine in

bipolar I nonresponders with lithium versus aripiprazole." Trials 14: 190.
BACKGROUND: The treatment of bipolar disorder (BD) remains a challenge due to
the complexity of the disease. Current guidelines represent an effort to assist
clinicians in routine practice but have several limitations, particularly
concerning long-term treatment. The ARIQUELI (efficacy and tolerability of the
combination of lithium or aripiprazole in young bipolar non or partial responders
to quetiapine monotherapy) study aims to evaluate two different augmentation
strategies for quetiapine nonresponders or partial responders in acute and
maintenance phases of BD treatment. METHODS/DESIGN: The ARIQUELI study is a single-
site, parallel-group, randomized, outcome assessor-blinded trial. BD I patients
according to the DSM-IV-TR, in depressive, manic/hypomanic or mixed episode, aged
18 to 40 years, are eligible. After diagnostic assessments, patients initiated
treatment in phase I with quetiapine. Nonresponders or partial responders after 8
weeks are allocated into one of two groups, potentiated with either lithium (0.5 to
0.8 mEq/l) or aripiprazole (10 or 15 mg). Patients will be followed up for 8 weeks
in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12
months in phase III (maintenance treatment). Outcome assessors are blinded to the
treatment. The primary outcome is the evaluation of changes in mean scores on the
CGI-BP-M between baseline and the endpoint at the end of each study phase.
DISCUSSION: The ARIQUELI study is currently in progress, with patients undergoing
acute treatment (phase I), potentiation (phase II) and maintenance (phase III). The
study will be extended until January 2015. Trials comparing lithium and
aripiprazole with potentiate treatment in young BD I nonresponders to quetiapine in
monotherapy can provide relevant information on the safety of these drugs in
clinical practice. Long-term treatment is an issue of great importance and should
be evaluated further through more in-depth studies given that BD is a chronic
disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01710163.

Miura, T., et al. (2014). "Comparative efficacy and tolerability of pharmacological

treatments in the maintenance treatment of bipolar disorder: a systematic review
and network meta-analysis." Lancet Psychiatry 1(5): 351-359.
BACKGROUND: Lithium is the established standard in the long-term treatment of
bipolar disorder, but several new drugs have been assessed for this indication. We
did a network meta-analysis to investigate the comparative efficacy and
tolerability of available pharmacological treatment strategies for bipolar
disorder. METHODS: We systematically searched Embase, Medline, PreMedline,
PsycINFO, and the Cochrane Central Register of Controlled Trials for randomised
controlled trials published before June 28, 2013, that compared active treatments
for bipolar disorder (or placebo), either as monotherapy or as add-on treatment,
for at least 12 weeks. The primary outcomes were the number of participants with
recurrence of any mood episode, and the number of participants who discontinued the
trial because of adverse events. We assessed efficacy and tolerability of bipolar
treatments using a random-effects network meta-analysis within a Bayesian
framework. FINDINGS: We screened 114 potentially eligible studies and identified 33
randomised controlled trials, published between 1970 and 2012, that examined 17
treatments for bipolar disorder (or placebo) in 6846 participants. Participants
assigned to all assessed treatments had a significantly lower risk of any mood
relapse or recurrence compared with placebo, except for those assigned to
aripiprazole (risk ratio [RR] 0.62, 95% credible interval [CrI] 0.38-1.03),
carbamazepine (RR 0.68, 0.44-1.06), imipramine (RR 0.95, 0.66-1.36), and
paliperidone (RR 0.84, 0.56-1.24). Lamotrigine and placebo were significantly
better tolerated than carbamazepine (lamotrigine, RR 5.24, 1.07-26.32; placebo, RR
3.60, 1.04-12.94), lithium (RR 3.76, 1.13-12.66; RR 2.58, 1.33-5.39), or lithium
plus valproate (RR 5.95, 1.02-33.33; RR 4.09, 1.01-16.96). INTERPRETATION: Although
most of the drugs analysed were more efficacious than placebo and generally well
tolerated, differences in the quality of evidence and the side-effect profiles
should be taken into consideration by clinicians and patients. In view of the
efficacy in prevention of both manic episode and depressive episode relapse or
recurrence and the better quality of the supporting evidence, lithium should remain
the first-line treatment when prescribing a relapse-prevention drug in patients
with bipolar disorder, notwithstanding its tolerability profile. FUNDING: None.

Molz Adams, A., et al. (2014). "Self-referent information processing in individuals

with bipolar spectrum disorders." J Affect Disord 152-154: 483-490.
BACKGROUND: Bipolar spectrum disorders (BSDs) are common and impairing, which
has led to an examination of risk factors for their development and maintenance.
Historically, research has examined cognitive vulnerabilities to BSDs derived
largely from the unipolar depression literature. Specifically, theorists propose
that dysfunctional information processing guided by negative self-schemata may be a
risk factor for depression. However, few studies have examined whether BSD
individuals also show self-referent processing biases. METHODS: This study examined
self-referent information processing differences between 66 individuals with and 58
individuals without a BSD in a young adult sample (age M=19.65, SD=1.74; 62%
female; 47% Caucasian). Repeated measures multivariate analysis of variance
(MANOVA) was conducted to examine multivariate effects of BSD diagnosis on 4 self-
referent processing variables (self-referent judgments, response latency,
behavioral predictions, and recall) in response to depression-related and
nondepression-related stimuli. RESULTS: Bipolar individuals endorsed and recalled
more negative and fewer positive self-referent adjectives, as well as made more
negative and fewer positive behavioral predictions. Many of these information-
processing biases were partially, but not fully, mediated by depressive symptoms.
LIMITATIONS: Our sample was not a clinical or treatment-seeking sample, so we
cannot generalize our results to clinical BSD samples. No participants had a
bipolar I disorder at baseline. CONCLUSIONS: This study provides further evidence
that individuals with BSDs exhibit a negative self-referent information processing
bias. This may mean that those with BSDs have selective attention and recall of
negative information about themselves, highlighting the need for attention to
cognitive biases in therapy.

Moon, E., et al. (2012). "Dropout rate and associated factors in patients with
bipolar disorders." J Affect Disord 141(1): 47-54.
OBJECTIVES: Effective, long-term therapy for bipolar disorders is a critical
goal of mental health care, but achieving this goal is complicated by numerous
factors in real clinical settings. The aim of this study was to investigate dropout
patterns and their associated factors in patients with bipolar disorders. METHODS:
The study participants were 275 patients with DSM-IV bipolar disorders, receiving
planned maintenance treatment among patients at the Mood Disorders Clinic of Seoul
National University Bundang Hospital between January 2005 and December 2007. The
rates of dropout in patients were prospectively examined for 3 years. The factors
affecting the dropouts were analyzed using a Cox regression model. RESULTS: The
dropout rates were 10.9%, 20.4%, 24.7%, 33.8%, 44.0%, and 50.2% at 1, 3, 6, 12, 24,
and 36 months after treatment entry, respectively. The dropout rates increased
rapidly during the first three months and slowed after 12 months. Past psychotic
symptoms (HR 0.523, 95% CI 0.339-0.807), longer illness duration (HR 0.975, 95% CI
0.955-0.966), past psychiatric diagnoses (bipolar disorder, HR 0.242, 95% CI 0.120-
0.490; other axis I disorders 0.434, 95% CI 0.268-0.701), and a past history of
dropouts (HR 1.746, 95% CI 1.028-2.965) significantly influenced the time to
dropout in bipolar patients. The main reasons for dropout were 'denial of
therapeutic need' (34.8%) and 'lack of treatment efficacy' (23.2%). Dropout from
the maintenance phase of treatment was mainly attributed to the patients' poor
understanding of the effects of their treatment. CONCLUSION: A high early dropout
rate for subjects with bipolar disorders was observed in this study, suggesting an
increased risk for insufficient maintenance treatment. These results may support
the role of psychoeducational approaches in enhancing adherence to treatment, as
well as social approaches to improving public awareness. Following the early
evaluation of a patient's concept of bipolar disorders, individualized
psychoeducational strategies are necessary to improve the long-term outcomes for
subjects with bipolar disorders.

Moro, M. F. and M. G. Carta (2014). "Evaluating aripiprazole as a potential bipolar

disorder therapy for adults." Expert Opin Investig Drugs 23(12): 1713-1730.
INTRODUCTION: Second generation antipsychotics (SGAs) have emerged as new
treatment options for bipolar disorders (BDs). Aripiprazole (ARI) is already an SGA
approved therapy for the treatment of BD type-I, both as a monotherapy as well as
an add-on therapy in acute mania and in long-term maintenance therapy. AREAS
COVERED: The authors provide a systematic review that illustrates ARI's
pharmacological profile including its efficacy on various aspects of BD in adults.
It also reviews its role in bipolar treatment algorithms and provides a focus on
future research developments and further potential uses of the compound. Additional
aspects such as safety and tolerability are also considered. EXPERT OPINION:
Compared with haloperidol, ARI shows fewer extrapyramidal symptoms (EPS), but has a
slightly lower efficacy in mania. It has a better metabolic parameter profile and
fewer cardiovascular adverse events than other SGAs although the add-on treatment
shows a higher risk of EPS. Presently, data doesn't support its use as a first
choice maintenance monotherapy but it may be useful as a combination therapy for BD
patients with comorbidities such as drug abuse and obsessive-compulsive disorders.
Studies on ARI in bipolar depression are disappointing. However, future studies on
the drug, at a low dose combined with a stabilizer or antidepressant may prove
interesting.

Morriss, R. K., et al. (2011). "Pragmatic randomised controlled trial of group

psychoeducation versus group support in the maintenance of bipolar disorder." BMC
Psychiatry 11: 114.
 BACKGROUND: Non-didactically delivered curriculum based group psychoeducation
has been shown to be more effective than both group support in a specialist mood
disorder centre in Spain (with effects lasting up to five years), and treatment as
usual in Australia. It is unclear whether the specific content and form of group
psychoeducation is effective or the chance to meet and work collaboratively with
other peers. The main objective of this trial is to determine whether curriculum
based group psychoeducation is more clinically and cost effective than unstructured
peer group support. METHODS/DESIGN: Single blind two centre cluster randomised
controlled trial of 21 sessions group psychoeducation versus 21 sessions group peer
support in adults with bipolar 1 or 2 disorder, not in current episode but relapsed
in the previous two years. Individual randomisation is to either group at each
site. The groups are carefully matched for the number and type of therapists,
length and frequency of the interventions and overall aim of the groups but differ
in content and style of delivery. The primary outcome is time to next bipolar
episode with measures of the therapeutic process, barriers and drivers to the
effective delivery of the interventions and economic analysis. Follow up is for 96
weeks after randomisation. DISCUSSION: The trial has features of both an efficacy
and an effectiveness trial design. For generalisability in England it is set in
routine public mental health practice with a high degree of expert patient
involvement.

Mueser, K. T., et al. (2010). "Randomized trial of social rehabilitation and

integrated health care for older people with severe mental illness." J Consult Clin
Psychol 78(4): 561-573.
OBJECTIVE: The Helping Older People Experience Success (HOPES) program was
developed to improve psychosocial functioning and reduce long-term medical burden
in older people with severe mental illness (SMI) living in the community. HOPES
includes 1 year of intensive skills training and health management, followed by a
1-year maintenance phase. METHOD: To evaluate effects of HOPES on social skills and
psychosocial functioning, we conducted a randomized controlled trial with 183 older
adults with SMI (58% schizophrenia spectrum) age 50 and older at 3 sites who were
assigned to HOPES or treatment as usual with blinded follow-up assessments at
baseline and 1- and 2-year follow-up. RESULTS: Retention in the HOPES program was
high (80%). Intent-to-treat analyses showed significant improvements for older
adults assigned to HOPES compared to treatment as usual in performance measures of
social skill, psychosocial and community functioning, negative symptoms, and self-
efficacy, with effect sizes in the moderate (.37-.63) range. Exploratory analyses
indicated that men improved more than women in the HOPES program, whereas benefit
from the program was not related to psychiatric diagnosis, age, or baseline levels
of cognitive functioning, psychosocial functioning, or social skill. CONCLUSIONS:
The results support the feasibility of engaging older adults with SMI in the HOPES
program, an intensive psychiatric rehabilitation intervention that incorporates
skills training and medical case management, and improves psychosocial functioning
in this population. Further research is needed to better understand gender
differences in benefit from the HOPES program.

Muneer, A. (2015). "Pharmacotherapy of bipolar disorder with quetiapine: a recent

literature review and an update." Clin Psychopharmacol Neurosci 13(1): 25-35.
Bipolar disorder is a chronic, recurrent condition with the usual onset
during adolescence or early adulthood. In the Diagnostic and Statistical Manual of
Mental Disorders 5th edition, it is conceptualized as a spectrum disorder usually
associated with such comorbidities as anxiety disorders and substance use
disorders. It is a relatively prevalent condition often complicated by mixed
episodes, rapid cycling, subsyndromal symptoms, and treatment refractoriness. In
spite of carrying substantial morbidity and mortality, effective treatments are few
and far between and conventional mood stabilizers are often unsuccessful in
controlling the various manifestations of the disorder. In this scenario, second
generation antipsychotics are emerging as treatments with valid efficacy in all
phases of bipolar disorder. Quetiapine is a versatile atypical antipsychotic which
was first approved for the treatment of schizophrenia, but latter on the basis of
controlled studies earned United States Food and Drug Administration's approval for
acute as well as maintenance treatment of this difficult to treat condition. In
this review, recently published studies in the last 10 years were examined to
update the knowledge about the efficacy and safety of quetiapine in the treatment
of bipolar disorder. The medication's clinical pharmacology was first considered
followed by a literature review summarizing its uses in bipolar disorder. The
conclusion was that quetiapine was efficacious in manic, mixed and depressive
episodes and as a maintenance agent with a good tolerability profile.

Murru, A., et al. (2011). "When should mood stabilizers be withdrawn due to lack of
efficacy? Some methodological considerations." Eur Psychiatry 26(3): 183-186.
Maintenance therapy in bipolar disorder is primarily aimed at preventing
recurrence of acute episodes. Clinicians often decide on the basis of their own
experience whether mood stabilizer (MS) is properly satisfying the objective of
preventing a relapse/recurrence. Evidence-based data seem far from clinical
practice in assessing a MS efficacy, as they mainly focus on a drug's efficacy to
first relapse and not considering the patient's course of illness. The problem of
assessing MS's efficacy seems further complicated when considering combination
therapy, which, due to lack of evidence-based data, economical aspects, attitude of
clinicians and legal issues may bring to cumulative prescriptions. Nowadays, the
drug therapy for a bipolar patient is usually tailored after longitudinal
observation of his specific course of illness. The course of illness should be
considered also when choosing practical criteria for the suspension of a MS due to
lack of efficacy. The authors propose some preliminary criteria which may help
clinicians evaluating whether a mood stabilizer is being useful or not, dividing
possible outcomes and suggesting subsequent therapeutic steps in the optimization
of a patient's treatment.

Murru, A., et al. (2016). "Antipsychotic switching in schizoaffective disorder: A

systematic review." World J Biol Psychiatry 17(7): 495-513.
OBJECTIVES: To systematically review the evidence about the switching of
antipsychotics in SZA in acute and maintenance treatment. METHODS: A systematic
review following the PRISMA statement identifying studies specifically conducted
on, or including, SZA patients. RESULTS: One analysis considered uniquely a SZA
population, 13 more studies including an adequate SZA subsample were considered.
Most of the studies were aimed at switching antipsychotic treatments to improve
tolerability issues. Despite the absolute lack of trials specifically conducted on
SZA populations, we found limited evidence on the use of aripiprazole, lurasidone,
and, to a lesser extent, risperidone and ziprasidone as possible agents to
substitute previous treatments whereas efficacy or, more frequently, tolerability
issues arise. Evidence supports also the switch to risperidone long-acting
injectable when the adherence to oral treatment may be a concern. CONCLUSIONS:
Antipsychotic switching in SZA is a neglected topic that would need better
profiling. Clinicians should keep in mind the receptor binding characteristics of
drugs in order to optimize transitions. Evidence supports the switch to
aripiprazole and lurasidone, less strongly to risperidone and ziprasidone. The
switch to risperidone long-acting injectable is supported, especially in patients
with limited treatment adherence to oral therapy.

Murru, A., et al. (2011). "What we know and what we don't know about the treatment
of schizoaffective disorder." Eur Neuropsychopharmacol 21(9): 680-690.
Schizoaffective disorder (SAD) is a chronic, severe and disabling illness
consisting on the concurrent presentation of symptoms of schizophrenia and
affective disorders (depression and/or mania). Evidence for the treatment of SAD
mostly derives from studies based on mixed samples (i.e. schizophrenic and
schizoaffective patients) or on extrapolations from studies on schizophrenia or
bipolar disorder. The objective of the present review is to systematically consider
and summarize the best evidence-based approaches to the treatment of SAD and
extensively point out the gap between treatment research and clinical practice of
this disorder. The complex problem of controlling the pleomorphic presentation of
SAD's syndromic construct is reflected in the lack of evidence on key topics,
including: diagnostic consistency, pharmacological approaches (mood stabilizers,
antidepressants, both in acute and maintenance treatment as well as their possible
combination), and the adjunctive role of psychosocial and biophysical
interventions. Finally, treatment strategies for SAD, both unipolar and bipolar
type, are proposed.

Musfeldt, D., et al. (2016). "Lithium toxicity after Roux-en-Y bariatric surgery."
BMJ Case Rep 2016.
A 61-year-old woman with medical history significant for morbid obesity, type
II diabetes mellitus, nephrogenic diabetes insipidus and bipolar disorder, had been
stable on lithium carbonate therapy for several years. She had undergone a Roux-en-
Y bypass surgery and, at the time of her surgery, her lithium level was found to be
0.61 mEq/L on a maintenance dose of 600 mg orally twice per day. She was discharged
8 days postoperatively on the same lithium dose, but presented to the emergency
department 12 days postoperatively with signs of lithium toxicity. Her lithium
level was elevated to 1.51 mEq/L and she was treated for lithium toxicity with
supportive care and, ultimately, reduction of her lithium dose. Clinicians should
be aware that dramatic and poorly understood changes in drug absorption may occur
after bariatric surgery.

Nierenberg, A. A. (2010). "A critical appraisal of treatments for bipolar

disorder." Prim Care Companion J Clin Psychiatry 12(Suppl 1): 23-29.
Recovery-the absence of all abnormal mood symptoms-is the goal of treatment
for bipolar disorder. Unfortunately, a minority of people suffering from bipolar
disorder achieve sustained recovery. Improving recovery rates for this population
will require clinicians in the primary care setting to be familiar with appropriate
treatments for acute bipolar mania and depression and for the maintenance phase.
Efficacy and tolerability of pharmacotherapeutic and psychotherapeutic options for
all phases of treatment and each type of mood episode are discussed. Primary care
physicians are encouraged to avoid prescribing antidepressant monotherapy for any
patient with depression and a history of mania or hypomania.

Nierenberg, A. A., et al. (2013). "Mitochondrial modulators for bipolar disorder: a

pathophysiologically informed paradigm for new drug development." Aust N Z J
Psychiatry 47(1): 26-42.
OBJECTIVES: Bipolar patients frequently relapse within 12 months of their
previous mood episode, even in the context of adequate treatment, suggesting that
better continuation and maintenance treatments are needed. Based on recent research
of the pathophysiology of bipolar disorder, we review the evidence for
mitochondrial dysregulation and selected mitochondrial modulators (MM) as potential
treatments. METHODS: We reviewed the literature about mitochondrial dysfunction and
potential MMs worthy of study that could improve the course of bipolar disorder,
reduce subsyndromal symptoms, and prevent subsequent mood episodes. RESULTS: MM
treatment targets mitochondrial dysfunction, oxidative stress, altered brain energy
metabolism and the dysregulation of multiple mitochondrial genes in patients with
bipolar disorder. Several tolerable and readily available candidates include N-
acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe),
coenzyme Q(10) (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and
melatonin. The specific metabolic pathways by which these MMs may improve the
symptoms of bipolar disorder are discussed and combinations of selected MMs could
be of interest as well. CONCLUSIONS: Convergent data implicate mitochondrial
dysfunction as an important component of the pathophysiology of bipolar disorder.
Clinical trials of individual MMs as well as combinations are warranted.

Nishida, K., et al. (2011). "Mechanisms of atrial tachyarrhythmias associated with

coronary artery occlusion in a chronic canine model." Circulation 123(2): 137-146.
 BACKGROUND: Coronary artery disease predisposes to atrial fibrillation (AF),
but the effects of chronic atrial ischemia/infarction on AF-related substrates are
unknown. METHODS AND RESULTS: Regional right atrial myocardial infarction (MI) was
created in 40 dogs by ligating an artery that supplies the right atrial free wall
and not the ventricles; 35 sham dogs with the same artery isolated but not ligated
were controls. Dogs were observed 8 days after MI and subjected to open-chest
study, in vitro optical mapping, and/or cell isolation for patch-clamp and Ca(2+)
imaging on day 8. Holter ECGs showed more spontaneous atrial ectopy in MI dogs (eg,
662+/-281 on day 7 versus 34+/-25 ectopic complexes per day at baseline; 52+/-21
versus 1+/-1 atrial tachycardia episodes per day). Triggered activity was increased
in MI border zone cells, which had faster decay of caffeine-evoked Ca(2+)
transients and enhanced (by approximately 73%) Na(+)-Ca(2+) exchange current.
Spontaneous Ca(2+) sparks (confocal microscopy) occurred under beta-adrenergic
stimulation in more MI dog cells (66+/-9%) than in control cells (29+/-4%; P<0.01).
Burst pacing induced long-lasting AF in MI dogs (1146+/-259 versus 30+/-14 seconds
in shams). Increased border zone conduction heterogeneity was confirmed by both
bipolar electrode mapping in vivo and optical mapping. Optical mapping demonstrated
stable border zone reentry in all 9 MI preparations but in none of 6 shams. Border
zone tissue showed increased fibrous tissue content. CONCLUSIONS: Chronic atrial
ischemia/infarction creates substrates for both spontaneous ectopy (Ca(2+)-release
events, increased Na(+)-Ca(2+) exchange current) and sustained reentry (conduction
abnormalities that anchor reentry). Thus, chronic atrial infarction in dogs
promotes both AF triggers and the substrate for AF maintenance. These results
provide novel insights into potential AF mechanisms in patients with coronary
artery disease.

Nolen, W. A. and R. H. Weisler (2013). "The association of the effect of lithium in

the maintenance treatment of bipolar disorder with lithium plasma levels: a post
hoc analysis of a double-blind study comparing switching to lithium or placebo in
patients who responded to quetiapine (Trial 144)." Bipolar Disord 15(1): 100-109.
OBJECTIVES: There is no robust proof that the efficacy of lithium in the
prevention of manic and depressive episodes in bipolar disorder depends on its
plasma level. This analysis aimed to compare the effect of lithium within the
presumed therapeutic range of 0.6-1.2 mEq/L and below 0.6 mEq/L with that of
placebo. METHODS: We carried out a post hoc analysis of a double-blind trial in
which patients aged >/=18 years with bipolar I disorder (DSM-IV) who had achieved
stabilization from a manic, depressive, or mixed episode during open-label
treatment with quetiapine were randomized to continue quetiapine or to switch to
lithium or placebo for up to 104 weeks. Of patients randomized to lithium, 201
obtained median lithium levels between 0.6 and 1.2 mEq/L, and 137 obtained median
lithium levels <0.6 mEq/L. Their outcomes were compared with those of patients
receiving placebo (n = 404). The primary outcome was time to recurrence of any mood
event; additional outcomes included time to recurrence of a manic or depressive
event. RESULTS: Times to recurrence of any mood event as well as a manic or
depressive event were significantly longer for the lithium 0.6-1.2 mEq/L group
versus placebo and versus lithium <0.6 mEq/L, with no differences between lithium
<0.6 mEq/L and placebo. CONCLUSIONS: The results support and expand previous
findings that lithium should be dosed high enough to achieve plasma levels >/=0.6
mEq/L in order to achieve an effect in the prevention of both manic and depressive
recurrences of bipolar I disorder. A major limitation is that the composition of
the two lithium groups was not based on randomization.

Norris, E. R., et al. (2013). "A double-blind, randomized, placebo-controlled trial

of adjunctive ramelteon for the treatment of insomnia and mood stability in
patients with euthymic bipolar disorder." J Affect Disord 144(1-2): 141-147.
BACKGROUND: Abnormalities in circadian rhythms are prominent features of
bipolar disorder. Disrupted circadian rhythms are associated with an increased risk
of relapse in bipolar disorder. Normalizing the circadian rhythm pattern of bipolar
patients may improve their sleep and lead to fewer mood exacerbations. This study
evaluated adjunctive ramelteon for the treatment of insomnia and mood stability in
euthymic bipolar patients. METHODS: Participants with euthymic bipolar disorder and
sleep disturbances were randomized to receive adjunctive ramelteon or placebo in
addition to their regular psychiatric medications for up to 24 weeks or until they
experienced a relapse (defined as a depressed or manic event). RESULTS: 83
participants were randomized to receive ramelteon (n=42) or placebo (n=41). Forty
participants relapsed (48.2%). Cox regression analyses indicated that participants
who received ramelteon (odds ratio 0.48, p=.024) were less likely to relapse.
Kaplan Meier curves also indicated longer median survival times in the ramelteon
group (Mdn=188 days) versus the placebo group (Mdn=84 days) X2(1)=5.33, p=.02.
There were no serious adverse events in this study. LIMITATIONS: This was a small
study with only 83 participants. The one-week window of confirmed stability is
shorter than time intervals used in other studies. CONCLUSIONS: The present study
shows that ramelteon was effective in maintaining stability for individuals with
bipolar disorder. Patients treated with ramelteon were approximately half as likely
to relapse as patients treated with placebo throughout the 24-week treatment
period.

Obiora, O., et al. (2012). "Maintenance electroconvulsive therapy in a patient with

multiple system atrophy and bipolar disorder." J ECT 28(2): e1-2.
Multiple system atrophy is a rapidly progressive neurodegenerative disorder
with no known cure. It is a clinical diagnosis with no confirmation available other
than brain biopsy after death. We report the successful treatment of multiple
system atrophy co-occurring with bipolar disorder in a 62-year-old man using
electroconvulsive therapy.

Offord, J. (2012). "Genetic approaches to a better understanding of bipolar

disorder." Pharmacol Ther 133(2): 133-141.
Bipolar disorder is a disease which causes major disability. The disease has
both a manic and depressive component. Current standard of care consists of
atypical antipsychotics for the treatment of mania, antidepressants for the
treatment of depression, and mood stabilizers for the maintenance of euthymia. The
molecular mechanisms which cause the disease are not well understood. Genome wide
association studies have provided a set of genes which are linked to the disease.
These genes show linkage to physiological and neuroanatomical alterations which are
also seen in bipolar disorder.

Ohgi, Y., et al. (2015). "Glutamate Signaling in Synaptogenesis and NMDA Receptors
as Potential Therapeutic Targets for Psychiatric Disorders." Curr Mol Med 15(3):
206-221.
Glutamate, a major excitatory neurotransmitter, plays important roles in
synaptic plasticity, such as long-term potentiation (LTP) and new synapse
formation. Growing evidence suggests that glutamate signaling is involved in the
neurobiology of psychiatric disorders, including schizophrenia, major depressive
disorder (MDD) and bipolar disorder (BP). Postmortem brain studies demonstrated
altered spine density in brains from patients with these psychiatric disorders,
indicating that remodeled neuronal circuits may contribute to the pathobiology of
these psychiatric diseases. Drugs targeting the glutamate system have typically
attracted attention as they show efficacy in animal studies and potential
therapeutic effects in the clinical setting. In particular, the Nmethyl- D-
aspartate (NMDA) receptor antagonist, ketamine exerts a rapid and robust
antidepressant effect in treatment-resistant patients with MDD and BP, whereas
conventional antidepressants require several weeks for therapeutic onset. Animal
studies showed that ketamine induced rapid synaptogenesis, suggestive of synaptic
plasticity via NMDA receptor signaling being an essential event in the treatment of
depression. Therefore, drugs modulating glutamate signaling could also be potential
therapeutic drugs for psychiatric disorders. First, we summarize the role of
glutamate signaling on dendritic spine formation, maintenance and remodeling. Then,
we discuss the abnormalities identified in dendritic spine and glutamate signaling
from postmortem brain studies and animal models of psychiatric disorders. Finally,
we review the potential benefits of drugs acting on the NMDA receptor in clinical
and animal models of psychiatric disorders.

Ohnishi, T., et al. (2014). "Defective craniofacial development and brain function
in a mouse model for depletion of intracellular inositol synthesis." J Biol Chem
289(15): 10785-10796.
myo-Inositol is an essential biomolecule that is synthesized by myo-inositol
monophosphatase (IMPase) from inositol monophosphate species. The enzymatic
activity of IMPase is inhibited by lithium, a drug used for the treatment of mood
swings seen in bipolar disorder. Therefore, myo-inositol is thought to have an
important role in the mechanism of bipolar disorder, although the details remain
elusive. We screened an ethyl nitrosourea mutant mouse library for IMPase gene
(Impa) mutations and identified an Impa1 T95K missense mutation. The mutant protein
possessed undetectable enzymatic activity. Homozygotes died perinatally, and E18.5
embryos exhibited striking developmental defects, including hypoplasia of the
mandible and asymmetric fusion of ribs to the sternum. Perinatal lethality and
morphological defects in homozygotes were rescued by dietary myo-inositol. Rescued
homozygotes raised on normal drinking water after weaning exhibited a hyper-
locomotive trait and prolonged circadian periods, as reported in rodents treated
with lithium. Our mice should be advantageous, compared with those generated by the
conventional gene knock-out strategy, because they carry minimal genomic damage,
e.g. a point mutation. In conclusion, our results reveal critical roles for
intracellular myo-inositol synthesis in craniofacial development and the
maintenance of proper brain function. Furthermore, this mouse model for cellular
inositol depletion could be beneficial for understanding the molecular mechanisms
underlying the clinical effect of lithium and myo-inositol-mediated skeletal
development.

Okanovic, M. and O. Zivanovic (2016). "Valproate, Bipolar Disorder and Polycystic

Ovarian Syndrome." Med Pregl 69(3-4): 121-126.
INTRODUCTION: Polycystic ovarian syndrome is a syndrome of ovarian
dysfunction with the principal features of hyperandrogenism and polycystic ovary
morphology. A large number of studies conducted on this topic have suggested a
possible role of anticonvulsants, particularly valproate, in the pathogenesis or
risk factors associated with polycystic ovarian syndrome. Bipolar treatment
guidelines from Canada and the United States of America recommend valproate as the
first line strategy in the acute treatment of bipolar disorder. DISCUSSION: Most
persons with bipolar disorder require maintenance treatment. Long-term
administration of valproate in women with bipolar disorder or epilepsy is believed
to result in the increased risk of hyperandrogenism, menstrual abnormalities and
polycystic ovaries. Valproate may also increase the risk of infertility and other
associated symptoms of polycystic ovarian syndrome. Therefore, particular caution
is indicated in the use of valproate in women of reproductive age. CONCLUSION: The
treatment of the female patients with bipolar disorder presents various challenges
for the clinician. Every woman of reproductive age needs to know the risk and
benefits of her pharmacologic treatment options. Bipolar disorder should be
considered chronic disorder, whose development is largely affected by hormonal
changes and reproductive cycle in women. These issues should be researched more
thoroughly in order to opt for the most appropriate treatment in women with bipolar
disorder.

Okerlund, N. D. and B. N. Cheyette (2011). "Synaptic Wnt signaling-a contributor to

major psychiatric disorders?" J Neurodev Disord 3(2): 162-174.
Wnt signaling is a key pathway that helps organize development of the nervous
system. It influences cell proliferation, cell fate, and cell migration in the
developing nervous system, as well as axon guidance, dendrite development, and
synapse formation. Given this wide range of roles, dysregulation of Wnt signaling
could have any number of deleterious effects on neural development and thereby
contribute in many different ways to the pathogenesis of neurodevelopmental
disorders. Some major psychiatric disorders, including schizophrenia, bipolar
disorder, and autism spectrum disorders, are coming to be understood as subtle
dysregulations of nervous system development, particularly of synapse formation and
maintenance. This review will therefore touch on the importance of Wnt signaling to
neurodevelopment generally, while focusing on accumulating evidence for a synaptic
role of Wnt signaling. These observations will be discussed in the context of
current understanding of the neurodevelopmental bases of major psychiatric
diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum
disorder. In short, this review will focus on the potential role of synapse
formation and maintenance in major psychiatric disorders and summarize evidence
that defective Wnt signaling could contribute to their pathogenesis via effects on
these late neural differentiation processes.

Oksanen, J. (2010). "[Psychosocial treatment of bipolar disorder]." Duodecim

126(4): 371-377.
Psychosocial treatment is an essential part of maintenance treatment of
bipolar disorder. It aims to improve cooperation in treatment, to provide support
to the family and to teach illness self-management skills. Group psychoeducation
and cognitive-behavioural treatment have shown the best efficacy in controlled
studies of specific treatment programs developed for this disorder. Central
ingredients of these treatment programs can be included in usual outpatient
treatment; they include teaching the patients to recognize early warning signs of
mood episodes, monitoring mood changes, encouraging regularity of diurnal rhythms
and relieving the emotional stress of family members. Group settings will provide
peer support.

Oksanen, J. (2015). "[Supporting adherence to drug therapy in psychiatry]."

Duodecim 131(16): 1437-1442.
Maintenance therapy to reduce the risk of recurrence is an essential part of
treatment of schizophrenia, bipolar disorder and major depressive disorder, but
poor treatment adherence is common, impairing the treatment outcome. Improvement in
the adherence to drug therapy requires a good therapeutic relationship. The patient
and her/his family must be provided with information about the illness and its
treatment. Drug therapy must be optimized on an individual basis. The use of long-
acting antipsychotic injections should be encouraged. Regular contact with patients
under long-term treatment must be maintained. The use of experts by experience is
an effective supportive measure.

Oliveira, M., et al. (2011). "Effects of acute autonomic modulation on atrial

conduction delay and local electrograms duration in paroxysmal atrial
fibrillation." Int J Cardiol 149(3): 290-295.
UNLABELLED: Slowed atrial conduction may contribute to reentry circuits and
vulnerability for atrial fibrillation (AF). The autonomic nervous system (ANS) has
modulating effects on electrophysiological properties. However, complex
interactions of the ANS with the arrhythmogenic substrate make it difficult to
understand the mechanisms underlying induction and maintenance of AF. AIM: To
determine the effect of acute ANS modulation in atrial activation times in patients
(P) with paroxysmal AF (PAF). METHODS AND RESULTS: 16P (9 men; 59+/-14years) with
PAF, who underwent electrophysiological study before AF ablation, and 15P (7 men;
58+/-11years) with atrioventricular nodal reentry tachycardia, without
documentation or induction of AF (control group). Each group included 7P with
arterial hypertension but without underlying structural heart disease. The study
was performed while off drugs. Multipolar catheters were placed at the high right
atrium (HRA), right atrial appendage (RAA), coronary sinus (CS) and His bundle area
(His). At baseline and with HRA pacing (600ms, shortest propagated S2) we measured:
i) intra-atrial conduction time (IACT, between RAA and atrial deflection in the
distal His), ii) inter-atrial conduction time (interACT, between RAA and distal
CS), iii) left atrial activation time (LAAT, between atrial deflection in the
distal His and distal CS), iv) bipolar electrogram duration at four atrial sites
(RAA, His, proximal and distal CS). In the PAF group, measurements were also
determined during handgrip and carotid sinus massage (CSM), and after
pharmacological blockade of the ANS (ANSB). AF was induced by HRA programmed
stimulation in 56% (self-limited - 6; sustained - 3), 68.8% (self-limited - 6;
sustained - 5), and 50% (self-limited - 5; sustained - 3) of the P, in basal,
during ANS maneuvers, and after ANSB, respectively (p=NS). IACT, interACT and LAAT
significantly lengthened during HRA pacing in both groups (600ms, S2). P with PAF
have longer IACT (p<0.05), a higher increase in both IACT, interACT (p<0.01) and
electrograms duration (p<0.05) with S2, and more fragmented activity, compared with
the control group. Atrial conduction times and electrograms duration were not
significantly changed during ANS stimulation. Nevertheless, ANS maneuvers increased
heterogeneity of the local electrograms duration. Also, P with sustained AF showed
longer interACT and LAAT during CSM. CONCLUSION: Atrial conduction times,
electrograms duration and fractionated activity are increased in PAF, suggesting a
role for conduction delays in the arrhythmogenic substrate. Acute vagal stimulation
is associated with prolonged interACT and LAAT in P with inducible sustained AF and
ANS modulation may influence the heterogeneity of atrial electrograms duration.

Oliveira, M., et al. (2010). "Effects of vagal stimulation on induction and

termination of atrial fibrillation in an in vivo rabbit heart model." Rev Port
Cardiol 29(3): 375-389.
INTRODUCTION: Vagal activity is thought to influence atrial
electrophysiological properties and play a role in the initiation and maintenance
of atrial fibrillation (AF). In this study, we assessed the effects of acute vagal
stimulation (vagus_stim) on atrial conduction times, atrial and pulmonary vein (PV)
refractoriness, and vulnerability to induction of AF in the rabbit heart with
intact autonomic innervation. METHODS: An open-chest epicardial approach was
performed in 11 rabbits (New Zealand; 3.9-5.0 kg), anesthetized and artificially
ventilated after neuromuscular blockade. A 3-lead ECG was obtained. Atrial
electrograms were recorded along the atria, from right to left (four monopolar
electrodes), together with a circular electrode adapted for proximal left PV
assessment. Acute vagus nerve stimulation was obtained with bipolar electrodes (20
Hz). Epicardial activation was recorded in sinus rhythm, and the conduction time
from right (RA) to left atrium (LA), and from RA to PVs, was measured in basal
conditions and during vagus_stim. The atrial effective refractory period (ERP) and
dispersion of refractoriness (Disp_A) were analyzed. Vulnerability to AF induction
was assessed at the right (RAA) and left (LAA) atrial appendages and the PVs.
Atrial stimulation (50 Hz) was performed alone or combined with vagus_stim. Heart
rate and blood pressure were monitored. RESULTS: In basal conditions, there was a
significant delay in conduction from RA to PVs, not influenced by vagus_stim, and
the PV ERPs were shorter than those measured in LA and LAA, but without significant
differences compared to RA and RAA. During vagus_stim, conduction times between RA
and LA increased from 16+8 ms to 27+6 ms (p < 0.05) and ERPs shortened
significantly in RA, LAA and LA (p < 0.05), but not in RAA. There were no
significant differences in Disp_A. AF induction was reproducible in 45% of cases at
50 Hz and in 100% at 50 Hz+vagus_stim (p < 0.05). The duration of inducible AF
increased from 1.0 +/- 0.2 s to 12.0 +/- 4.5 s with 50 Hz+vagus_stim (p < 0.01). AF
lasted >10 s in 45.4% of rabbits during vagus_stim, and ceased after vagus_stim in
4 out of these 5 cases. In 3 animals, PV tachycardia, with fibrillatory conduction,
induced with 50 Hz PV pacing during vagus_stim. CONCLUSIONS: Vagus_stim reduces
interatrial conduction velocity and significantly shortens atrial ERP, contributing
to the induction and duration of AF episodes in the in vivo rabbit heart. This
model may be useful for the assessment of autonomic influence on the
pathophysiology of AF

Oncu, B., et al. (2014). "Lamotrigine for attention deficit-hyperactivity disorder

comorbid with mood disorders: a case series." J Psychopharmacol 28(3): 282-283.
Attention de fi cit-hyperactivity disorder (ADHD) is frequently comorbid with
mood disorders in both children and adults. Comorbidity is shown to have negative
consequences and it needs to be treated effectively. Lamotrigine, an anticonvulsant
indicated for the maintenance treatment of bipolar depression is reported to be
effective in adult ADHD comorbid with bipolar II disorder. We conducted a
retrospective chart review to identify patients with adult ADHD and comorbid mood
disorders on lamotrigine, along with ADHD medications, and/or antidepressants and
antipsychotics. We identified 40 patients (17 women, 42.5%; age range 16 - 55 yrs),
50% with bipolar II and 50% with recurrent depression. Their treatment response was
evaluated by Clinical Global Impression scales. We found that 31 patients (77.5%)
improved with lamotrigine, there was no change in 7 patients (17.5%) and 2 patients
got worse, with a mean lamotrigine dose of 125.6 +/- 47.8 mg (25 - 250 mg). To our
knowledge, this is the first study to report that lamotrigine might be a safe and
effective treatment option for adult ADHD comorbid with bipolar and recurrent
depression.

O'Neill, S. (2015). "The countertransference impact of autistic defence in an

otherwise neurotic patient." Int J Psychoanal 96(5): 1283-1303.
This paper investigates the question of why, in the psychoanalytic
psychotherapy of a patient with encapsulated autistic pathology, the steady
maintenance of a therapeutically neutral stance can be especially difficult.
Transference and countertransference vicissitudes are examined. The author notices
that the patient's intolerance of 'opposites' (cf. Tustin, 1986), combined with
extreme antipathy to having that intolerance noticed, can elicit corresponding, and
potentially destabilizing, countertransference reactions. These reactions comprise
an unstable tension between co-existing pressures towards fusion with, or expulsion
of, the patient, their co-existence under further pressure to remain unnoticed.
Until perceived, this state of affairs risks collusion with the pressure either to
merge with or to expel the patient, and compromises the capacity to notice the
detail of the transference process and even to notice co-existent positive and
negative transference images. Detailed clinical illustration is given, including a
session where it was difficult to notice the patient's experience of a couple as a
combined object. The author finds these observations of bipolar countertransference
tensions illuminated by Green's concepts of positive and negative narcissism and of
the disobjectalizing function, and specifically accounted for by Ribas's theory of
autism as radical drive defusion.

Ong, W. Y., et al. (2015). "Synthetic and natural inhibitors of phospholipases A2:
their importance for understanding and treatment of neurological disorders." ACS
Chem Neurosci 6(6): 814-831.
Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze
membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic
acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes),
and lysophospholipids are converted to platelet-activating factors. These lipid
mediators play critical roles in the initiation, maintenance, and modulation of
neuroinflammation and oxidative stress. Neurological disorders including
excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's
disease; Parkinson's disease; multiple sclerosis; experimental allergic
encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are
characterized by oxidative stress, inflammatory reactions, alterations in
phospholipid metabolism, accumulation of lipid peroxides, and increased activities
of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of
PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl
fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based
inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and
polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including
curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and
used for the treatment of neurological disorders in cell culture and animal model
systems. The purpose of this review is to summarize information on selective and
potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants,
for treatment of oxidative stress and neuroinflammation associated with the
pathogenesis of neurological disorders.

Ostacher, M. J., et al. (2016). "Florida Best Practice Psychotherapeutic Medication

Guidelines for Adults With Bipolar Disorder: A Novel, Practical, Patient-Centered
Guide for Clinicians." J Clin Psychiatry 77(7): 920-926.
OBJECTIVE: This report describes the 2014 update of the Florida Best Practice
Psychotherapeutic Medication Guidelines for Adults With Bipolar Disorder, intended
to provide frontline clinicians with a simple, evidence-based approach to
treatments for 3 phases of bipolar disorder: acute depression, acute mania, and
maintenance. PARTICIPANTS: The consensus meeting included representatives from the
Florida Agency for Health Care Administration, pharmacists, health care policy
experts, mental health clinicians, and experts in bipolar disorder. The effort was
funded by the Florida Agency for Health Care Administration. EVIDENCE: The
available published and nonpublished data from trials in the treatment of bipolar I
disorder were reviewed. Evidence for efficacy and harm from replicated randomized
clinical trials, systematic reviews and meta-analyses, or non-replicated randomized
clinical trials was included. No recommendations were made with evidence from other
sources. CONSENSUS PROCESS: Decisions regarding the structure of the guidelines
were made during a stakeholder meeting in Tampa, Florida, on September 20 and 21,
2013. Better proven and safer/more efficacious treatments were to be utilized
before using those with less evidence and/or greater risk. Safety and risk of harm
were balanced against potential benefit. Lower-quality evidence was recommended
only if higher-level treatments were found to be ineffective or not tolerated,
because of patient preference, or because of past treatment success. While
respecting patient and clinician choice, the guidelines are structured to encourage
evidence-based, safe prescribing first. CONCLUSIONS: This iteration of the Florida
guidelines for the treatment of bipolar disorder is a practical, simple, patient-
focused guide to treatment for acute mania and acute bipolar depression and
maintenance treatment that considers safety and harm in the hierarchy of treatment
choices. While using strict evidence-based criteria for inclusion in
recommendations, it eliminates expert opinion as a level of evidence while
respecting clinician and patient choice in treatment decision-making.

Owen, R. T. (2010). "Olanzapine: a review of rapid and long-acting parenteral

formulations." Drugs Today (Barc) 46(3): 173-181.
Olanzapine, an atypical antipsychotic was first introduced in 1996 as an oral
formulation and is used in the treatment of schizophrenia and bipolar disorder.
Recent developments have included parenteral formulations to improve compliance in
the treatment of schizophrenia and to treat agitation in patients with
schizophrenia and bipolar mania. Olanzapine pamoate long acting injection (depot)
is a novel formulation of the atypical antipsychotic olanzapine, which is licensed
for the maintenance treatment of schizophrenia. When administered as the pamoate
salt, olanzapine has an elimination half-life of approximately 30 days, allowing it
to be given at 2- or 4-weekly intervals. An 8-week, randomized, double-blind study
in 404 patients acutely ill with schizophrenia demonstrated significant
antipsychotic efficacy (versus placebo). A 24-week, randomized, double-blind,
active-controlled study in 1,065 schizophrenia patients stabilized with oral
olanzapine demonstrated the depot formulation could delay exacerbation of positive
symptoms or hospitalization. Apart from local injection reactions and a
postinjection delirium/sedation syndrome, no new adverse events additional to those
seen with oral olanzapine have been notedto date. The pivotal clinical trials of
olanzapine rapid-acting intramuscular injection are reviewed in addition to post-
hoc analyses, controlled and naturalistic studies since its launch.

Ozten, M., et al. (2015). "Impulsivity in bipolar and substance use disorders."
Compr Psychiatry 59: 28-32.
BACKGROUND: Bipolar disorder (BD) is commonly associated with increased
impulsivity, particularly during manic and depressed episodes; also impulsivity
remains elevated during euthymic phases. Impulsivity is also a factor in the
initiation and maintenance of substance use disorders (SUD). Impulsivity can
predispose to substance abuse or can result from it. Impulsivity appears to be
relatively independent of mood state and is higher in individuals with past
substance use. Thus, we wanted to compare the impulsivity of BD and SUD closely
associated with impulsivity and identify potential differences. METHODS:
Impulsivity was evaluated by the Barratt Impulsiveness Scale (BIS-11A), in 35
bipolar interepisode disorder male patients without comorbid substance use disorder
and 40 substance use disorder male patients. The BIS-11A mean scores for the two
groups were compared through one-way between-groups ANOVA. RESULTS: There was no
difference between the BD and substance use disorder groups on total and subscale
attentional, motor impulsivity measures. However, for the male patients there was
difference on the nonplanning subscale. The male BD patient group scored higher
than the male substance use disorder patient group regarding nonplanning
impulsivity. CONCLUSIONS: Our results replicate the findings that interepisode BD
and substance use disorder patients both have increased total impulsivity;
furthermore, the findings also indicate that trait impulsivity is not completely
the same in subscales. Both groups were similar on attention and motor impulsivity
subscales; however, on the nonplanning subscale, BD patients were more impulsive
than the substance use disorder patients.

Paaren, A., et al. (2013). "Hypomania spectrum disorders from adolescence to

adulthood: a 15-year follow-up of a community sample." J Affect Disord 145(2): 190-
199.
BACKGROUND: There is a lack of scientific knowledge about the broader
spectrum of hypomania in adolescence and the course over time. To investigate this,
we used longitudinal data spanning from adolescence to age 31 years. METHOD: A
community sample of adolescents (N=2300) was screened for depressive symptoms.
Adolescents (16-17 years) with a positive screening and matched controls were
interviewed with a structured diagnostic interview. A blinded follow-up assessment
was conducted 15 years later, with a structured diagnostic interview covering the
age span 19-31 years. Questions about treatment and family history were included.
RESULTS: Ninety adolescents (16-17 years) with a lifetime hypomania spectrum
episode (3.9% of the total sample) were identified: 40 with fullsyndromal, 18 with
brief-episode (<4 day), and 32 with subsyndromal (1-2 main symptoms and 1-2
additional symptoms) hypomania. The hypomania symptoms reported by the
fullsyndromal and the brief-episode groups were similar, whereas the subsyndromal
group per definition reported fewer symptoms. Of the 90 adolescents with a
hypomania spectrum episode, 64 (71%) participated in the follow-up interview. Mania
in adulthood was reported by 2 (3%), hypomania by an additional 4 (6%), and major
depression by 38 (59%). Incidence of mood episodes in adulthood did not differ
between the subgroups of hypomania spectrum. LIMITATIONS: 29% of the participants
with hypomania spectrum were lost to follow-up. CONCLUSION: The results indicate
that only a small proportion of adolescents with hypomania spectrum episodes
continue to have (hypo)mania in adulthood. Thus, maintenance or prophylactic
treatment does not seem warranted for this group.

Paholpak, S., et al. (2014). "Clinical outcome of valproate maintenance treatment

in bipolar I disorder at Srinagarind Hospital." J Med Assoc Thai 97(4): 431-438.
OBJECTIVE: To determine-in a clinical setting-the rate and time to recurrence
of any mood episode during valproate maintenance treatment for bipolar I disorder.
MATERIAL AND METHOD: A retrospective cohort based on medical records of both in-
and out-patient with bipolar I disorder (DSM-IV-TR) seen at Srinagarind Hospital
between January 1, 2009 and December 31, 2010 was done. A recurrence was observed
if the patient had fulfilled the remission criteria and valproate was the
maintenance drug. Survival analysis and Cox regression analysis were used to
analyze the data. RESULTS: Eighty-five patients with 124 remitted mood episodes met
the inclusion criteria. Of the 85 patients, the average age was 41.4 +/- 17.1 years
(range, 18-89); 49.4% were males; 48.2% married; 42.4% completed secondary school,
30.6% completed a bachelor degree; 35.3% were unemployed, and 34.1% were government
employees. Twenty remitted mood episodes (16.1%) were in maintenance treatment with
valproate only. The remaining 104 (83.9%) were in maintenance treatment with
valproate in combination with other agents. There were 50 recurrences from 36
patients during the two years of study, the recurrence per a patient ranged from 1
to 3 times. The rate of recurrence was 21%/year or 2.2/100 person-months (95% CI =
1.65-2.93). The average time to recurrence to any mood episode was 33 months (95%
CI = 15.06-50.94). With multivariable Cox regression, a statistically significant
greater risk for a recurrence was associated with: (a) the previous episode being
hospitalized (adjusted hazard ratio = 5.88, 95% CI = 2.76-12.36, p < 0.001); (b)
blood valproate concentration during maintenance treatment < 50 microg/mL (adjusted
hazard ratio = 3.07, 95% CI = 1.11-8.53, p = 0.03); and (c) time duration (month)
of valproate maintenance treatment (adjusted hazard ratio = 0.98, 95% CI = 0.96-
0.99, p = 0.001). With the adjusted hazard ratio 0.98, it could be interpreted in
the other way that each additional month of taking valproate was associated with a
statistically significant protective factor that decreased the risk of recurrence
by 2% from the previous month. CONCLUSION: In the authors'clinical setting,
valproate both singly and in combination with other psychotropic agents used for
maintenance treatment of bipolar I disorder yielded a recurrence rate of 21% per
year or 2.2 per 100 person-months and time to any mood episode recurrence of 33
months. The present result has importance for both clinical treatment decision-
making and patient economic status.

Palma, M., et al. (2016). "Efficacy of Electroconvulsive Therapy in Bipolar

Disorder with Mixed Features." Depress Res Treat 2016: 8306071.
Introduction. Mixed states represent a frequent presentation of bipolar
disorder, associated with higher resistance to psychopharmacology. Limited evidence
supports the use of ECT in these patients. We aim to report our experience on
treating bipolar mixed states with ECT. Methods. Retrospective data were collected
from all bipolar patients submitted to acute ECT treatment, between June 2006 and
June 2011. Three groups were created in terms of affective polarity of the episode.
CGI rating was used to establish clinical remission and demographic and clinical
variables were compared among groups. Long-term outcome was assessed through
readmission measures, considering the use of continuation or maintenance ECT.
Results. During the study time frame, a total of 50 ECT course treatments were
performed on 41 bipolar patients. All affective episodes, except one mixed state,
showed a positive clinical response. Patients with mixed state presentation tended
to be younger and have an earlier first hospitalization than depressed patients. No
differences were found in terms of ECT sessions performed, length of hospital
admission, referral to continuation ECT treatment, number of readmissions, and time
until next readmission. Conclusions. Our results support the effectiveness of ECT
in patients experiencing a mixed affective state.

Pan, P. Y., et al. (2014). "Olanzapine is superior to lamotrigine in the prevention

of bipolar depression: a naturalistic observational study." BMC Psychiatry 14: 145.
BACKGROUND: Bipolar disorder is a highly recurrent disease and has great
impact on the function of patients. Depressive symptoms consist of more than 50% of
life time during the illness and may lead to self harm or suicidal behaviors.
Little is known about the antidepressant effects of olanzapine, an atypical
antipsychotic, as monotherapy despite its indication for preventing manic episodes.
In contrast, lamotrigine, a mood stabilizer, has been proven to be effective in
preventing depression in patients with bipolar disorder. However, no studies have
compared the efficacy between lamotrigine and olanzapine in the maintenance
treatment of bipolar disorder. This enriched naturalistic study was implemented to
assess the effectiveness of olanzapine and lamotrigine as monotherapy in the
prevention of recurrence of bipolar disorder. METHODS: Patients with bipolar
disorder in a euthymic state (Young's Mania Rating Scale (YMRS) score <12, and 21-
item Hamilton Depression Rating Scale (HAM-D) score <7) for at least two months,
having already received either olanzapine or lamotrigine as the maintenance
treatment were recruited. The patients maintained with olanzapine (n = 22) were
applied to olanzapine group whereas those maintained with lamotrigine (n = 29) were
applied to lamotrigine group. They were followed up for 12 months. Differences in
the efficacy between olanzapine and lamotrigine in recurrence prevention were
analyzed. The Kaplan-Meier method was used to generate time-to-recurrence curves,
and differences between the two groups were compared using the log-rank test.
RESULTS: Olanzapine had a significantly lower recurrence rate of depressive
episodes than lamotrigine (20.0% vs. 57.7%, chi2 = 6.62, p = .010). However,
olanzapine and lamotrigine had similar mania (15.0% vs. 0%, chi2 = 4.17, p = .075,
Fisher's exact test) and any mood episode (35.0% vs. 57.7%, chi2 = 2.33, p = .127)
recurrence rates. Olanzapine was significantly superior to lamotrigine in the time
to recurrence of depressive episodes (chi2 = 4.55, df = 1, p = .033), but there was
no difference in the time to recurrence of any mood episode (chi2 = 1.68, df = 1, p
= .195). CONCLUSIONS: This prospective naturalistic study suggests that olanzapine
is more effective than lamotrigine in the prevention of depressive episodes in
patients with bipolar disorder. Future large-scale randomized studies are warranted
to validate our results. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01864551.

Parabiaghi, A., et al. (2015). "Lithium use from 2000 to 2010 in Italy: a
population-based study." Pharmacopsychiatry 48(3): 89-94.
INTRODUCTION: Lithium is a highly specific and evidence-supported drug for
the acute and maintenance treatment of bipolar disorder. METHODS: The purpose of
this study was to calculate the prevalence and incidence of lithium use and to
investigate the prescribing patterns of other mood-stabilizing agents in lithium
users. We analyzed lithium utilization from 2000 to 2010 in a large area in Italy
on the basis of dispensing data drawn from the regional administrative database.
For each calendar year those who had at least one recorded dispensation of lithium
were defined as lithium users. Those who received more than 4 dispensations per
year were defined as lithium-treated. RESULTS: Rates of lithium utilization did not
change during the observation period, but the amount of drug prescribed increased
as a result of longer treatment and higher doses. The prevalence of use showed an
initial increase of 8% (2000-2002), followed by a 13% decrease (2002-2006) and a
subsequent rise of 11% (2006-2010). The prevalence of treatment grew by 38% during
the whole observation period. The proportion of former lithium users who received
other drugs or discontinued any treatment increased from 41% in 2002 to 52% in
2006, and then fell to 40% in 2010. CONCLUSION: The initial decline (2002-2006) and
the subsequent rise (2006-2010) of lithium use can be explained by a fall and rise
of new prescriptions. This finding together with a similar but opposite change in
prescriptions of the other mood-stabilizing agents suggests a temporary change in
prescribing attitudes which was subsequently reconsidered.

Park, S. and D. C. Gooding (2014). "Working Memory Impairment as an Endophenotypic

Marker of a Schizophrenia Diathesis." Schizophr Res Cogn 1(3): 127-136.
This chapter focuses on the viability of working memory impairment as an
endophenotypic marker of a schizophrenia diathesis. It begins with an introduction
of the construct of working memory. It follows with a review of the operational
criteria for defining an endophenotype. Research findings regarding the working
memory performance of schizophrenia and schizophrenia-spectrum patients, first-
degree relatives of schizophrenia patients and healthy controls, are reviewed in
terms of the criteria for being considered an endophenotypic marker. Special
attention is paid to specific components of the working memory deficit (namely,
encoding, maintenance, and manipulation), in terms of which aspects are likely to
be the best candidates for endophenotypes. We consider the extant literature
regarding working memory performance in bipolar disorder and major depression in
order to address the issue of relative specificity to schizophrenia. Despite some
unresolved issues, it appears that working memory impairment is a very promising
candidate for an endophenotypic marker of a schizophrenia diathesis but not for
mood disorders. Throughout this chapter, we identify future directions for research
in this exciting and dynamic area of research and evaluate the contribution of
working memory research to our understanding of schizophrenia.

Parker, G. and S. McCraw (2015). "The 'disconnect' between initial judgments of

lamotrigine vs. its real-world effectiveness in managing bipolar disorder. A tale
with wider ramifications." Acta Psychiatr Scand 132(5): 345-354.
OBJECTIVE: To detail the disconnect between the quantified efficacy of the
mood stabilizer lamotrigine in its registration controlled trials and its later
judged clinical effectiveness and consider some determinants of disconnects between
some efficacy trial findings and 'real-world' clinical effectiveness judgments.
METHOD: Published articles considering lamotrigine as a treatment for the bipolar I
or II disorders were selected for review. While randomized controlled trials were
weighted, we also consider open trials and effectiveness observations from
clinician researchers and demonstrate that lamotrigine has been quite variably
judged over time. RESULTS: We suggest that the early trials evaluating lamotrigine
for acute bipolar disorder depression focused on a suboptimal clinical target, and
in so doing, ensured less lamotrigine efficacy compared with trials of bipolar
disorder preventative treatment. Moreover, a number of additional methodological
limitations compromised analyses. We also detail variable reporting of actual study
results. The initial sharp disconnect (between efficacy and effectiveness
judgments) has narrowed as lamotrigine has been evaluated and progressively taken
up as a maintenance mood stabilizer. CONCLUSION: The lamotrigine disconnect story
provides a number of salutary lessons that are salient to evaluating the
effectiveness and ecological niche of any psychotropic medication. The lamotrigine
story presented here argues strongly for the wisdom of encouraging an iterative
process between efficacy studies and clinical observation.

Paton, C., et al. (2013). "Monitoring lithium therapy: the impact of a quality
improvement programme in the UK." Bipolar Disord 15(8): 865-875.
OBJECTIVES: The study was designed to test an audit-based quality improvement
programme (QIP) addressing lithium prescribing and monitoring in UK mental health
services. METHODS: A baseline clinical audit was conducted against the following
standards: (i) measurement of renal and thyroid function before initiating
treatment with lithium and (ii) recommended monitoring of serum lithium and renal
and thyroid function during maintenance treatment. A re-audit was conducted at 18
months and a supplementary audit at three years. RESULTS: Data were submitted for
patients at baseline (n = 3,373), re-audit (n = 3,647), and supplementary audit (n
= 5,683), 57% of whom had bipolar disorder. The baseline findings prompted a
patient safety alert issued by the National Patient Safety Agency. By supplementary
audit, the proportion of patients having four serum lithium tests over the previous
year had increased from 30% at baseline to 48%, and the respective proportions that
had two tests of renal function from 55% to 70% and thyroid function from 49% to
66%. Elderly patients and those prescribed a drug known to interact with lithium
were not more likely to be monitored in line with the audit standards. Between
baseline and supplementary audit, the proportion of patients with a diagnosis of
bipolar disorder prescribed an antidepressant increased from 36% to 41%.
CONCLUSIONS: Improvements in biochemical monitoring of lithium treatment were
achieved over time with participation in a QIP that included benchmarking of
performance against clinical standards and customized change interventions.
Nevertheless, gaps remain between the standard and current practice.
Antidepressants are frequently prescribed in patients with bipolar disorder despite
a paucity of evidence supporting their efficacy.

Peng, L., et al. (2016). "Targeting astrocytes in bipolar disorder." Expert Rev
Neurother 16(6): 649-657.
Astrocytes are homeostatic cells of the central nervous system, which are
critical for development and maintenance of synaptic transmission and hence of
synaptically connected neuronal ensembles. Astrocytic densities are reduced in
bipolar disorder, and therefore deficient astroglial function may contribute to
overall disbalance in neurotransmission and to pathological evolution. Classical
anti-bipolar drugs (lithium salts, valproic acid and carbamazepine) affect
expression of astroglial genes and modify astroglial signalling and homeostatic
cascades. Many effects of both antidepressant and anti-bipolar drugs are exerted
through regulation of glutamate homeostasis and glutamatergic transmission, through
K(+) buffering, through regulation of calcium-dependent phospholipase A2 (that
controls metabolism of arachidonic acid) or through Ca(2+) homeostatic and
signalling pathways. Sometimes anti-depressant and anti-bipolar drugs exert
opposite effects, and some effects on gene expression in drug treated animals are
opposite in neurones vs. astrocytes. Changes in the intracellular pH induced by
anti-bipolar drugs affect uptake of myo-inositol and thereby signalling via
inositoltrisphosphate (InsP3), this being in accord with one of the main theories
of mechanism of action for these drugs.

Peruzzolo, T. L., et al. (2013). "Pharmacotherapy of bipolar disorder in children

and adolescents: an update." Rev Bras Psiquiatr 35(4): 393-405.
OBJECTIVE: To review the options for acute and maintenance pharmacological
treatment of bipolar disorder in children and adolescents, including the treatment
of bipolar depression and comorbid attention deficit/hyperactivity disorder (ADHD).
METHODS: Narrative review of randomized clinical trials and open-label studies
published from 2000 to 2012. The PubMed and PsycINFO websites were queried. Case
series were included when a higher level of evidence was not available. RESULTS:
Published data from randomized controlled trials (RCTs) in acute mania/hypomania
with significant responses are available for lithium, topiramate, risperidone,
olanzapine, and aripiprazole. Open trials of lithium and lamotrigine show that
these drugs may be effective in the treatment of depressive episodes. No trials of
selective serotonin reuptake inhibitors (SSRIs) have been conducted. In the
treatment of comorbid ADHD, there are encouraging findings with mixed amphetamine
salts and atomoxetine; conflicting results are observed with methylphenidate.
CONCLUSIONS: Published RCTs of traditional mood stabilizers are scarce, but the
best available evidence (results from meta-analytic regression) suggests that
second-generation antipsychotics (SGAs) as a group are more effective in reducing
manic symptoms. Risperidone was the only one included in head-to-head comparisons
(vs. lithium and divalproex), showing superiority in terms of efficacy, but with
more metabolic side effects, which were also more common in most of the SGAs. There
are few studies addressing the treatment of ADHD and depression. Brazilian
guidelines for the treatment of pediatric bipolar disorder should also include some
SGAs (especially risperidone and aripiprazole) as first-line treatment, and these
drugs should be provided by the public health services.

Peselow, E. D., et al. (2016). "Prophylactic efficacy of lithium, valproic acid,

and carbamazepine in the maintenance phase of bipolar disorder: a naturalistic
study." Int Clin Psychopharmacol 31(4): 218-223.
Mood stabilizers are used clinically for the management of bipolar disorder.
Prophylactic therapy with mood stabilizers is the primary treatment for preventing
depressive and manic relapses in bipolar patients once they are stabilized. In this
study, we examined the relative efficacy of the three most commonly used mood-
stabilizing agents: lithium (Li), valproic acid (VPA), and carbamazepine (CBZ), in
preventing relapse episodes. A total of 225 patients with bipolar disorder were
included in the present analysis. Patients taking Li, VPA, or CBZ were followed up
for up to 124 months, until suffering a manic, mixed, or depressive episode
(relapse), or until the end of the study/study termination (no relapse), whichever
came first. The median unadjusted survival time was 36 months for patients taking
VPA, 42 months for patients taking CBZ, and 81 months for patients taking Li. These
results indicate that patients stayed longer on Li, suggesting that it might have
been better tolerated than either CBZ or VPA. chi-Analysis showed that patients
taking Li were significantly less likely to experience relapse during the
observational period than patients taking either VPA or CBZ (P<0.05). A Cox
regression model showed that the hazard of experiencing relapse was significantly
predicted by the total number of depressive (P=0.007) and manic symptoms (P=0.02)
assessed before the observation period. In addition, after controlling for symptom
covariates, the hazard of experiencing relapse was 1.66 times (95% confidence
interval 1.03-2.67) or 66% higher for patients taking VPA compared with patients
taking Li (P=0.037). Although the hazard of experiencing relapse was higher for
patients taking CBZ compared with those taking Li, the risk was not elevated by a
significant amount. Notwithstanding the limitations of the naturalistic design of
this study, the differences in relapse prevention and survival time observed in
these medications show Li fairing relatively better in prophylactic therapy.

Peselow, E. D., et al. (2016). "Polypharmacy in Maintenance of Bipolar Disorder."

Clin Neuropharmacol 39(3): 132-134.
OBJECTIVES: To track the outcomes of bipolar patients who had remitted from
an acute manic episode on single- and multiple-drug regimens including lithium
(LI), valproate (VPA), and carbamazepine (CBZ), in order to compare relapse rates
on 1, 2, or 3 medications. METHODS: Following treatment of an acute manic episode
and a 1-month period of no signs of mood episodes, patients were evaluated at 1- to
2-month intervals as to the kind of regimen required to maintain their stability
while continuing on this regimen for 2 years. Medication regimens included 1, 2, or
3 of the following drugs: LI, VPA, and/or CBZ. The 3 medication groups were
followed from entry into the study through 3 possible end points based on the
Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition checklist:
"NO-Relapse," "Relapse," or "Dropped out." RESULTS: Of the 1312 patients included
in the study and followed up for 2 years, 281 patients (21.4%) were maintained on a
single drug (LI, VPA, or CBZ), 852 (65%) on 2 drugs, and 179 (13.6%) on 3 or more
drugs. A smaller percentage of patients on 1 medication had NO-Relapse for 2 years
(22.8%), compared with patients on 2 medications (43.9%) and patients on 3 or more
medications (41.9%): chi2 = 40.3, P < 0.001. CONCLUSIONS: This study showed that
overall, of the bipolar patients who were asymptomatic at 1 month, a smaller
percentage of patients on 1 medication continued to be stable for 2 years, compared
with patients on 2 medications and patients on 3 or more medications.

Petrides, G., et al. (2011). "Continuation and maintenance electroconvulsive

therapy for mood disorders: review of the literature." Neuropsychobiology 64(3):
129-140.
BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective treatment
for mood disorders. Continuation ECT (C-ECT) and maintenance ECT (M-ECT) are
required for many patients suffering from severe and recurrent forms of mood
disorders. This is a review of the literature regarding C- and M-ECT. METHODS: We
conducted a computerized search using the words continuation ECT, maintenance ECT,
depression, mania, bipolar disorder and mood disorders. We report on all articles
published in the English language from 1998 to 2009. RESULTS: We identified 32
reports. There were 24 case reports and retrospective reviews on 284 patients. Two
of these reports included comparison groups, and 1 had a prospective follow-up in a
subset of subjects. There were 6 prospective naturalistic studies and 2 randomized
controlled trials. CONCLUSIONS: C-ECT and M-ECT are valuable treatment modalities
to prevent relapse and recurrence of mood disorders in patients who have responded
to an index course of ECT. C-ECT and M-ECT are underused and insufficiently studied
despite positive clinical experience of more than 70 years. Studies which are
currently under way should allow more definitive recommendations regarding the
choice, frequency and duration of C-ECT and M-ECT following acute ECT.

Pfennig, A., et al. (2013). "The diagnosis and treatment of bipolar disorder:
recommendations from the current s3 guideline." Dtsch Arztebl Int 110(6): 92-100.
BACKGROUND: Bipolar disorder is a serious mental illness, characterized by
frequent recurrences and major comorbidities. Its consequences can include suicide.
METHODS: An S3 guideline for the treatment of bipolar disorder was developed on the
basis of a systematic literature search, evaluation of the retrieved publications,
and a formal consensus-finding procedure. Several thousand publications were
screened, and 611 were included in the analysis, including 145 randomized
controlled trials (RCT). RESULTS: Bipolar disorder should be diagnosed as early as
possible. The most extensive evidence is available for pharmacological monotherapy;
there is little evidence for combination therapy, which is nonetheless commonly
given. The appropriate treatment may include long-term maintenance treatment, if
indicated. The treatment of mania should begin with one of the recommended mood
stabilizers or antipsychotic drugs; the number needed to treat (NNT) is 3 to 13 for
three weeks of treatment with lithium or atypical antipsychotic drugs. The
treatment of bipolar depression should begin with quetiapine (NNT = 5 to 7 for
eight weeks of treatment), unless the patient is already under mood-stabilizing
treatment that can be optimized. Further options in the treatment of bipolar
depression are the recommended mood stabilizers, atypical antipsychotic drugs, and
antidepressants. For maintenance treatment, lithium should be used preferentially
(NNT = 14 for 12 months of treatment and 3 for 24 months of treatment), although
other mood stabilizers or atypical antipsychotic drugs can be given as well.
Psychotherapy (in addition to any pharmacological treatment) is recommended with
the main goals of long-term stabilization, prevention of new episodes, and
management of suicidality. In view of the current mental health care situation in
Germany and the findings of studies from other countries, it is clear that there is
a need for prompt access to need-based, complex and multimodal care structures.
Patients and their families need to be adequately informed and should participate
in psychiatric decision-making. CONCLUSION: Better patient care is needed to
improve the course of the disease, resulting in better psychosocial function. There
is a need for further high-quality clinical trials on topics relevant to routine
clinical practice.

Pichler, E. M., et al. (2015). "Safety and tolerability of anticonvulsant

medication in bipolar disorder." Expert Opin Drug Saf 14(11): 1703-1724.
INTRODUCTION: Anticonvulsants (AC) are widely used and recommended as a
treatment option in different phases of bipolar disorder (BD). In contrast to ample
evidence for efficacy in acute mania, there is generally less unambiguous evidence
for maintenance treatment or bipolar depression, and data on long-term tolerability
in BD are sparse, although this varies greatly between different compounds. This
review summarizes the clinically relevant tolerability and safety profile of ACs
commonly used for the treatment of BD based on findings from randomized controlled
trials (RCT). AREAS COVERED: Systematic search of the English literature between
January 1991 and May 2015 revealed a total of nine RCTs investigating valproate,
five RCTs with carbamazepine and 8 with lamotrigine For these ACs we found
information on side effect profiles for both acute and maintenance RCTs, albeit of
varying quality, whereas for topiramate (five RCTs), gabapentin and
esclicarbazepine acetate (one RCT each) only acute treatment RCTs have been
published. Descriptive side effect profiles from open-label studies exist for
several other ACs rarely used in BD, and are included in this review as a brief
narrative chapter. EXPERT OPINION: Whereas both valproate and carbamazepine are
associated with, in part, severe adverse events, lamotrigine emerges as a
relatively safe and well tolerated treatment option, especially in maintenance
treatment and prevention of depressive relapse in BD. Lack of proven efficacy and
side effect profile of other, less rigorously studied ACs restricts their use only
to very selected BD cases.

Pikalov, A., et al. (2017). "Long-term use of lurasidone in patients with bipolar
disorder: safety and effectiveness over 2 years of treatment." Int J Bipolar Disord
5(1): 9.
BACKGROUND: Bipolar disorder is a chronic illness with a 2-year recurrence
rate of approximately 50% among individuals receiving treatment in the community.
The aim of this 18-month, open-label, continuation study was to evaluate the long-
term safety and effectiveness of lurasidone in patients who initially presented
with a major depressive episode associated with bipolar disorder, and who had
completed at least 6 months of initial treatment with lurasidone. METHODS: Patients
with bipolar I depression were enrolled in one of three 6-week, double-blind,
placebo-controlled trials (monotherapy with lurasidone, 1 study; adjunctive therapy
with lurasidone; and lithium or valproate, 2 studies). Study completers were
eligible for a 6-month, open-label extension study of lurasidone utilizing flexible
daily doses of 20-120 mg; extension completers were then eligible for an additional
18 months of continuation treatment with flexible, once-daily doses of lurasidone
in the range of 20-80 mg. Concomitant therapy with mood stabilizers was permitted
throughout the open-label extension and continuation studies. RESULTS: A total of
1199 patients entered, and 941 (78.5%) completed initial, double-blind, acute
treatment, of whom 817/941 (86.8%) entered, and 559 (68.4%) completed the 6-month
extension study; 122/559 patients (21.8%) entered the 18-month continuation study,
of whom 19.7% of discontinued, including 6.6% due to adverse events and 1.6% due to
insufficient efficacy. The mean dose of lurasidone during the 18-month continuation
study was 61.8 mg/day, and the modal dose was 60 mg/day. Mean change in weight,
from acute baseline to 18-month continuation endpoint was +0.8 kg (completers, n =
55); median changes in cholesterol and triglycerides were -3.0 mg/dL and +26.0
mg/dL, respectively. Based on a Kaplan-Meier analysis, the probability of relapse
during 18 months of continuation treatment with lurasidone was estimated to be
18.3% in the monotherapy group and 29.1% in the adjunctive therapy group.
Improvement in global illness severity was also maintained during 18 months of
continuation therapy (CGI-S at continuation baseline, 2.1; 18-month completers,
1.7; LOCF-endpoint, 1.9). CONCLUSIONS: Up to 2 years of treatment with lurasidone
was safe and well tolerated in this bipolar disorder population presenting with an
index episode of depression. Improvement in depressive symptoms was maintained in
the majority of patients treated with lurasidone, with relatively low rates of
relapse, and with minimal effects on weight and metabolic parameters.

Pilhatsch, M., et al. (2010). "Comparison of paroxetine and amitriptyline as

adjunct to lithium maintenance therapy in bipolar depression: a reanalysis of a
randomized, double-blind study." J Affect Disord 126(3): 453-457.
OBJECTIVE: To compare the efficacy and safety of adjunctive treatment with
paroxetine or amitriptyline in patients with bipolar disorder who relapsed into a
depressive episode during lithium maintenance therapy. METHODS: Data from a
randomized, double-blind trial comparing paroxetine (N=18) or amitriptyline (N=22)
as adjunctive treatment for an episode of depression during lithium maintenance
therapy were reanalyzed. Only patients with a diagnosis of bipolar disorder were
included. The primary endpoint was the change in Hamilton Rating Scale for
Depression (HAM-D21) from randomization to study end (week 6). RESULTS: There was a
significant reduction of HAM-D21 total score from randomization to study end in
both treatment groups. The mean change in HAM-D21 score in the paroxetine and
amitriptyline groups at study end was -14.9 and -15.5 (p=0.798), and the mean HAM-
D21 at study end was 8.2 vs. 9.9 (p=0.420), respectively. The patients treated with
paroxetine showed a more rapid improvement with lower HAM-D21 scores between weeks
3 and 5. Tolerability was similar in both groups. LIMITATIONS: No placebo
comparator group and relatively small study sample size. CONCLUSIONS: Adjunctive
treatment with either paroxetine or amitriptyline is a viable option for
breakthrough depression during lithium maintenance therapy.

Plosker, G. L. (2012). "Quetiapine: a pharmacoeconomic review of its use in bipolar

disorder." Pharmacoeconomics 30(7): 611-631.
This article briefly summarizes the burden of bipolar disorder and the
clinical profile of quetiapine (Seroquel(R)) in the management of bipolar disorder,
followed by a detailed review of pharmacoeconomic analyses. Quetiapine is an
atypical antipsychotic that is available in numerous countries as immediate-release
and extended-release tablets for the treatment of major psychiatric disorders,
including bipolar disorder. Randomized, double-blind, placebo-controlled trials
with quetiapine have demonstrated its efficacy in bipolar I and II disorders, and
the drug has been generally well tolerated in clinical trials. Three cost-
effectiveness analyses of maintenance therapy in bipolar I disorder, which used
similar Markov models and incorporated data from key clinical trials and a number
of other sources, showed that quetiapine, as adjunctive therapy with mood
stabilizers (lithium or divalproex), was a cost-effective treatment option from the
healthcare payer perspective in the UK and the US. Quetiapine either dominated
comparators (typically mood stabilizers alone) or was associated with incremental
cost-effectiveness ratios that were usually well below widely accepted thresholds
of cost effectiveness. One of the studies evaluated extended-release quetiapine,
although clinical efficacy data used in the Markov model were for the immediate-
release formulation. In another analysis, which used a discrete-event simulation
model and was conducted from the perspective of the UK healthcare payer, quetiapine
monotherapy was cost effective compared with olanzapine monotherapy as maintenance
treatment for all phases of bipolar I or II disorder. In this model, favourable
results were also shown for quetiapine (with or without mood stabilizers) compared
with a wide range of maintenance therapy regimens. Another modelled analysis
conducted from the UK healthcare payer perspective showed that quetiapine was
dominated by haloperidol in the short-term treatment of a manic episode in patients
with bipolar I disorder. Both favourable and unfavourable results have been
reported in cost analyses of quetiapine in bipolar disorder (type I or type not
specified). Possible explanations for some of the variability in results of the
pharmacoeconomic analyses include heterogeneity among the models in terms of input
parameters or assumptions in the base-case analyses, country- or region-specific
differences in estimates of healthcare resource use and associated costs,
variability in treatment alternatives, and differences in the year of costing and
discounting used in the analyses. In addition, some of the studies had short time
horizons and focused on acute manic episodes only, whereas others were longer-term
analyses that considered the full spectrum of health states in patients with
bipolar disorder. Various limitations of the studies have been recognized, and
results from one country may not be applicable to other countries. In conclusion,
results of available pharmacoeconomic analyses provide evidence of the cost
effectiveness of quetiapine as an adjunct to mood stabilizers for maintenance
therapy in (primarily type I) bipolar disorder from a healthcare payer perspective
in the UK and the US. Some evidence is available to support the cost effectiveness
of quetiapine monotherapy or the use of extended-release quetiapine as adjunctive
therapy with mood stabilizers in this setting, although further analyses appear to
be warranted. Whether these findings apply to other geographical regions requires
further study. Evidence for the long-term (>2-year) cost effectiveness of
quetiapine in bipolar disorder is currently limited and further studies are also
needed to address the cost effectiveness of quetiapine from a societal perspective
and in bipolar II disorder.

Poletti, S., et al. (2017). "Th17 cells correlate positively to the structural and
functional integrity of the brain in bipolar depression and healthy controls."
Brain Behav Immun 61: 317-325.
Abnormalities of T cell-mediated immune activation, in the absence of active
somatic immune diseases, have consistently been reported in mood disorders. Apart
from being important players in the regulation of cells of the immune system, T
cells are essential for normal brain development. We here report studies on the
relationship between circulating levels of T helper cells and structural and
functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis
is an important entry to the brain we differentiated the various T helper cell
subpopulations on the basis of their chemokine receptor expression. METHODS: FACS
staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen
leukocytes of 25 consecutively admitted inpatients affected by a major depressive
episode, without psychotic features, in the course of Bipolar Disorder I and 21
healthy controls. The frequency of the T helper populations was associated with DTI
and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial
statistic was used to obtain measures of white matter integrity (fractional
anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with
35 directions. Patients were also studied for fMRI through a moral valence decision
task were subjects had to decide whether morally tuned stimuli were positive or
negative. RESULTS: The percentage of circulating Th17 (CCR6+CXCR3negCCR4+CCR10neg)
cells correlated positively with higher fractional anisotropy in fiber tracts
contributing to the functional integrity of the brain both in patients and healthy
controls, while the frequency of circulating T regulatory (CD4+CD25+FOXP3+) cells
correlated positively with higher radial and mean diffusivity in patients. The
frequency of circulating T regulatory cells also correlated to lower neuronal
responses to negative versus positive morally tuned stimuli in the right
dorsolateral prefrontal cortex of patients. Th1 cells correlated negatively with
white matter integrity in several tracts (healthy controls), while the cells showed
a positive correlation to the levels of pro-inflammatory cytokines (patients).
CONCLUSION: This study shows a new putative role for Th17 cells. Th17 cells are not
only playing a role in inducing autoimmunity and auto-inflammation, but might also
play a counter intuitive anabolic role in the maintenance of the functional and
structural integrity of the brain.

Pompili, M., et al. (2013). "Insomnia as a predictor of high-lethality suicide

attempts." Int J Clin Pract 67(12): 1311-1316.
INTRODUCTION: Research has demonstrated that patients with insomnia are at an
increased risk of experiencing suicidal ideation and/or making a suicide attempt.
OBJECTIVES: To evaluate the relation between insomnia and suicidal behaviour. AIMS:
To examine factors associated with a diagnosis of insomnia in patients admitted to
an Emergency Department (ED) and assessed by the psychiatrist in charge. METHODS:
Participants were 843 patients consecutively admitted to the ED of Sant'Andrea
Hospital in Rome, between January 2010 and December 2011. All patients admitted
were referred to a psychiatrist. A clinical interview based on the Mini
International Neuropsychiatric Interview (MINI) and a semi-structured interview was
conducted. Patients were asked about 'ongoing' suicidal ideation or plans for
suicide. RESULTS: Forty-eight percent of patients received a diagnosis of bipolar
disorder (BD), major depressive disorder (MDD) or an anxiety disorder; whereas,
17.1% were diagnosed with Schizophrenia or other non-affective psychosis. Patients
with insomnia (compared to patients without insomnia) more frequently had a
diagnosis of BD (23.9% vs. 12.4%) or MDD (13.3% vs. 9.5%; p < 0.001). Moreover,
patients with insomnia less frequently had attempted suicide in the past 24 h (5.3%
vs. 9.5%; p < 0.05) as compared with other patients, but those patients with
insomnia who attempted suicide more frequently used a violent method (64.3% vs.
23.6%; p < 0.01) compared to other suicide attempters. CONCLUSIONS: Our results do
not support an association between insomnia and suicidal behaviour. However,
suicide attempters with insomnia more frequently used violent methods, and this
phenomenon should be taken into serious consideration by clinicians.

Pope, S. and S. G. Zaraa (2016). "Efficacy of Long-Acting Injectable Antipsychotics

in Adolescents." J Child Adolesc Psychopharmacol 26(4): 391-394.
INTRODUCTION: The number of long-acting injectable antipsychotics (LAIA) has
increased in recent years. The safety and efficacy of that treatment are not
established in children. This study aims to address this gap of information by
studying such treatments in a case series. METHODS: This retrospective chart review
of patients identified by the investigators at an academic acute inpatient
psychiatric unit included all patients from the past 24 months who required new
initial treatment with LAIA. This study included a case series of the nine patients
along with Clinical Global Impression-Severity (CGI-S) scores from admission and
discharge and Clinical Global Impression-Improvement (CGI-I) scores. Other
observations included the presentation of primary psychiatric diagnosis,
psychiatric and medical comorbidities, age, sex, previous and LAIA psychiatric
medications, reasoning for LAIA treatment, adverse events, CGI-S and CGI-I scores,
and outpatient resources utilized to continue treatment. RESULTS: The case series
included two females and seven males within the ages of 14-17 years. Of those
patients, five were treated with paliperidone palmitate, one treated with
risperidone, one treated with fluphenazine, and one treated with aripiprazole.
Primary psychiatric diagnosis of the patients in the case series included five with
schizophrenia, one with schizoaffective disorder, one with bipolar affective
disorder-type I, one with bipolar affective disorder-not otherwise specified, and
one with mood disorder-not otherwise specified. In all nine cases, noncompliance
was a consideration in treatment with LAIA. Frequent running away and severity of
illness were also considerations in one case each. All of the patients required
community resources with injectable services. CONCLUSION: This study describes
initiation of treatment with LAIA in 14-17-year olds in an acute inpatient
psychiatric unit with serious mental illness. This study also demonstrates the need
for outpatient community resources with the ability to provide long-acting
injectable medication. Limitations of this study include a small patient
population, other factors changing CGI-S and CGI-I scores beyond the medication,
and the nature of the study as a retrospective chart review. This study did not
compare medications between each other. Maintenance dosing and long-term safety
were beyond the scope of this study. Future directives for safety studies, open-
label trials, and randomized double-blinded control trails in the pediatric
population would be needed.

Popovic, D., et al. (2011). "Number needed to treat analyses of drugs used for
maintenance treatment of bipolar disorder." Psychopharmacology (Berl) 213(4): 657-
667.
RATIONALE: Due to the episodic and chronic nature of bipolar disorder (BD),
maintenance therapy represents a critical part of treatment; however, there is a
paucity of studies comparing effectiveness of available long-term treatments.
OBJECTIVE: The aim of this study is to determine and compare the efficacy of
pharmacological treatments for maintenance treatment of BD by means of the number
needed to treat (NNT). METHODS: The efficacy of drugs used for maintenance
treatment of BD, as emerging from the results of randomized controlled trials, was
assessed using the size effect measure of NNT. PubMed searches were conducted on
English-language articles published until May 2010 using the search terms "bipolar
disorder," "mania," "mixed episode," or "bipolar depression," cross-referenced with
trial characteristic search phrases and generic names of medications. The search
was supplemented by manually reviewing reference lists from identified
publications. RESULTS: In 15 studies, aripiprazole, olanzapine, quetiapine,
risperidone long-acting injection, lithium, lamotrigine, and divalproex proved
effectiveness in terms of NNTs (>/= 10% advantage over placebo) for prevention of
relapse into any mood episode. Quetiapine, lithium, risperidone long-acting
injection, aripiprazole, and olanzapine are effective in manic recurrence
prevention. Lamotrigine, quetiapine, and lithium present significant NNTs for
prevention of depressive relapses. CONCLUSIONS: All of the pharmacological agents
assessed were effective in the prevention of any kind of mood episode; however,
different efficacy profiles were found for prevention of manic and/or depressive
relapses. The comparison of NNT values of the available agents may represent a
useful tool in clinical settings, in order to facilitate implementation of long-
term pharmacological interventions in patients with BD.

Popovic, D., et al. (2012). "Polarity index of pharmacological agents used for
maintenance treatment of bipolar disorder." Eur Neuropsychopharmacol 22(5): 339-
346.
Over one half of bipolar patients have been reported to be more prone to
either depressive or manic relapses. This study aimed to define profiles of drugs
used for maintenance treatment of bipolar disorder (BD) by the means of Polarity
Index. Polarity Index is a new metric indicating the relative antimanic versus
antidepressive preventive efficacy of drugs. Polarity Index was retrieved by
calculating Number Needed to Treat (NNT) for prevention of depression and NNT for
prevention of mania ratio, as emerging from the results of randomized placebo-
controlled trials. Included trials were randomized and double blind, with a minimal
duration of 24 weeks, assessing effectiveness of a mood stabilizer or antipsychotic
drug alone or in combination with a mood stabilizing agent versus a placebo
comparator in BD maintenance treatment. Polarity Index value above 1.0 indicates a
relative greater antimanic prophylactic efficacy, number below 1.0 a relative
greater antidepressive efficacy. The polarity index for the drugs used in
maintenance therapy for bipolar disorder was 12.09 for risperidone, 4.38 for
aripiprazole, 3.91 for ziprasidone, 2.98 for olanzapine, 1.39 for lithium, 1.14 for
quetiapine, and 0.40 for lamotrigine. Polarity index of valproate and oxcarbazepine
may not be reliable due to the failure of their maintenance trials. The polarity
index provides a measure of how much antidepressant versus antimanic a drug is in
bipolar disorder prophylaxis, and may guide the choice of maintenance therapy in
bipolar patients.

Popovic, D., et al. (2013). "Polarity index of psychological interventions in

maintenance treatment of bipolar disorder." Psychother Psychosom 82(5): 292-298.
BACKGROUND: Although several adjunctive psychological interventions are
effective in the maintenance of bipolar disorders (BD), no attempt has been made to
classify them according to their ability to prevent manic versus depressive
episodes. Our study aims to rank the adjunctive psychotherapies for the prophylaxis
of BD by means of their polarity index (PI). METHODS: Randomized controlled trials
comparing the efficacy of a psychological intervention with a comparator in BD
maintenance treatment in patients aged over 18 were systematically reviewed.
Exclusion criteria were a small sample size, a study sample not exclusively
composed of bipolar patients and the absence of a control group. PI is a novel
metric indicating the relative antimanic versus antidepressive preventive efficacy
of treatments. PI was retrieved by calculating the ratio of the number needed to
treat (NNT) for prevention of depression and the NNT for prevention of mania. PI
>1.0 indicates a relatively higher antimanic prophylactic efficacy and PI <1.0 a
greater antidepressive efficacy. RESULTS: A total of 9 studies were included. PI
was 0.33, 0.63 and 0.89 for cognitive-behavioral therapy, 0.42 for family-focused
therapy, 0.73 and 0.78 for psychoeducation, 1 for enhanced relapse prevention, 1.78
for caregiver group psychoeducation and 3.36 for brief technique-driven
interventions. With regard to the PI for 1 cognitive-behavioral study, enhanced
relapse prevention and brief technique-driven interventions may not be reliable
since those trials were negative. CONCLUSIONS: The PI provides a measure of how
much depression-preventive or (hypo) mania-preventive an intervention is and may
guide the choice of adjunctive psychotherapy in the context of individualized long-
term treatment of BD.

Popovic, D., et al. (2014). "Clinical implications of predominant polarity and the
polarity index in bipolar disorder: a naturalistic study." Acta Psychiatr Scand
129(5): 366-374.
OBJECTIVE: Predominant polarity (PP) is an important variable in maintenance
treatment of bipolar disorder (BD). This study aimed at determining the role of
polarity index (PI), a metric indicating antimanic versus antidepressive
prophylactic potential of drugs, in clinical decision-making. METHOD: Two hundred
and fifty-seven of 604 (43%) of patients with BD-I or II fulfilled criteria for
manic (MPP) or depressive PP (DPP). The PI, representing the ratio of number needed
to treat (NNT) for depression prevention to NNT for mania prevention, was
calculated for patients' current treatment. MPP and DPP groups were compared
regarding sociodemographic, clinical and therapeutic characteristics. RESULTS: One
hundred and forty-three patients (55.6%) fulfilled criteria for DPP and 114 (44.4%)
for MPP. Total PI, Antipsychotics' PI, and mood stabilizers PI were higher,
indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of
BD-I, male gender, younger age, age at onset and at first hospitalization, more
hospitalizations, primary substance misuse, and psychotic symptoms. DP correlated
with BD-II, depressive onset, primary life events, melancholia, and suicide
attempts. CONCLUSION: The results confirm the usefulness of the PI. In this large
sample, clinical differences among these groups justify differential treatment
approach. The PI appears to be a useful operationalization of what clinicians do
for maintenance therapy in BD.
Post, R. M., et al. (2014). "Controversies in the psychopharmacology of bipolar
disorder." J Clin Psychiatry 75(11): e30.
Few studies have examined the decision-making process for selecting a mood
stabilizer or antipsychotic for patients with bipolar disorder. Despite a lack of
evidence regarding their efficacy, conventional unimodal antidepressants continue
to be used in bipolar treatment regimens. This article examines pharmacologic
principles that can facilitate the evidence-based use of mood stabilizers and
antipsychotics in patients with bipolar disorder. Choosing therapies for the
maintenance of bipolar disorder, clinical decision making upon observation of a
partial response, the use of combination therapies, and benefit/harm considerations
when choosing a treatment for bipolar depression will be reviewed.

Post, T., et al. (2015). "[Efficacy of continuation and maintenance

electroconvulsive therapy (c/m ECT) in the treatment of patients with therapy-
resistant affective disorders: a retrospective analysis]." Neuropsychiatr 29(3):
133-138.
BACKGROUND: Continuation and maintenance electroconvulsive therapy (c/m ECT)
is a long-term treatment option in severely and chronically ill patients with mood
disorders, who are unresponsive or intolerant to medication. Due to the current
lack of empirical studies, c/m ECT is still a clinical tool with little evidence.
METHODS: We conducted a retrospective analysis of patients' charts who received c/m
ECT over a 10-year period. Outcome was measured by comparing the number of pre-c/m
ECT and post-c/m ECT hospitalizations, as well as inpatient days per year and mean
duration of hospital stays. RESULTS: In 19 patients (63% female; mean age 53.5 +/-
12.0 years) with either bipolar (42%) or unipolar (58%) mood disorder, with the
majority of patients suffering from a depressive episode at hospital admission
(95%), c/m ECT was initiated after a successful series of ECT. In a 5-year interval
before and after starting c/m ECT the number of hospitalizations per year (0.87 vs.
0.28, p < 0.001), inpatient days per year (30.8 vs. 4.5 days, p < 0.001), as well
as the mean duration of hospital days (30.5 vs. 16.7 days, p = 0.02) decreased
significantly. CONCLUSION: Our data support previous results showing that c/m ECT
is an efficacious option in treating and favourably altering the course of therapy-
resistant affective disorders. Further research using a controlled study design and
larger sample sizes are needed to convincingly define indication and performance of
c/m ECT.

Praharaj, S. K. (2016). "Metformin for Lithium-induced Weight Gain: A Case Report."

Clin Psychopharmacol Neurosci 14(1): 101-103.
Lithium is the first line treatment for maintenance treatment of bipolar
disorder. Among the long term adverse effects, weight gain is likely to affect a
subset of patients. There is no specific guideline for the treatment of lithium-
induced weight gain. We report a young male with bipolar disorder who had
significant weight gain with lithium (25 kg), which responded to metformin
treatment at 500 mg twice daily. The proposed mechanism of weight lowering effect
of metformin includes changes in hypothalamic physiology, including leptin and
insulin sensitivity, as well as circadian rhythm changes affecting food intake,
regulation of fat oxidation and storage in liver, skeletal muscle, and adipose
tissue.

Prajapati, A. R., et al. (2016). "Efficacy and safety of second-generation

antipsychotic long-acting injections (SGA LAIs) in maintenance treatment of bipolar
disorder: protocol for a systematic review and meta-analysis." BMJ Open 6(1):
e010237.
INTRODUCTION: Bipolar disorder requires long-term treatment but non-adherence
is a common problem. Antipsychotic long-acting injections (LAIs) have been
suggested to improve adherence but none are licensed in the UK for bipolar.
However, the use of second-generation antipsychotics (SGA) LAIs in bipolar is not
uncommon albeit there is a lack of systematic review in this area. This study aims
to systematically review safety and efficacy of SGA LAIs in the maintenance
treatment of bipolar disorder. METHODS AND ANALYSIS: The protocol is based on
Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and
will include only randomised controlled trials comparing SGA LAIs in bipolar.
PubMed, EMBASE, CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS,
http://www.clinicaltrials.gov will be searched, with no language restriction, from
2000 to January 2016 as first SGA LAIs came to the market after 2000. Manufacturers
of SGA LAIs will also be contacted. Primary efficacy outcome is relapse rate or
delayed time to relapse or reduction in hospitalisation and primary safety outcomes
are drop-out rates, all-cause discontinuation and discontinuation due to adverse
events. Qualitative reporting of evidence will be based on 21 items listed on
standards for reporting qualitative research (SRQR) focusing on study quality
(assessed using the Jadad score, allocation concealment and data analysis), risk of
bias and effect size. Publication bias will be assessed using funnel plots. If
sufficient data are available meta-analysis will be performed with primary effect
size as relative risk presented with 95% CI. Sensitivity analysis, conditional on
number of studies and sample size, will be carried out on manic versus depressive
symptoms and monotherapy versus adjunctive therapy. ETHICS AND DISSEMINATION:
Ethical approval is not required as primary data will not be collected. The results
will be disseminated through a peer-reviewed publication, conference presentation
and the press. STUDY REGISTRATION NUMBER: PROSPERO CRD42015023948.

Prakash, C., et al. (2016). "Maternal and Fetal Outcomes After Lamotrigine Use in
Pregnancy: A Retrospective Analysis from an Urban Maternal Mental Health Centre in
New Zealand." Psychopharmacol Bull 46(2): 63-69.
INTRODUCTION: Pregnancy is a vulnerable period for recurrence of bipolar
disorder. Discontinuation of mood stabilisers during pregnancy and the postpartum
period can significantly increase the risk of recurrence of bipolar disorder.
Lamotrigine is an anti-epileptic drug that has been approved for the maintenance
treatment of bipolar disorder. Epilepsy literature has indicated that lamotrigine
has a reassuring safety profile in pregnancy but there is little information on its
effectiveness and safety in pregnant women with mental disorders. METHOD: We
conducted a retrospective review of all pregnant women who presented to an urban
maternal mental health centre in Auckland, New Zealand between 2012 and 2014 and
were treated with antipsychotics and/or mood stabilisers. Pregnancy outcome,
obstetric and perinatal complications, congenital malformations and maternal mental
health in the postnatal period were considered. RESULTS: Here, we present the
outcomes in the subset of six women who were treated with lamotrigine 100-400
mg/day for the entire pregnancy. Five were diagnosed with bipolar disorder and one
with major depression. Three women received additional psychotropic medication
during pregnancy. No women needed psychiatric hospitalisation. All babies were live
birth after 36 weeks gestation. Two babies had low birth weight and required NICU
admissions. Two women required lower segment caesarean section and the other 4 were
induced. A trachea-esophageal fistula was noted in one baby. Four babies who were
breastfed while their mothers received uninterrupted treatment with lamotrigine,
experienced no complications. DISCUSSION: This naturalistic study indicates that
lamotrigine can be an effective treatment option for maintenance of bipolar illness
in women of childbearing age.

Prencipe, M., et al. (2013). "[The acute renal and cerebral toxicity of lithium: a
cerebro-renal syndrome? A case report]." G Ital Nefrol 30(3).
This descriptive report describes the case of a 50 year-old woman with
bipolar disorder, whose maintenance therapy comprised risperidone, sodium valproato
and lithium carbonate without any past occurrence of toxicity. Her past medical
history was significant for hypertension, cardiopathy and obesity. She presented
with a 1-week history of fever, increasing confusion and slurred speech. At
presentation, the patient was somnolent. Laboratory investigations revealed a serum
creatinine of 3,6 mg/dl, BUN 45 mg/dl serum lithium 3,0 mEq/L with polyuria defined
as more than 3 litres a day. EEG and ECG were abnormal. CT brain scanning and
lumbar puncture were negative for brain haemorrage or infection. Lithium toxicity
causes impairment of renal concentration and encephalopathy due to lithium
recirculation, a mechanism responsible for the so-called cerebro-renal syndrome,
where dialysis plays an important role in treatment.The patient was treated with
continous veno-venous haemodiafiltration (CVVHDF) over 35 hours with gradual
improvement of her general condition and efficacy of renal concentration. Our case
highlights a few important points. Lithium nefrotoxicity and neurotoxicity can
cause a cerebro-renal syndrome even when serum lithium levels are not particularly
raised (2,5-3,5 mEq/L). Haemodialysis is the treatment of choice to reduce the
molecular mechanisms of lithium-related changes in urinary concentration and
reinstate dopaminergic activity in the brain.

Price, A. L. and G. R. Marzani-Nissen (2012). "Bipolar disorders: a review." Am Fam

Physician 85(5): 483-493.
Bipolar disorders are common, disabling, recurrent mental health conditions
of variable severity. Onset is often in late childhood or early adolescence.
Patients with bipolar disorders have higher rates of other mental health disorders
and general medical conditions. Early recognition and treatment of bipolar
disorders improve outcomes. Treatment of mood episodes depends on the presenting
phase of illness: mania, hypomania, mixed state, depression, or maintenance.
Psychotherapy and mood stabilizers, such as lithium, anticonvulsants, and
antipsychotics, are first-line treatments that should be continued indefinitely
because of the risk of relapse. Monotherapy with antidepressants is contraindicated
in mixed states, manic episodes, and bipolar I disorder. Maintenance therapy for
patients involves screening for suicidal ideation and substance abuse, evaluating
adherence to treatment, and recognizing metabolic complications of pharmacotherapy.
Active management of body weight reduces complications and improves lipid control.
Patients and their support systems should be educated about mood relapse, suicidal
ideation, and the effectiveness of early intervention to reduce complications.

Priebe, S., et al. (2013). "Effectiveness of financial incentives to improve

adherence to maintenance treatment with antipsychotics: cluster randomised
controlled trial." BMJ 347: f5847.
OBJECTIVE: To test whether offering financial incentives to patients with
psychotic disorders is effective in improving adherence to maintenance treatment
with antipsychotics. DESIGN: Cluster randomised controlled trial. SETTING:
Community mental health teams in secondary psychiatric care in the United Kingdom.
PARTICIPANTS: Patients with a diagnosis of schizophrenia, schizoaffective disorder,
or bipolar disorder, who were prescribed long acting antipsychotic (depot)
injections but had received 75% or less of the prescribed injections. We randomly
allocated 73 teams with a total of 141 patients. Primary outcome data were
available for 35 intervention teams with 75 patients (96% of randomised) and for 31
control teams with 56 patients (89% of randomised). INTERVENTIONS: Participants in
the intervention group were offered pound15 (euro17; $22) for each depot injection
over a 12 month period. Participants in the control condition received treatment as
usual. MAIN OUTCOME MEASURE: The primary outcome was the percentage of prescribed
depot injections given during the 12 month intervention period. RESULTS: 73 teams
with 141 consenting patients were randomised, and outcomes were assessed for 131
patients (93%). Average baseline adherence was 69% in the intervention group and
67% in the control group. During the 12 month trial period adherence was 85% in the
intervention group and 71% in the control group. The adjusted effect estimate was
11.5% (95% confidence interval 3.9% to 19.0%, P=0.003). A secondary outcome was an
adherence of >/= 95%, which was achieved in 28% of the intervention group and 5% of
the control group (adjusted odds ratio 8.21, 95% confidence interval 2.00 to 33.67,
P=0.003). Although differences in clinician rated clinical improvement between the
groups failed to reach statistical significance, patients in the intervention group
had more favourable subjective quality of life ratings (beta=0.71, 95% confidence
interval 0.26 to 1.15, P=0.002). The number of admissions to hospital and adverse
events were low in both groups and did not show substantial differences.
CONCLUSION: Offering modest financial incentives to patients with psychotic
disorders is an effective method for improving adherence to maintenance treatment
with antipsychotics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN77769281.

Provencher, M. D., et al. (2011). "Psychotherapies for comorbid anxiety in bipolar

spectrum disorders." J Affect Disord 133(3): 371-380.
BACKGROUND: Comorbid anxiety disorders are highly prevalent in bipolar
disorder and have been shown to have serious negative impacts on the course of
illness. The pharmacological treatment of anxiety can interact with the bipolar
disorder and has not been proven effective. As such, many have recommended the
psychological treatment of anxiety. This paper reviews the literature on
psychological treatments for anxiety comorbid to bipolar disorder. METHOD: The
Medline, PsychInfo and Web of Science databases were thoroughly examined for
relevant treatment studies. RESULTS: Despite frequent recommendations in the
literature, surprisingly few have studied the psychological treatment of comorbid
anxiety in bipolar disorders. Nevertheless, preliminary results suggest that
comorbid anxiety disorders can be effectively treated in a bipolar clientele using
cognitive-behavioral therapy, mindfulness-based cognitive-behavioral therapy or
relaxation training. In contrast, interpersonal, family therapy and psychoeducation
alone would not seem to be beneficial treatment alternatives for anxiety.
Cognitive-behavioral therapy appears to reduce the symptoms of obsessive-compulsive
disorder, generalized anxiety disorder, panic disorder, post-traumatic stress
disorder and general symptoms of anxiety among patients with bipolar disorder.
However, the long-term maintenance of anxiety treatment effects may be somewhat
reduced and adaptations may be called for to augment and sustain benefits.
CONCLUSIONS: There is an urgent need for randomized controlled trials of different
forms of psychotherapy for anxiety disorders comorbid to bipolar disorder. Until
such trials are available, the most promising approach would appear to be the
sequential or modular CBT-based treatment of the anxiety disorder.

Putnins, S. I., et al. (2012). "Poor sleep at baseline predicts worse mood outcomes
in patients with co-occurring bipolar disorder and substance dependence." J Clin
Psychiatry 73(5): 703-708.
BACKGROUND: Sleep problems are common in patients with bipolar disorder and
have been shown to predict subsequent mood symptoms. Sleep problems have also been
shown to lead to worse substance use outcomes in individuals with substance use
disorder. However, the relationship between sleep and clinical outcomes in a
population with co-occurring bipolar disorder and substance use disorder is
unclear. METHOD: This secondary analysis included 60 outpatients (mean age = 38.1
years; recruited via advertisements, fliers, clinician referrals, and hospital
treatment programs) who met DSM-IV criteria for both bipolar disorder and substance
use disorder (assessed with the Structured Clinical Interview for DSM-IV Axis I
Disorders) and who participated in a randomized clinical trial comparing integrated
group therapy for bipolar disorder and substance use disorder to group drug
counseling for substance use disorder alone. A 12-week treatment period preceded a
24-week follow-up. Poor sleep was assessed with the Pittsburgh Sleep Quality Index,
which provides 7 component subscores and an overall sleep score. Data were
collected from August 2003 through April 2007. RESULTS: When analyses were
controlled for baseline mood, substance use, and treatment condition, baseline
sleep score predicted mood over the course of the 12-week treatment (beta = 0.28; P
< .05) and 24-week follow-up (beta = 0.46; P < .01): worse sleep was associated
with worse mood outcomes. Sleep was not associated with substance use outcomes.
CONCLUSIONS: Impaired sleep is a prognostic factor for mood outcomes in patients
with co-occurring bipolar and substance use disorders. Further investigation is
warranted into the long-term clinical outcomes of poor sleep in this population
with co-occurring bipolar disorder and substance use disorder so that appropriate
interventions can be developed.

Quiroz, J. A., et al. (2010). "Risperidone long-acting injectable monotherapy in

the maintenance treatment of bipolar I disorder." Biol Psychiatry 68(2): 156-162.
 BACKGROUND: Treatment adherence is a significant problem in patients with
bipolar disorder. This study was designed to determine the efficacy of risperidone
long-acting injectable (LAI) in the maintenance treatment of bipolar I disorder.
METHODS: Eligible patients with current or recent manic or mixed episodes (n = 559,
aged 18-65 years) were treated with open-label oral risperidone for 3 weeks (period
II) and open-label risperidone LAI for 26 weeks (n = 501; period III). Patients who
maintained response (n = 303) were randomly allocated 1:1 to placebo injections (n
= 149) or to continue risperidone LAI (n = 154) for up to 24 months (period IV).
RESULTS: Most (77%) patients on risperidone LAI received a dose of 25 mg every 2
weeks during period IV. Time to recurrence for any mood episode (primary outcome
variable) was significantly longer in the risperidone LAI group versus placebo (p <
.001); the difference was significant for time to recurrence of elevated-mood
episode (p < .001) but not time to recurrence of depressive episode (p = .805).
Weight gains > or = 7% (compared with the period's baseline) occurred in 15% of
patients in period III; in 12% of patients on risperidone LAI and 3% of patients on
placebo in period IV. CONCLUSIONS: Risperidone LAI monotherapy significantly
delayed the time to recurrence of mood episodes, versus placebo, in this
controlled, randomized study in patients with bipolar I disorder. Risperidone LAI
was tolerable and no new safety concerns emerged compared with previous studies of
risperidone LAI.

Rabheru, K. (2012). "Maintenance electroconvulsive therapy (M-ECT) after acute

response: examining the evidence for who, what, when, and how?" J ECT 28(1): 39-47.
OBJECTIVE: To examine the evidence for maintenance electroconvulsive therapy
(M-ECT) to help determine who, when, and how long ECT should be continued. METHOD:
A review of published literature on the use of maintenance ECT (M-ECT) was
conducted. It focused primarily on trials published since 1997, meeting the
following additional criteria: randomized controlled trial or cohort study with a
comparison (matched group or before and after), and at least 10 patients receiving
M-/continuation ECT. Where such data are not available, recent case series were
reviewed. RESULTS: Relapse rates after discontinuation of ECT are very high.
Maintenance ECT is an underused treatment option that can substantially reduce
risks of relapse in patients with major depressive disorder and likely in bipolar
disorder and schizophrenia as well. Little data are available for the use of M-ECT
in neurological disorders, and no cost-effectiveness analyses in the maintenance
setting were found. CONCLUSIONS: Whereas no clear answers emerge from the
literature, there is now a growing body of evidence to suggest that for those who
have not responded well to medications but have responded to ECT, M-ECT must be
presented as an option to the patient and the family for consideration. Clear
consensus guidelines for the use of M-ECT are needed.

Rahioui, H., et al. (2015). "[Interpersonal psychotherapy from research to

practice]." Encephale 41(2): 184-189.
THEORETICAL BACKGROUND: Interpersonal therapy (IPT) is a brief, structured
psychotherapy initially intended to treat adult depression that was developed in
the 1970s and manualized in 1984 by G. Klerman and his team. Two main theories
served as a basis for its design: Bowlby's attachment theory and communication
theory. Klerman theorized that tensions and problems in interpersonal relationships
(i.e. disputes) cause psychological distress in vulnerable individuals that may
lead to a major depressive episode. Clinical and epidemiological studies have shown
that an insecure attachment style is strongly associated with lifetime depression.
Severe depressive episodes have been correlated with avoidant attachment in women.
THERAPY STRUCTURE AND TECHNIQUES: IPT is based on the hypothesis that recent or
ongoing disturbances in interpersonal relationships either trigger or follow the
onset of mood disorder. In practice, IPT assists patients in analysing their
interpersonal relationship modes, correlating their relational states with their
mood and in learning to use better communication. Resolving difficulties in
interpersonal relationships through the use of better communication skills promotes
the improvement of depressive symptoms. Klerman identified four interpersonal areas
that seem to be highly correlated with depressive episodes: grief (a close and
important personal relation who has died), interpersonal disputes (conflicts with
significant people such as a spouse or another close family member), role
transition (significant life changes such as retirement, parenthood or chronic and
invalidating illness) and interpersonal deficits (patients who have limited social
contacts and few interpersonal relations). Classically, IPT is planned around 12-16
weekly sessions. During the initial sessions, the therapist will explore all
existing interpersonal relations and any significant dysfunctions, both recent and
ongoing. Following this interview, the area the patient considers as driving the
current depressive episode will be designated as the focus of therapy. Evaluation
of depressive symptoms by a quantitative measure (i.e. Visual Analogue Scale) and
qualitative measures (activity, pleasure, quality of life) reoccurs at each
session. During the intermediate sessions, therapy uses current situations and
events in the designated area that particularly affect the patient's mood. Coping,
communication and decision-making skills are gradually improved through a number of
techniques. These include non-directive and directive exploration, clarification,
encouragement of affect, and communication analysis. The therapeutic relationship
is empathetic and encouraging of all progress the patient makes. The final phases
close the therapy and help the patient to plan future actions and improvements.
CLINICAL TRIALS OF IPT AND DEVELOPMENTS: Several controlled clinical trials in
adult populations have demonstrated the efficacy of IPT in treating Major
Depressive Disorder (initial and recurrent episodes). It has been recommended as an
appropriate treatment option in several guidelines. It can be provided in
individual, couple or group formats. There remains an ongoing discussion of the
efficacy of monthly maintenance sessions in recurrent depression. Since its
conception, clinical trials have explored its use in specific populations such as
adolescents and the elderly. IPT has also been the object of trial in other
disorders such as post-partum depression, bipolar disorder, social phobia and
eating disorders. CONCLUSION: This article reviews the basic principles and
objectives of this therapeutic model. Theoretical concepts and results from
research are also discussed. The approach is briefly described and the various
therapeutic phases are discussed. Clinical trials have shown that IPT is effective
in treating major depressive disorder in a wide variety of populations. Further
trials are necessary to determine its efficacy in other psychiatric disorders.

Raja, M. and S. Raja (2013). "Sleepwalking in four patients treated with

quetiapine." Psychiatr Danub 25(1): 80-83.

Rapinesi, C., et al. (2015). "Maintenance Deep Transcranial Magnetic Stimulation

Sessions are Associated with Reduced Depressive Relapses in Patients with Unipolar
or Bipolar Depression." Front Neurol 6: 16.
INTRODUCTION: Deep transcranial magnetic stimulation (dTMS) is a new form of
TMS allowing safe stimulation of deep brain regions. The objective of this
preliminary study was to assess the role of dTMS maintenance sessions in protecting
patients with bipolar disorder (BD) or recurrent major depressive disorder (MDD)
from developing depressive or manic relapses in a 12-month follow-up period.
METHODS: Twenty-four drug-resistant patients with a current depressive episode and
a diagnosis of MDD or BD have been enrolled in the study. All the participants
underwent daily dTMS sessions for 4 weeks. One group (maintenance - M group)
received additional maintenance dTMS sessions weekly or twice a week. RESULTS:
After the first dTMS cycle, a significant reduction of Hamilton Depression Rating
Scale (HDRS) scores was observed in all participants. Subsequently, the HDRS mean
scores did not significantly change over time in the M group, while it
significantly increased in the non-M-group after 6 and 12 months. DISCUSSION: This
study confirms previous evidence of a positive therapeutic effect of dTMS on
depressive symptoms and suggests that, after recovery from acute episodes,
maintenance dTMS sessions may be helpful in maintaining euthymia in a 12-month
follow-up period.
Rapinesi, C., et al. (2012). "Successful and rapid response to electroconvulsive
therapy of a suicidal patient with comorbid bipolar I disorder and histrionic
personality disorder." J ECT 28(1): 57-58.
A woman with bipolar disorder I, histrionic personality disorder, and
suicidal ideation with repeated suicide attempts, who had been treated for 2 years
with mood stabilizers, antipsychotics, and benzodiazepines, received a total of 8
bitemporal-biparietal electroconvulsive therapy sessions. Her suicidal ideation and
self-harm behavior disappeared immediately after the first session and her
psychopathology soon after. This supports the existence of a relatively independent
suicidal syndrome and confirms data on its immediate responsiveness to
electroconvulsive therapy. Electroconvulsive therapy must not be long withheld from
patients with such characteristics to reduce unnecessary sufferance and
suicidality.

Rass, O., et al. (2010). "Auditory steady state response in bipolar disorder:
relation to clinical state, cognitive performance, medication status, and substance
disorders." Bipolar Disord 12(8): 793-803.
OBJECTIVES: Abnormalities in auditory steady state response (ASSR) at gamma
range frequencies have been found in bipolar disorder, but the relationship of
these neurophysiological disturbances to clinical factors has not been well
characterized. We therefore evaluated the ASSR in bipolar disorder and examined its
sensitivity to clinical symptoms, cognitive function, and pharmacological
treatment. METHODS: A total of 68 patients with bipolar disorder and 77 control
participants were evaluated. Click trains presented at 20, 30, 40, and 50 Hz evoked
ASSRs. Mean trial power (MTP) and phase locking factor (PLF) measured response
magnitude and phase synchronization of the ASSR at each stimulation frequency.
Clinical state, pharmacological treatment, and neuropsychological performance were
assessed, and their respective relationships with ASSR measures were evaluated.
RESULTS: Patients with bipolar disorder showed reduced MTP and PLF compared to
control participants. Bipolar disorder patients taking psychotropic medications had
decreased PLF relative to patients withdrawn from medications. Control participants
performed better on neuropsychological tests than bipolar disorder patients;
however, test scores did not correlate with ASSR measures. CONCLUSIONS: Deficits in
the generation and maintenance of ASSR are present in bipolar disorder, implicating
disturbances in auditory pathways. ASSR may be sensitive to medication status.
Other clinical features, including mood state, psychotic features, cognitive
performance, smoking, or history of substance use disorder, were unrelated to MTP
or PLF.

Rastelli, C. P., et al. (2013). "Differences between unipolar depression and

bipolar II depression in women." J Affect Disord 150(3): 1120-1124.
BACKGROUND: Bipolar disorder II (BPII) and unipolar depression (UD) are both
characterized by episodes of major depression (MDE), however DSM-IV criteria for
MDE are identical, regardless of diagnosis. As a result, misdiagnosis of BP II and
UD is common, leading to inappropriate treatment. Because women are twice as likely
as men to experience MDE, differentiating UD from BP II in the context of
depression is especially important for women. We examined symptoms and clinical
features of MDE in women with UD and BPII to compare presentations of the two
disorders in women. METHODS: We compared characteristics of depressed women meeting
DSM-IV criteria for BPII (n=48) or UD (n=48), matched on age. RESULTS: Feelings of
worthlessness occurred in 98% of participants with UD versus 85% with BPII
(p=0.03). Participants with UD experienced either insomnia or hypersomnia, but
participants with BPII were more likely to experience both simultaneously (p=0.04).
Those with UD were significantly less likely to have >5 prior mood episodes
compared to those with BP II (12% versus 61%; p<0.0001) and had a later age of
onset (p=0.003). LIMITATIONS: Small sample size and exclusion criteria (i.e.,
comorbid substance abuse) may limit generalizability of findings. CONCLUSIONS:
Among a sample of women, number of prior episodes, feelings of worthlessness, age
of onset, and sleep patterns distinguished between UD and BP II depressive
episodes. A better understanding of differential presentation of BP II versus UD
depression in women may help guide clinicians to more accurate diagnoses and,
ultimately, better treatment.

Reid, J. G., et al. (2013). "Lamotrigine in psychiatric disorders." J Clin

Psychiatry 74(7): 675-684.
OBJECTIVE: Owing to the prevalence of medication side effects and treatment
resistance, prescribers often consider off-label uses of US Food and Drug
Administration (FDA)-approved agents for the treatment of persistent symptoms. The
authors review the available literature on the FDA-approved and non-FDA-approved
uses of lamotrigine in adults with psychiatric disorders. DATA SOURCES: We used
PubMed, MEDLINE, and a hand search of relevant literature to find studies published
between 1990 and 2012 and available in English language. The following keywords
were searched: lamotrigine, psychiatric, mood disorders, depression, personality
disorders, anxiety, schizophrenia, side effects, and rash. STUDY SELECTION: Data
were selected from 29 randomized controlled trials (RCTs). When RCTs were not
available, open-label trials (6), retrospective case reviews (10), and case series
(4) were summarized. DATA EXTRACTION: We extracted results of monotherapy and
augmentation trials of lamotrigine on primary and secondary outcome measures.
RESULTS: Lamotrigine is generally well tolerated, with the best evidence for the
maintenance treatment of bipolar disorder, particularly in prevention of depressive
episodes. In acute bipolar depression, meta-analyses suggested a modest benefit,
especially for more severely depressed subjects, with switch rates similar to
placebo. In unipolar depression, double-blind RCTs noted benefit on subsets of
symptoms and improved response in more severely depressed subjects. Data are
limited but promising in borderline personality disorder. Use of lamotrigine in
schizophrenia and anxiety disorders has little supportive evidence. CONCLUSIONS:
Lamotrigine is recommended in bipolar maintenance when depression is prominent. It
also has a role in treating acute bipolar depression and unipolar depression,
though the latter warrants more research. Data are too limited in other psychiatric
disorders to recommend its use at this time.

Reilly, J. L., et al. (2016). "Impaired Context Processing is Attributable to

Global Neuropsychological Impairment in Schizophrenia and Psychotic Bipolar
Disorder." Schizophr Bull.
BACKGROUND: Context processing may reflect a specific cognitive impairment in
schizophrenia. Whether impaired context processing is observed across psychotic
disorders or among relatives of affected individuals, and whether it is a deficit
that is independent from the generalized neuropsychological deficits seen in
psychotic disorders, are less established. METHODS: Schizophrenia, schizoaffective,
and psychotic bipolar probands (n = 660), their first-degree relatives (n = 741),
and healthy individuals (n = 308) studied by the Bipolar-Schizophrenia Network on
Intermediate Phenotypes consortium performed an expectancy task requiring use of
contextual information to overcome a pre-potent response. Sensitivity for target
detection and false alarm rates on trials requiring inhibition or goal maintenance
were measured. RESULTS: Proband groups and relatives with psychosis spectrum
personality traits demonstrated reduced target sensitivity and elevated false alarm
rates. False alarm rate was higher under inhibition vs goal maintenance conditions
although this difference was attenuated in schizophrenia and schizoaffective
proband groups. After accounting for global neuropsychological impairment, as
reflected by the composite score from the Brief Assessment of Cognition in
Schizophrenia neuropsychological battery, deficits in schizophrenia and bipolar
proband groups were no longer significant. Performance measures were moderately
familial. CONCLUSION: Reduced target detection, but not a specific deficit in
context processing, is observed across psychotic disorders. Impairments in both
goal maintenance and response inhibition appear to contribute comparably to
deficits in schizophrenia and schizoaffective disorder, whereas greater difficulty
with response inhibition underlies deficits in bipolar disorder. Yet, these
deficits are not independent from the generalized neurocognitive impairment
observed in schizophrenia and psychotic bipolar disorder.

Remlinger-Molenda, A., et al. (2012). "Selected cytokine profiles during remission

in bipolar patients." Neuropsychobiology 66(3): 193-198.
OBJECTIVES: The aim of the study was to examine the cytokine status in
bipolar patients during immediate remission after acute episodes of mania or
depression and in patients with sustained (>/=6 months) remission, compared with
healthy controls. METHODS: The study was performed on 121 bipolar patients, of whom
35 were in immediate remission after mania, 41 were in immediate remission after
depression, and 45 were in >6-month remission on lithium monotherapy or lithium
combined with other drugs. The control group consisted of 78 healthy individuals
without any history of psychiatric or immunological illnesses. Serum concentrations
of IL-1beta, IL-2, IL-6, IL-10, TNF-alpha and IFN-gamma were determined using the
Human Th1/Th2 Cytometric Bead Array method. RESULTS: The concentration of IL-10 was
higher in patients in remission after mania and the concentration of IFN-gamma was
higher in those in remission after depression than in healthy controls. On the
other hand, cytokine concentrations in patients with sustained remission were not
different from those of healthy subjects. CONCLUSIONS: The results obtained in this
study show that sustained remission in bipolar patients achieved mostly by lithium
maintenance brings the cytokine status to a level similar to healthy control
subjects.

Richieri, R., et al. (2010). "[Affective disorders and repetitive transcranial

magnetic stimulation: Therapeutic innovations]." Encephale 36 Suppl 6: S197-201.
Depression is the most common psychiatric disorder with a particularly
important disability due to its evolution to chronicity and treatment-resistance.
In the same way, the outcome of bipolar disorder is similar. Only 75% subjects
remain remitted in the year following the onset of mood episode and depressive
episode leads to worth responsiveness than patients in phase hypo/manic. Thus,
treating mood episodes and fighting against resistant and residual symptoms or
chronicity of the disorders constitute major clinical issues and economic
challenges. They have generated great interest in finding new non-pharmacological
approaches such as repetitive transcranial magnetic stimulation (rTMS). TMS is a
non-invasive means of focal brain stimulation, rapidly fluctuating magnetic fields.
Given the hypothesis that the right and left sides of the dorsolateral prefrontal
cortex have opposing effects in mood control, high-frequency rTMS activates the
left side and low-frequency to inhibit the right side in the treatment of
depression. A literature review was conducted to study the efficacy of rTMS in the
treatment of unipolar and bipolar depression, acute mania and long-term maintenance
therapy. During the last decade, numerous studies including several meta-analyses
have indicated the efficacy of rTMS in acute treatment of major depressive
disorder. Overall, rTMS seems to be effective in the treatment of bipolar
depression but further trials with larger cohorts should determine optimal
parameters of stimulation. There are also few studies about rTMS in the treatment
of acute mania. Protocols are reversed than in the treatment of depression. Results
are promising but confounded by the presence of concurrent medications. Finally,
the literature on the use of maintenance rTMS in the prevention of depressive
relapse or as a mood stabiliser is limited. Nevertheless it demonstrates the
importance of developing maintenance protocols to maintain the clinical improvement
achieved at the end of the acute treatment. New techniques to improve the
effectiveness of rTMS are already appearing.

Rihmer, Z., et al. (2016). "[Antidepressant-resistant depression and the bipolar

spectrum -- diagnostic and therapeutic considerations]." Psychiatr Hung 31(2): 157-
168.
According to the results of epidemiological studies mood disorders with
unipolar (major and minor depressive disorder; dysthymia) or bipolar features are
among the most prevalent psychiatric disorders. These disorders with their frequent
comorbidities (alcohol and/or drug use disorders, smoking, suicide, cardiovascular
disorders) pose great public health challenge and cause substantial individual and
familar burdens as well. Since SSRIs and other new antidepressant agents entered
the market the possibilities to treat depression improved substantially but 25-35
percent of major depressives do not respond even to the second antidepressant trial
but the rate of patients who are resistant after the third and fourth adequate
antidepressant trial are around only 15-25 and 10 percent, respectively.
Pharmacotherapy-resistant depression is a multicausal phenomenon. Along with its
well-known risk-factors investigations of the past decade have revealed that
unrecognised or hidden (subsyndromal or subthreshold) bipolarity is one of the most
frequent causes of treatment resistance. In the case of bipolar depression (either
as a part of syndromal bipolar I or II disorder or a subsyndromal manifestation)
antidepressant monotherapy should be avoided and, instead of it, the administration
of a mood stabilizer (primarily lithium and lamotrigine) or some atypical
antipsychotics (preferably quetiapine) are recommended. If antidepressant is
inevitably necessary in bipolar depression, we should use it always in combination
with mood stabilizers or atypical antipsychotics.

Roberti, G., et al. (2014). "Nerve growth factor modulation of retinal ganglion
cell physiology." J Cell Physiol 229(9): 1130-1133.
Nerve growth factor (NGF) is an endogenous neurotrophin involved in the
development, maintenance and regeneration of mammalian sympathetic and sensory
neurons. Additionally, NGF is known to have trophic and differentiating activity on
several populations of cholinergic neurons of the central nervous system (CNS), and
to act as a differentiation factor in the development of the visual cortex. The
paramount functions of NGF in the visual system are also highlighted by the
presence of this neurotrophin and both its receptors TrkA and p75 in most intra-
ocular tissues, including lens, vitreous, choroid, iris, and trabecular meshwork.
In the retina, NGF is produced and utilized specifically by retinal ganglion cells
(RGC), bipolar neurons and glial cells, and is thought to have crucial protective
effects in several disease states. Studies on the role of NGF on RGCs survival
following optic nerve transection, ischemic injury, ocular hypertension and
glaucoma are discussed in this review.

Robinson, L. J., et al. (2013). "Performance monitoring and executive control of

attention in euthymic bipolar disorder: employing the CPT-AX paradigm." Psychiatry
Res 210(2): 457-464.
Reduced cognitive test performance has been demonstrated in patients with
bipolar disorder (BD), even when euthymic. Several studies have explored aspects of
attention, including sustained attention, and reported patients show lower accuracy
compared to controls. It is necessary to modify existing attentional paradigms to
fully characterise such deficits. The present study sought to examine if there are
changes in the profile of performance and error-types during a sustained attention
task in BD. Twenty-two euthymic patients with DSM-IV diagnosed BD and 21 healthy
controls were recruited. Participants completed a modified CPT-AX paradigm with a
high proportion of target trials (70%) with cues and probes presented at continuous
intervals. This modification increases the demands on response inhibition and
permits the deconstruction of attentional/executive deficits previously described.
Overall, BD patients showed significantly poorer target discriminability compared
to controls. In block one (first quarter) of the task, patients showed no
significant differences to controls, but by the final fourth block (last quarter)
they made significantly fewer hits and more errors (both 'AX' misses and 'BX' false
alarms). BD patients completed initial stages of the task similarly to controls,
but as demands on the attentional system continued difficulties emerged, consistent
with problems in context-maintenance.

Rodriguez-Jimenez, R., et al. (2015). "Maintenance Electroconvulsive Therapy: Cost-

effectiveness and Patient/Family Satisfaction." J ECT 31(4): 279.

Rohrbaugh, M. J., et al. (2012). "Family consultation for psychiatrically

complicated health problems." J Clin Psychol 68(5): 570-580.
We describe a social cybernetic view of health behavior problems and a team-
based family consultation (FAMCON) format for strategic intervention based on that
view. This approach takes relationships rather than individuals as the primary unit
of analysis and attaches more importance to problem maintenance than to etiology.
Treatment aims to interrupt two types of interpersonal problem maintenance-ironic
processes and symptom-system fit (conceptualized, respectively, as positive and
negative feedback cycles)-and to mobilize communal coping as a relational resource
for change. A case example features a depressed husband and bipolar wife
complaining of severe communication difficulties related to the husband's kidney
cancer and diabetes. Over 6 consultation sessions, strategic interventions focused
on interrupting ironic interpersonal patterns resolved the presenting complaint.
Although cost-effectiveness is an open question, FAMCON may offer a useful
alternative to psychoeducational and cognitive-behavioral treatments in the
framework of stepped care.

Romeo, B., et al. (2015). "Meta-analysis of short- and mid-term efficacy of

ketamine in unipolar and bipolar depression." Psychiatry Res 230(2): 682-688.
Among treatments currently assessed in major depression, ketamine, has been
proposed of great interest, especially because of its very rapid action. However,
the time-course of the antidepressive action of ketamine remained unclear. In the
present meta-analysis, we provided a clear and objective view regarding the
putative antidepressive effect of ketamine and its time-course. We searched the
MEDLINE and PsycINFO databases through December 2013, without limits on year of
publication, using the key words ketamine and synonyms for mood disorder or
episode. Six randomized, double-blind and placebo-controlled trials of ketamine in
major depression (n=103 patients) were thus identified. Authors were contacted and
they all provided original data necessary for this meta-analysis. Standardized mean
differences (SMD) were calculated between the depression scores in ketamine and
placebo groups at days 1, 2, 3-4, 7 and 14. Ketamine showed an overall
antidepressive efficacy from day 1 to day 7. However, the maintenance of its
efficacy over time failed to reach significance in bipolar depression after day 3-
4. Significant SMDs were not explained by demographic or clinical characteristics
of included samples. The present meta-analysis provides a high level of evidence
that ketamine has a rapid antidepressive action during one week, especially in
unipolar disorder.

Rosa, A. R., et al. (2010). "Why do clinicians maintain antidepressants in some

patients with acute mania? Hints from the European Mania in Bipolar Longitudinal
Evaluation of Medication (EMBLEM), a large naturalistic study." J Clin Psychiatry
71(8): 1000-1006.
OBJECTIVE: Antidepressants are supposed to be withdrawn during a manic
episode. The aim of this study was to analyze the characteristics of manic patients
who received antidepressants during a manic phase in a large, naturalistic study.
METHOD: The European Mania in Bipolar Longitudinal Evaluation of Medication was a
2-year prospective observational study of inpatients and outpatients with acute
mania/mixed mania (DSM-IV or ICD-10 criteria) conducted in 14 European countries.
Of 2,416 manic patients who continued into the maintenance phase of the study, 345
(14%) were taking an antidepressant and 2,071 (86%) were not taking an
antidepressant at baseline, week 1, and/or week 2 postbaseline. Demographic and
clinical variables were collected at baseline and each study visit up to 24 months.
Outcome measures included the Clinical Global Impressions-Bipolar Disorder scale
(CGI-BP overall, mania, and depression scores) at 12 weeks and 24 months, the 5-
item Hamilton Depression Rating Scale (HDRS-5), and the Young Mania Rating Scale
(YMRS) at 12 weeks only. The present study was conducted from December 2002 to June
2004. RESULTS: More antidepressant maintenance use was seen in patients with mixed
episodes (P < .001), rapid cyclers (P < .02), patients with more previous
depressive episodes (P < .001), and patients with higher mean HDRS-5 score at
baseline (P < .001)-specifically patients with anxiety (P = .013). Patients in the
antidepressant group had significantly higher CGI-BP depression scores (P < .001)
and a significantly higher rate of depression relapse (P < .001) at both 12 weeks
and 24 months. CONCLUSIONS: Patients with mania receiving antidepressants are more
likely to be outpatients with mixed episodes, anxiety, or rapid cycling and have a
higher risk of depression relapse during follow-up.

Rothschild, A. J. (2013). "Challenges in the treatment of major depressive disorder

with psychotic features." Schizophr Bull 39(4): 787-796.
Psychotic depression is associated with significant morbidity and mortality
but is underdiagnosed and undertreated. In recent years, there have been several
studies that have increased our knowledge regarding the optimal treatment of
patients with psychotic depression. The combination of an antidepressant and
antipsychotic is significantly more effective than either antidepressant
monotherapy or antipsychotic monotherapy for the acute treatment of psychotic
depression. Most treatment guidelines recommend either the combination of an
antidepressant with an antipsychotic or ECT for the treatment of an acute episode
of unipolar psychotic depression. The optimal maintenance treatment after a person
responds to either the antidepressant/antipsychotic combination or the ECT is
unclear particularly as it pertains to length of time the patient needs to take the
antipsychotic medication. Little is known regarding the optimal treatment of a
patient with bipolar disorder who has an episode of psychotic depression or the
clinical characteristics of responders to medication treatments vs ECT treatments.

Sacchetti, E., et al. (2011). "Oral ziprasidone in the treatment of patients with
bipolar disorders: a critical review." Expert Rev Clin Pharmacol 4(2): 163-179.
Ziprasidone, a benzisothiazolyl piperazine derivative of tiospirone, is a
second-generation antipsychotic with high-affinity antagonism for 5-
hydroxytryptophan (5HT)(2A), 5HT(2C), 5HT(1D) and D(2) receptors, pre- and post-
synaptic agonism for 5HT(1A) receptors, and inhibition of reuptake for serotonin
and norepinephrine. Initially approved for the treatment of adults with
schizophrenia, ziprasidone has more recently received supplementary indications for
acute manic and mixed episodes and as maintenance therapy for people affected by
bipolar disorder. Based on MEDLINE citations up to November 2010 and hand-searched
references, this article relating to ziprasidone addresses its short- and long-term
efficacy and safety, according to the results of randomized clinical trials, open-
label studies and real-world experiences. Emerging evidence indicates that in
patients with bipolar disorder, ziprasidone provides valid efficacy and remarkable
safety when administered alone for the treatment of manic and mixed episodes. The
same applies when ziprasidone is administered in combination with lithium or
valproate for the prevention of affective relapses and recurrences. Any conclusion
on the potential of ziprasidone as an antidepressant should be postponed because of
insufficient evidence.

Sachs, G. S., et al. (2011). "The pharmacologic treatment of bipolar disorder." J

Clin Psychiatry 72(5): 704-715.
Over the past half century, substantial clinical trial data have accumulated
to guide clinical management of bipolar disorder, and 13 medications have gained US
Food and Drug Administration approval for the treatment of mania or bipolar
depression or the maintenance treatment of bipolar disorder. While the number of
studies has grown and many controversies related to pharmacologic treatment of
bipolar disorder are not yet resolved, the task of transforming the accumulated
evidence into useful guidance for clinical practice becomes more manageable and
less error prone by limiting consideration to the highest quality studies.
Therefore, this article emphasizes points of relative clarity by highlighting
findings supported by double-blind, placebo-controlled clinical trials with samples
of at least 100 subjects. A MEDLINE search was conducted and augmented by a manual
search of bibliographies, textbooks, and abstracts from recent scientific meetings
for randomized controlled trials published in English between 1950 and April 2010
with at least 100 subjects. Keywords used in the search included randomized
controlled trial, mania, hypomania, depression, relapse prevention, placebo,
antidepressant, switch, and maintenance treatment of bipolar disorder. A paradigm
for implementing evidence-based treatment is offered along with consideration of
patterns emerging across clinical trials.

Saddichha, S., et al. (2010). "Perceived reasons for and consequences of substance
abuse among patients with psychosis." Prim Care Companion J Clin Psychiatry 12(5).
BACKGROUND: Substance use is a common comorbidity with psychotic illnesses.
Although several theories exist to explain this link, individual reasons for use
may differ. The aim of this study was to evaluate patient perceptions of the
reasons for and consequences of their substance use in patients with psychosis and
compare them with those of an age-, sex-, and tobacco use-matched control sample
without psychosis. METHOD: Consecutively admitted patients were divided into 2
groups, those who had substance dependence without psychosis (n = 32), admitted in
our addiction unit, and those who had psychotic illness with substance dependence,
admitted in our inpatient psychosis unit and referred to as the dual-diagnosis
group (n = 62). Patients were administered the Schedules for Clinical Assessment in
Neuropsychiatry for ICD-10 Diagnostic Criteria for Research to confirm
schizophrenia, bipolar affective disorder, and substance dependence diagnoses and
were asked open-ended questions to evaluate the perceived reasons for and
consequences of their substance use. The study was conducted from July to September
2006. RESULTS: There were significant differences between the 2 groups in reasons
for maintenance and relapse of both cannabis use and alcohol use, the 2 most common
substances. While the substance dependence without psychosis group attributed both
maintenance and relapse to external factors such as nature of work, social milieu,
or peer pressure, the dual-diagnosis group attributed them to internal factors such
as enhancement of positive mood and alleviation of withdrawal effects. CONCLUSIONS:
Individuals with psychosis have greater vulnerability to internal factors, which
may maintain substance use. Targeting perceived internal factors may play a useful
role in management and possibly identification and prevention of psychosis in
vulnerable individuals in the future.

Sajatovic, M., et al. (2016). "Dosing patterns and medication adherence in bipolar
disorder patients treated with lurasidone: a US retrospective claims database
analysis." Ther Adv Psychopharmacol 6(6): 355-368.
BACKGROUND: The aim of this study was to describe dosing patterns and
medication adherence among bipolar patients who initiated lurasidone in a real-
world setting. METHODS: Adult bipolar patients who initiated lurasidone between 1
November 2010 and 31 December 2012 (index period) with 6-month pre- and post-index
continuous enrollment were identified from the IMS RWD Adjudicated Claims US
database. Patients were grouped by starting lurasidone daily dose: 20 mg (7.1%), 40
mg (62.2%), 60-80 mg (28.7%), and 120-160 mg (2.1%). Patient characteristics were
compared across doses using Cochran-Armitage trend tests. Multivariable ordinal
logistic regression assessed the association between initial lurasidone dose and
patient characteristics. Medication adherence was measured using medication
possession ratio (MPR). RESULTS: Of 1114 adult bipolar patients (mean age 40.6
years, 70.6% female), 90% initiated lurasidone at 40 mg or 80 mg/day (mean 51.9
mg/day). Of these, 16.2% initiated lurasidone as monotherapy. Mean lurasidone
maintenance dose was 55.2 mg/day and mean MPR was 0.53 [standard deviation (SD) =
0.34] over the 6-month follow up. Substance use, hyperglycemia, obesity, and prior
antipsychotic use were associated with higher initial lurasidone doses (p < 0.05).
Odds of a 20 mg/day increase in initial lurasidone dose was 1.6-times higher for
patients with substance use [95% confidence interval (CI): 1.16-2.24], 2.6-times
higher with hyperglycemia problems (95% CI: 1.15-5.83), 1.7-times higher with
obesity (95% CI: 1.05-2.60), and 1.3 (95% CI: 1.01-1.78) and 1.8-times higher (95%
CI: 1.17-2.86) with prior use of second- and first-generation antipsychotics,
respectively. CONCLUSIONS: This real-world analysis of bipolar patients indicated
that 40 mg or 80 mg/day were the most common starting doses of lurasidone. A
majority of patients used concomitant psychiatric medications (polypharmacy).
Higher doses of lurasidone were prescribed to patients with comorbidities or prior
antipsychotic use. Adherence to lurasidone was comparable to or better than
antipsychotic adherence reported in bipolar disorder literature.

Sajatovic, M., et al. (2013). "Prospective, open-label trial measuring satisfaction

and convenience of two formulations of lamotrigine in subjects with mood
disorders." Patient Prefer Adherence 7: 411-417.
BACKGROUND: Lamotrigine is an anticonvulsant drug indicated for the
maintenance treatment of bipolar I disorder and for various types of epilepsy. An
orally disintegrating tablet (ODT) of lamotrigine was developed to provide a
formulation option that might increase patient convenience and satisfaction.
METHODS: Subjects with mood disorders who reported difficulty swallowing currently
prescribed lamotrigine immediate-release medication (baseline) were enrolled and
treated with lamotrigine ODT for three weeks (end of treatment). Subject
satisfaction and convenience were measured using the Treatment Satisfaction
Questionnaire for Medication (TSQM). Also measured were global psychopathology
using the Clinical Global Impression severity index (CGI-S) and depressive symptoms
using the Beck Depression Inventory (BDI-II). RESULTS: Lamotrigine ODT was found to
be significantly more convenient to use than lamotrigine immediate-release (change
in baseline TSQM convenience score: 23.3, n = 97, P < 0.001). The mean TSQM global
satisfaction score was similar at baseline (76.3) and after treatment with
lamotrigine ODT (76.0). There were no significant changes on CGI-S and BDI-II.
CONCLUSION: Subjects reported that lamotrigine ODT was significantly more
convenient than lamotrigine immediate-release, while both formulations were
associated with good satisfaction. Lamotrigine ODT may be a treatment option for
patients who have difficulty swallowing medication.

Salloum, N. C., et al. (2017). "Emergence of mania in two middle-aged patients with
a history of unipolar treatment-refractory depression receiving vagus nerve
stimulation." Bipolar Disord.
OBJECTIVES: We report on two patients who experienced emergence of full manic
symptoms while receiving vagal nerve stimulation (VNS). METHODS: Two patients, both
with a well-documented and verified history of longstanding unipolar depression,
were initiated on VNS for treatment of their severe major depressive episodes.
RESULTS: The two patients had emergence of full manic symptoms after 8 and 9 months
of VNS, respectively. Manic symptoms were adequately managed with standard
treatments (mood stabilizer and electroconvulsive therapy) and VNS was continued in
the two subjects for up to 5 years without any further occurrences of
manic/hypomanic episodes. CONCLUSIONS: These cases suggest that some patients with
treatment-resistant depression may have a previously unrecognized bipolar disorder,
triggered only by VNS. This report also provides evidence that VNS-induced manic
switches, however serious and troubling to patients, can be managed safely, and
that VNS maintenance can be continued for an extended period of time without manic
relapses. Although the mechanism of action of VNS is not known, emerging evidence
supports central nervous system dopaminergic and possibly cholinergic system
involvement.

Samalin, L., et al. (2013). "[French Society for Biological Psychiatry and
Neuropsychopharmacology task force: Formal Consensus for the prescription of depot
antipsychotics]." Encephale 39 Suppl 4: 189-203.
BACKGROUND: Compliance is often partial with oral antipsychotics and
underestimated for patients with serious mental illness. Despite their demonstrated
advantages in terms of relapse prevention, depot formulations are still poorly used
in routine. As part of a process to improve the quality of care, French Association
for Biological Psychiatry and Neuropsychopharmacology (AFPBN) Task Force elaborated
a Formal Consensus for the prescription of depot antipsychotics in clinical
practice. METHODS: The Task Force recommends as first-line choice, the use of long-
acting injectable (LAI) second-generation antipsychotics in patients with
schizophrenia, schizoaffective disorder and delusional disorder. They can be
considered as a second-line option as a monotherapy to prevent manic recurrence or
in combination with mood stabilizer to prevent depressive recurrence in the
maintenance treatment of bipolar disorder. LAI second-generation antipsychotics can
also be used after a first episode of schizophrenia. Depot neuroleptics are not
recommended during the early course of schizophrenia and are not appropriate in
bipolar disorder. They are considered as a second-line option for maintenance
treatment in schizophrenia. RESULTS: LAI formulations should be systematically
proposed to any patients for whom maintenance antipsychotic treatment is indicated.
LAI antipsychotics can be used preferentially for non-compliant patients with
frequent relapses or aggressive behaviors. CONCLUSION: A specific information
concerning the advantages and inconveniences of the LAI formulations, in the
framework of shared-decision making must be delivered to each patient.
Recommendations for switching from one oral/LAI form to another LAI and for using
LAI antipsychotics in specific populations (pregnant women, elderly patients,
subjects in a precarious situation, and subjects having to be treated in a prison
establishment) are also proposed.

Samalin, L., et al. (2011). "[Guidelines for the biological treatment of bipolar
depression]." Encephale 37 Suppl 3: S218-223.
Numerous guidelines for the treatment of bipolar disorder have been published
in the recent years. A review focusing on recent international and French
guidelines the last 5 years on the management of bipolar depression was conducted.
The comparison of guidelines showed differences in the choice of initial treatment:
monotherapy (in first line: quetiapine and lamotrigine) or polypharmacotherapy (in
first line: combination olanzapine/fluoxetine). All guidelines recommend in
patients with inadequate response a therapeutic strategy in two steps. An initial
clinical stage seeking the causes of poor therapeutic response and a second
therapeutic stage trying to optimize the current treatment, to change treatment or
to consider a co-therapy. In first line, the prophylactic drugs recommended are:
lithium, valproate, quetiapine; olanzapine, risperidone (and long-acting
formulation) and aripiprazole mainly for the prevention of manic episodes;
lamotrigine limited to prevention of depressive episodes. The duration of treatment
before patient reassessment and that of maintenance therapy are not consensual. The
development of second-generation antipsychotics in bipolar depression is an
interesting development for our therapeutic armamentarium and has been incorporated
in recent guidelines.

Samalin, L., et al. (2013). "Asenapine in bipolar I disorder: evidence and place in
patient management." Ther Adv Chronic Dis 4(1): 5-14.
Asenapine is a new second-generation antipsychotic approved in September 2010
by the European Medicines Agency for the treatment of bipolar disorder. It
demonstrated significant efficacy compared with placebo in acute mania or mixed
episodes as monotherapy or adjunctive therapy to mood stabilizers (lithium or
valproate). Early improvement was noted at day 2 and was strongly associated with
response and remission at week 3. Asenapine also appeared effective in treating
acute mania in older patients with bipolar disorder. Post hoc analyses of asenapine
showed efficacy in treating depressive symptoms during manic or mixed episodes
compared with placebo. The efficacy of asenapine in patients with acute mania
appeared to remain constant during maintenance treatment. Asenapine was reasonably
well tolerated, especially with regard to metabolic effects. There were minimal
signs of glucose elevation or lipid changes and the risk of weight gain appeared
limited. The prolactin elevation was smaller than other antipsychotic comparators.
Only oral hypoesthesia occurred as a new adverse event compared with other second-
generation antipsychotics. Asenapine presents several advantages over other second-
generation antipsychotics, such as sublingual formulation, early efficacy and good
metabolic tolerability. This tolerability profile confirms the heterogeneity of the
second-generation antipsychotic class and supports the view of some authors for the
need to re-evaluate the boundaries of this group.
Samalin, L., et al. (2010). "Patient perspectives on use of long-acting
antipsychotics in bipolar disorder: focus on risperidone injection." Patient Prefer
Adherence 4: 325-334.
In the last few years, oral second-generation antipsychotics have
demonstrated mood-stabilizing properties and are now widely used in the treatment
of bipolar disorder. Unfortunately, treatment of this chronic and complex illness
is hampered with poor adherence on the part of patients. Long-acting injectable
formulations of second-generation antipsychotics could combine the effect of oral
second-generation antipsychotics in patients with bipolar disorder and the benefits
of depot formulation with the assurance of steady medication delivery and thereby
improve adherence. In this context, the efficacy and tolerance of risperidone long-
acting injection (RLAI) for maintenance treatment in patients with bipolar disorder
is assessed. The relevant studies found RLAI to be effective in preventive
treatment of manic but not depressive recurrences in bipolar patients, with good
tolerance. RLAI appeared to be particularly suitable for patients with known poor
adherence to treatment or severe bipolar disorder (such as patients who relapse
frequently). Lastly, if RLAI, unlike the first-generation antipsychotics, does not
induce depressive symptoms, the different studies do not enable us to consider its
use in monotherapy in the preventive treatment of patients with depressive
polarity. Long-acting second-generation antipsychotics in bipolar patients are
therefore associated with long-term benefits, but their use in clinical practice
needs to be improved.

Samalin, L., et al. (2013). "Methodological differences between pharmacological

treatment guidelines for bipolar disorder: what to do for the clinicians?" Compr
Psychiatry 54(4): 309-320.
OBJECTIVE: Numerous guidelines for bipolar disorder have been published. The
aim of this article is to underline the main differences between consensus-based
guidelines (CBG) and evidence-based guidelines (EBG) currently available for the
management of bipolar disorder. METHODS: A literature search for guidelines
published since 2006 was performed. A qualitative analysis was then conducted to
compare the methodologies and the guidelines contents. RESULTS: Comparison between
CBG and EBG found more similarities than differences. However, discordances were
found in the first-line choice of treatment (monotherapy or combination, use of
lamotrigine or lithium in bipolar depression), time to reassessment and duration of
maintenance treatment, introduction as from the acute phase a regimen compatible
with long-term use and pharmacotherapy during pregnancy. CONCLUSIONS: The choice of
policy, whatever the methodology used, is up to the authors and can, therefore,
depend on their interpretation of the available scientific evidence. Combining both
methodologies (CBG and EBG) enables us to meet the complete definition of evidence-
based medicine.

Samalin, L., et al. (2016). "Management of inter-episodic periods in patients with

bipolar disorder." Expert Rev Neurother 16(6): 659-670.
The management of inter-episodic periods of bipolar disorder (BD) appears
complex as it combines several therapeutic approaches and takes into account
individual characteristics of BD patients. Over recent decades, new evidence has
been provided about pharmacological treatments, psychosocial interventions or
models of care for the long-term management of BD patients. Considering this,
guidelines for the maintenance treatment of BD should be regarded as an evidence-
based ground for everyday clinical practice in real-life setting. This article
critically reviews recently published clinical guidelines on the management of BD
patients during the inter-episodic phases of illness, in order to highlight the
consensual or controversial recommendations.

Samalin, L., et al. (2014). "What is the evidence for the use of second-generation
antipsychotic long-acting injectables as maintenance treatment in bipolar
disorder?" Nord J Psychiatry 68(4): 227-235.
BACKGROUND: In recent years, the use of second-generation antipsychotics
long-acting injectable in the maintenance treatment of bipolar disorder has sparked
interest in improving adherence and reducing the risk of relapse. AIMS: This report
aims to review the available evidence concerning the use of second-generation
antipsychotics depot in bipolar disorder and specify the typology of patients that
could be eligible for this formulation. METHODS: A systematic review of the
literature was conducted using Pubmed and EMBASE. RESULTS: Data available for the
clinician assessing the interests of second-generation antipsychotics depot in
long-term treatment of bipolar disorder are limited to risperidone. It seems
particularly relevant for bipolar patients with poor adherence or early in the
course of illness and can be used as monotherapy with manic polarity. It should
always be considered for use in combination with at least one other mood stabilizer
in patients with depressive polarity. As for other medications, the benefit/risk
ratio for a long-acting should be evaluated individually. CONCLUSIONS: If using a
depot formulation could be considered for all patients in order to approach a
perfect compliance, patients with certain clinical profiles could be an argument
for prioritizing the use of long-acting injectable as maintenance treatment.
Additional studies are needed with other second-generation antipsychotics depot in
bipolar patients to generalize their use in the maintenance treatment of bipolar
disorder but the future golden standard of studies with long-acting formulations
remains to be defined.

Samalin, L., et al. (2011). "[Lithium and anticonvulsants in bipolar depression]."

Encephale 37 Suppl 3: S203-208.
For decades, lithium and anticonvulsants have been widely used in the
treatment of bipolar disorder. Their efficacy in the treatment of mania is
recognized. These drugs have been initially evaluated in old and methodologically
heterogeneous studies. Their efficacy in bipolar depression has not always been
confirmed in more recent and methodologically more reliable studies. Thus,
lithium's efficacy as monotherapy was challenged by the study of Young (2008) that
showed a lack of efficacy compared with placebo in the treatment of bipolar
depression. In two recent meta-analyses, valproate has shown a modest efficacy in
the treatment of bipolar depression. As for lithium, valproate appeared to have a
larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In
contrast, lamotrigine is more effective on the depressive pole of bipolar disorder
with better evidence for the prevention of depressive recurrences. The guidelines
include these recent studies and recommend lamotrigine as a first-line treatment of
bipolar depression and for maintenance treatment. Because of more discordant data
concerning lithium and valproate, these two drugs are placed either as first or as
second line treatment of bipolar depression. The different safety/efficacy ratios
of mood stabilizers underlie the complementarity and the importance of combination
between them, or with some second-generation antipsychotics, in the treatment of
patients with bipolar disorder.

Sanford, M. and G. M. Keating (2012). "Quetiapine: a review of its use in the

management of bipolar depression." CNS Drugs 26(5): 435-460.
Quetiapine (Seroquel(R)) is an orally administered atypical antipsychotic
that is indicated for the treatment of schizophrenia and bipolar disorder,
including bipolar depression. An extended-release (XR) formulation of quetiapine is
also available. This review summarizes the pharmacological properties, efficacy and
tolerability of quetiapine and quetiapine XR in patients with bipolar depression.
Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and
its antipsychotic effects are thought to stem from interactions at these receptors.
The antidepressant effects of quetiapine are poorly understood, but may be related
to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in
the prefrontal cortex in association with increased extracellular dopamine release
in the region, or to reduced synaptic reuptake of noradrenaline resulting from
inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite
norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-
week, randomized, double-blind, placebo-controlled, multicentre or multinational
trials in patients with a major depressive episode (MDE) associated with bipolar
disorder. Across trials, monotherapy with oral quetiapine 300 or 600 mg/day (or
quetiapine XR 300 mg/day) produced significantly greater improvements than placebo
in depressive symptoms (primary endpoint), according to the change in the
Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and
quetiapine XR were also associated with significantly higher MDE response and
remission rates than placebo. Across trials, quetiapine and quetiapine XR produced
significantly greater improvements in global severity of illness scores than
placebo, according to changes in the Clinical Global Impressions scale score. There
were no differences in treatment outcomes between quetiapine 300 mg/day and 600
mg/day dosage groups. Patients with bipolar depression who responded to quetiapine
during two 8-week acute treatment trials also benefited from continuing quetiapine
therapy for up to 52 weeks. Compared with quetiapine responders randomized to
placebo, quetiapine responders who continued quetiapine 300 or 600 mg/day had a
significantly reduced risk of recurrence of any mood events and of depression mood
events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-
controlled trial, quetiapine maintenance therapy for up to 104 weeks was more
efficacious than placebo or lithium in prolonging the time to recurrence of any
mood event (primary endpoint). Patients in this trial had bipolar I disorder with
mania, depression or a mixed episode as the index episode, and the trial included
only patients who were responsive to acute phase quetiapine, which may have
introduced a positive bias in favour of quetiapine over lithium during maintenance
therapy. Quetiapine 300 or 600 mg/day and quetiapine XR 300 mg/day was generally
well tolerated in patients with bipolar depression, with most treatment-emergent
adverse events being of mild to moderate severity. The most frequent adverse events
occurring during the acute treatment phase were dry mouth, sedation, somnolence,
dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased
appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine
and placebo groups, but there were no significant differences between quetiapine
and placebo recipients on objective measures of EPS and akathisia. In some trials,
quetiapine recipients experienced significantly greater weight gain than placebo
recipients. Across trials, some quetiapine recipients had clinically relevant
increases in blood glucose or lipid parameters, although these also occurred in
patients from other treatment groups. The clinical significance of these changes is
uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to
the first-line treatments for bipolar depression. Further head-to-head trials of
quetiapine versus other drug regimens that are effective in bipolar depression
would be of considerable interest.

Santos, C. O., et al. (2011). "Mania and stroke: a systematic review." Cerebrovasc
Dis 32(1): 11-21.
BACKGROUND: Mania is a rare consequence of stroke and according to the sparse
published information it is difficult to describe its demographic, clinical and
prognostic characteristics. METHODS: We performed a systematic review of all cases
of mania and stroke to describe those characteristics. Studies were identified from
comprehensive searches of electronic databases, reference lists of the studies
collected and handbooks. Two authors independently assessed abstracts, and
collected and extracted data. RESULTS: From 265 abstracts, 139 were potentially
relevant. For the first analysis, which tries to answer the clinical question of
the relationship between mania and stroke, 49 studies met the inclusion criteria
and described 74 cases. For the second analysis, we looked for an explicit temporal
and causal relationship between manic symptoms and stroke, and selected 32 studies
describing 49 cases. In both analyses, the typical patient was male, without a
personal or family history of psychiatric disorder, with at least one vascular risk
factor, but without subcortical atrophy and had suffered a right cerebral infarct.
The majority of patients (92%) presented elevated mood as the first symptom. The
other frequent symptoms were an increased rate or amount of speech (71%), insomnia
(69%) and agitation (63%). CONCLUSIONS: Post-stroke mania should be considered in
any manic patient who presents concomitant neurological focal deficits and is older
than expected for the onset of primary mania. The results of a systematic study of
mania in acute stroke with subsequent follow-up and data from diffusion MR or
perfusion CT in a multicenter study with a central database would be relevant.

Santos Pina, L., et al. (2016). "Maintenance Electroconvulsive Therapy in Severe

Bipolar Disorder: A Retrospective Chart Review." J ECT 32(1): 23-28.
OBJECTIVE: The aim of this study was to evaluate the effectiveness of
continuation and maintenance electroconvulsive therapy (C/M-ECT) in patients with
bipolar or schizoaffective disorder. METHODS: We reviewed the charts of all
patients diagnosed with a bipolar or schizoaffective disorder treated with C/M-ECT
from August 2009 until December 2013. We gathered demographic data and treatment
variables (electrode placement, stimulus dose, and concomitant use of medication;
number of C/M-ECT sessions; and number of new ECT courses). Primary outcome measure
was the number of hospitalization days during C/M-ECT as compared with an equal
period before starting the index course. RESULTS: Twenty women (64.5%) and 11 men
(35.5%) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition bipolar disorder (n = 22, 71%) or schizoaffective disorder (n = 9, 29%)
received C/M-ECT. The mean (SD) age was 51.23 (14.86; range, 28-74) years. Before
the start of the index ECT, patients had a mean of 290 hospitalization days (248.4
days, full hospitalization; 41.6 days, partial hospitalization), whereas during
C/M-ECT, they had a mean of 214.7 hospitalization days (85.4 days, full
hospitalization; 129.3 days, partial hospitalization). The number of readmissions
before ECT was 2.13, whereas during C/M-ECT, it decreased to 1.48. Only the
decrease in number of full hospitalization days was significant. Most patients (n =
23, 74.19%) needed an acute course of ECT during M-ECT. CONCLUSIONS: Maintenance
ECT seems to significantly reduce the number of full hospitalization days in
patients with severe bipolar or schizoaffective disorder.

Santos-Cubina, J., et al. (2013). "Menstrual psychosis: presenting symptom of

bipolar disorder not otherwise specified in a 13-years-old Hispanic female." Bol
Asoc Med P R 105(3): 53-55.
Exacerbation of symptoms in mood disorders such as bipolar disorders, major
depressive disorders and premenstrual dysphoric disorders could be influenced by
the hormonal changes of the menstrual cycles in female patients. Menarche has been
related to onset of mood symptoms, which at times have been described as menstrual
psychoses and could represent an early presentation of Pediatric bipolar disorders.
Pediatric bipolar disorders appear to be characterized by less clearly defined mood
episodes, shorter duration of these episodes, and different hallmark symptoms than
in adults. This report describes a pediatric patient who had no previous
psychiatric symptoms and for whom menstrual psychosis was the presenting symptom of
bipolar disorder not otherwise specified.

Saroukhani, S., et al. (2013). "Aspirin for treatment of lithium-associated sexual

dysfunction in men: randomized double-blind placebo-controlled study." Bipolar
Disord 15(6): 650-656.
OBJECTIVES: The aim of the present study was to assess the effect of aspirin
on lithium-related sexual dysfunction in men with stable bipolar affective disorder
(BAD). METHODS: In a randomized, double-blind, placebo-controlled study, 32 men
with stable BAD who had been on lithium maintenance therapy randomly received
aspirin (240 mg/day) or placebo for six weeks. The International Index for Erectile
Function (IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6.
Depressive and mania symptoms and plasma lithium concentrations were assessed at
baseline and Week 6. Side effects were assessed using a checklist. RESULTS: Thirty
patients (15/group) completed the study. Baseline and endpoint lithium
concentrations and mania and depressive symptoms did not differ significantly
between the two groups. Significant effects of time x treatment interaction were
observed for total score [Greenhouse-Geisser: F(1.410,39.466) = 6.084, p = 0.010]
and erectile function [Greenhouse-Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By
Week 6, patients in the aspirin group showed significantly greater improvement in
the total (63.9% improvement from the baseline) and erectile function domain (85.4%
improvement from the baseline) scores than the placebo group (14.4% and 19.7%
improvement from the baseline, p-values = 0.002 and 0.001, respectively). By Week
6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo
group met the criteria of minimal clinically important change [chi(2) (1) = 10.800,
p = 0.001]. Other IIEF domains also showed significant improvement at the end of
the trial. The frequency of side effects was similar between the two groups.
CONCLUSION: Aspirin effectively improves lithium-related sexual dysfunction in men
with stable BAD.

Savage, N. (2016). "Privacy: The myth of anonymity." Nature 537(7619): S70-72.

Sayyaparaju, K. K., et al. (2014). "When to start aripiprazole therapy in patients

with bipolar mania." Neuropsychiatr Dis Treat 10: 459-470.
Aripiprazole is a third generation atypical antipsychotic with compelling
evidence as a highly effective treatment option in the management of acute manic
and mixed episodes of bipolar I disorders. It has a unique mode of action, acting
as a partial agonist at dopamine D2 and D3, and serotonin 5-HT1A; and exhibiting
antagonistic action at the 5-HT2A and H1 receptors. Overall, it has a favorable
safety and tolerability profile, with low potential for clinically significant
weight gain and metabolic effects, especially compared to other well-established
treatments. It also has a superior tolerability profile when used as maintenance
treatment. Side effects like headache, insomnia, and extrapyramidal side effects
(EPSEs), such as tremor and akathisia may be treatment limiting in some cases. It
is efficacious in both acute mania and mixed states, and in the long-term
prevention of manic relapses. Aripiprazole therefore, is a significant player in
the current portfolio of anti-manic pharmacological treatments. The data sources
for this article are from EMBASE, MEDLINE, and the clinical trial database searches
for all the literature published between January 2003 and September 2013. The key
search terms were "aripiprazole" combined with "bipolar disorder", "mania",
"antipsychotics", "mood stabilizer", "randomized controlled trial", and
"pharmacology". Abstracts and proceedings from national and international
psychiatric meetings were also reviewed, along with reviews of the reference lists
of relevant articles.

Schaffer, C. B., et al. (2011). "Efficacy and safety of nonbenzodiazepine hypnotics

for chronic insomnia in patients with bipolar disorder." J Affect Disord 128(3):
305-308.
BACKGROUND: Insomnia in patients with bipolar disorder (BD) can cause
distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic
symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD
patients with insomnia although no hypnotic has a specific FDA indication for this
use. In this study, the patterns of use, efficacy and safety of five
nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients
with BD. METHOD: A chart review was performed for all older adolescents and adult
BD outpatients in a private outpatient clinic. Clinical data was collected for any
patient who had ever been prescribed a NBZH for insomnia and included successful
current use, past unsuccessful treatments, side effects, duration of use,
concurrent psychiatric medications, and absence or presence of untoward events
often associated with chronic use of hypnotics. RESULTS: A significant number of BD
patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success
rates; ramelteon was limited in efficacy. Some patients experienced satisfactory
results from a NBZH after unsuccessful trials with one or more other NBZHs. About
half of the current NBZH users are taking them on a daily long-term basis, and none
of these patients have experienced unacceptable untoward events. About three
quarters of the chronic NBZH users are taking antimanic medications concurrently,
and less than half of the chronic users are taking antidepressants. LIMITATIONS:
The results may not be generalizable to other BD populations. A control group was
not included in the design. Chronic users of NBZHs were not asked to discontinue
their NBZH in order to confirm indication for long-term use. CONCLUSIONS: Most
NBZHs can be effective and safe agents for selected BD outpatients with episodic or
chronic insomnia. Failure to respond to one or more NBZH does not preclude a
satisfactory response to a different NBZH. Some BD patients who take maintenance
antimanic agents also require NBZH treatment. Overactivation from antidepressant
treatment does not contribute to chronic NBZH use in most BD patients.

Schaffer, C. B., et al. (2016). "An Open Trial of Lurasidone as an Acute and
Maintenance Adjunctive Treatment for Outpatients With Treatment-Resistant Bipolar
Disorder." J Clin Psychopharmacol 36(1): 88-89.

Schaffer, C. B., et al. (2016). "An Open Trial of Lurasidone as an Acute and
Maintenance Adjunctive Treatment for Outpatients With Treatment-Resistant Bipolar
Disorder: Response to Letter to the Editors." J Clin Psychopharmacol 36(5): 522-
523.

Schaffer, L. C., et al. (2013). "An open trial of pregabalin as an acute and
maintenance adjunctive treatment for outpatients with treatment resistant bipolar
disorder." J Affect Disord 147(1-3): 407-410.
BACKGROUND: Pregabalin is a structural analog of GABA, similar to gabapentin.
It does not have a FDA indication for any psychiatric disorder in the USA. There
has been one case report of the successful use of pregabalin as an augmenting agent
in a patient with Bipolar Disorder (BD). In the present open label study, not
subsidized by the manufacturer, the investigators prospectively evaluated the acute
and maintenance efficacy of pregabalin as an adjunctive medication for a group of
treatment refractory outpatients with BD. METHODS: Older adolescent and adult
outpatients with any type of DSM-IV diagnosed BD, who were considered treatment
nonresponders to multiple standard medications for BD, were treated with adjunctive
pregabalin. The baseline mood state before initiation of pregabalin was compared to
the mood state after an acute trial of pregabalin using the Clinical Global
Impression-Bipolar Version Scale (CGI-BP). All acute responders were treated for a
minimum of two months. Follow-up maintenance treatment data was obtained for the
acute pregabalin responders for three years after the 18 month acute phase of the
study. RESULTS: Fifty-eight total patients were treated adjunctively with
pregabalin. Twenty-four (41%) were rated as acute responders. For the acute
responders, pregabalin produced either a mood stabilizing effect, antidepressant
effect or antimanic effect. Intolerable side-effects were the most common reason
(79%) for a failed acute trial of pregabalin. None of the side effects resulted in
serious medical complications. No patient abused pregabalin, and there were no
adverse drug-drug interactions despite an average of 3.3 concurrent other
psychiatric medications. The maintenance data revealed that 10 (42%) of the
original 24 acute pregabalin responders were still taking pregabalin as an add-on
medicine for an average of 45.2 months (range 42-48, SD: 2.35). LIMITATIONS: This
study has an open label observation design. CONCLUSIONS: The results of this
preliminary open study suggest that pregabalin is a safe and effective acute and
maintenance adjunctive treatment for a significant number of treatment-resistant
outpatients with any type of BPD. It appears to have mood stabilizing and
antidepressant properties in addition to antimanic effects. Similar studies using a
double-blind, randomly controlled design would be useful to confirm the reliability
and validity of the results of this study.

Scheidemantel, T., et al. (2015). "Asenapine for bipolar disorder." Neuropsychiatr

Dis Treat 11: 3007-3017.
Asenapine (Saphris((R))) is an atypical antipsychotic drug which has been
approved by the US Food and Drug Administration for the treatment of schizophrenia
in adults, as well as the treatment of acute manic or mixed episodes of bipolar I
in both adult and pediatric populations. Asenapine is a tetracyclic drug with
antidopaminergic and antiserotonergic activity with a unique sublingual route of
administration. In this review, we examine and summarize the available literature
on the safety, efficacy, and tolerability of asenapine in the treatment of bipolar
disorder (BD). Data from randomized, double-blind trials comparing asenapine to
placebo or olanzapine in the treatment of acute manic or mixed episodes showed
asenapine to be an effective monotherapy treatment in clinical settings; asenapine
outperformed placebo and showed noninferior performance to olanzapine based on
improvement in the Young Mania Rating Scale scores. There are limited data
available on the use of asenapine in the treatment of depressive symptoms of BD, or
in the maintenance phase of BD. The available data are inconclusive, suggesting the
need for more robust data from prospective trials in these clinical domains. The
most commonly reported adverse effect associated with use of asenapine is
somnolence. However, the somnolence associated with asenapine use did not cause
significant rates of discontinuation. While asenapine was associated with weight
gain when compared to placebo, it appeared to be modest when compared to other
atypical antipsychotics, and its propensity to cause increases in hemoglobin A1c or
serum lipid levels appeared to be similarly modest. Asenapine does not appear to
cause any clinically significant QTc prolongation. The most commonly reported
extra-pyramidal symptom associated with asenapine was akathisia. Overall, asenapine
appears to be a relatively well-tolerated atypical antipsychotic, effective in the
treatment of acute manic and mixed episodes of BD.

Schnaar, R. L., et al. (2014). "Sialic acids in the brain: gangliosides and
polysialic acid in nervous system development, stability, disease, and
regeneration." Physiol Rev 94(2): 461-518.
Every cell in nature carries a rich surface coat of glycans, its glycocalyx,
which constitutes the cell's interface with its environment. In eukaryotes, the
glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the
compositions of which vary among different tissues and cell types. Many of the
linear and branched glycans on cell surface glycoproteins and glycolipids of
vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic
acid, a glycerol side-chain, and an N-acyl group that, along with their display at
the outmost end of cell surface glycans, provide for varied molecular interactions.
Among their functions, sialic acids regulate cell-cell interactions, modulate the
activities of their glycoprotein and glycolipid scaffolds as well as other cell
surface molecules, and are receptors for pathogens and toxins. In the brain, two
families of sialoglycans are of particular interest: gangliosides and polysialic
acid. Gangliosides, sialylated glycosphingolipids, are the most abundant
sialoglycans of nerve cells. Mouse genetic studies and human disorders of
ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon
stability, axon regeneration, and the modulation of nerve cell excitability.
Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues
attached to select glycoproteins, especially the neural cell adhesion molecule in
the brain. Molecular, cellular, and genetic studies implicate polysialic acid in
the control of cell-cell and cell-matrix interactions, intermolecular interactions
at cell surfaces, and interactions with other molecules in the cellular
environment. Polysialic acid is essential for appropriate brain development, and
polymorphisms in the human genes responsible for polysialic acid biosynthesis are
associated with psychiatric disorders including schizophrenia, autism, and bipolar
disorder. Polysialic acid also appears to play a role in adult brain plasticity,
including regeneration. Together, vertebrate brain sialoglycans are key regulatory
components that contribute to proper development, maintenance, and health of the
nervous system.

Schweitzer, I., et al. (2013). "Aripiprazole as augmentation therapy in bipolar

patients with current minor or subsyndromal mood symptoms." Int J Bipolar Disord 1:
4.
BACKGROUND: This study aims to evaluate the effectiveness of aripiprazole
augmentation of maintenance treatment for bipolar disorder in patients with minor
or subsyndromal mood episodes while on a stable dose of a mood stabiliser and/or
antidepressant. METHODS: All subjects had a diagnosis of bipolar I or II disorder
(Diagnostic and Statistical Manual of Mental Disorders-4th Edition, Text Revision).
Open-label aripiprazole was given over 8 weeks initially. The starting dose was 5
to 15 mg/day with a mean final dose of 11.5 mg (+/-4.6). Patients were assessed at
weeks 0, 2, 4 and 8 with the Montgomery-Asberg Depression Rating Scale (MADRS),
Young Mania Rating Scale (YMRS) and Clinical Global Impression of Severity (CGI-S).
RESULTS AND DISCUSSION: Seventeen of 20 (85%) patients completed week 4, while 14
(70%) patients completed 8 weeks. For intention-to-treat data, there was a
significant decrease in MADRS scores over the course of treatment, with a reduction
of 6.40 points at endpoint (p < 0.0005). Improvement from baseline was significant
at week 2 and remained through to week 8. Similarly, CGI-S scores significantly
decreased over the course of study, but not YMRS scores. Aripiprazole was shown to
be a modestly effective augmentation therapy for depressive symptoms in bipolar I
and II in this small open-label study.

Scott, J. and B. Etain (2011). "Which psychosocial interventions in bipolar

depression?" Encephale 37 Suppl 3: S214-217.
This review of psychosocial interventions in bipolar disorders demonstrates
that some therapies, when combined with medication, are more efficacious at
preventing or delaying depressive relapse, and can be more effective than
medication alone in reducing time to recovery from an acute bipolar depressive
episode. However, apparent benefits diminish over time, suggesting that maintenance
or << booster >> therapy sessions may be needed. Given the scarcity of trained
therapists, further studies are needed to determine which bipolar depressed
patients should be targeted and to establish more clearly the potential cost and
benefits of such interventions.

Seo, H. J., et al. (2011). "Safety and tolerability of lamotrigine: results from 12
placebo-controlled clinical trials and clinical implications." Clin Neuropharmacol
34(1): 39-47.
The mechanism of action of lamotrigine depends on voltage-sensitive sodium
channels by which the neuronal membrane is stabilized and the release of excitatory
neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is
indicated for maintenance treatment of bipolar I disorder to delay the time to the
occurrence of mood episodes for those treated for acute mood episodes with standard
therapy. There are significant gaps between clinical practices and research
settings; data from controlled clinical trials of lamotrigine provide essential
information about safety in bipolar populations because they result from large
samples of patients with a specific disease and include comparisons with placebo or
other comparators with randomized designs. In addition, lamotrigine's safety and
tolerability data differ slightly in relation to disease entities, age ranges of
the patients taking lamotrigine, and treatment conditions. For example, the
incidence of serious rashes, including Stevens-Johnson syndrome, is approximately
0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as
adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy
for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of
serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as
initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as
adjunctive therapy. Hence, in this study, we focus on the data regarding the safety
and tolerability of lamotrigine in the treatment of bipolar disorder gathered from
12 placebo-controlled trials, regardless of publication status, that were sponsored
by GlaxoSmithKline. We also inform clinicians of practical issues in safety and
tolerability in the use of lamotrigine in the treatment of bipolar disorders.

Seok Seo, J., et al. (2014). "The Korean Medication Algorithm for Depressive
Disorder: second revision." J Affect Disord 167: 312-321.
AIM: This study constitutes a revision of the guidelines for the treatment of
major depressive disorder (MDD) issued by the Korean Medication Algorithm Project
for Depressive Disorder (KMAP-DD) 2006. In incorporates changes in the experts
consensus that occurred between 2006 and 2012 as well as information regarding
newly developed and recently published clinical trials. METHODS: Using a 44-item
questionnaire, an expert consensus was obtained on pharmacological treatment
strategies for (1) non-psychotic MDD, (2) psychotic MDD, (3) dysthymia and
depression subtypes, (4) continuous and maintenance treatment, and (5) special
populations; consensus was also obtained regarding (6) the choice of an
antidepressant (AD) in the context of safety and adverse effects, and (7) non-
pharmacological biological therapies. RESULTS: AD monotherapy was recommended as
the first-line strategy for nonpsychotic depression in adults, children and
adolescents, elderly adults, and patients with postpartum depression or
premenstrual dysphoric disorder. The combination of AD and atypical antipsychotics
(AAP) was recommended for psychotic depression. The duration of the initial AD
treatment for psychotic depression depends on the number of depressive episodes.
Most experts recommended stopping the initial AD and AAP therapy after a certain
period in patients with one or two depressive episodes. However, for those with
three or more episodes, maintenance of the initial treatment was recommended for as
long as possible. Monotherapy with various selective serotonin reuptake inhibitors
(SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) was
recommended for dysthymic disorder and melancholic type MDD. CONCLUSION: The
pharmacological treatment strategy of KMAP-DD 2012 is similar to that of KMAP-DD
2006; however, the preference for the first-line use of AAPs was stronger in 2012
than in 2006.

Severus, E., et al. (2012). "State of the art: treatment of bipolar disorders." CNS
Neurosci Ther 18(3): 214-218.
Bipolar disorders are lifelong lasting affective disorders, with an episodic
course of the illness in most cases. The lifetime prevalence is around 2-5%, the
illness usually appears in early adulthood and causes significant impairment in
psychosocial functioning. This is a selective review focusing on recent
developments and issues of interest in the psychopharmacological treatment of
bipolar disorders. It is based primarily on the results of adequately powered,
randomised, controlled trials (RCTs). These studies were systematically retrieved
by means of a Medline search. The past 10 years have led to a broadening of the
psychopharmacological treatment options for bipolar disorders. The proof of
efficacy for the combination of fluoxetine/olanzapine as well as quetiapine in the
acute treatment of bipolar I depression were important steps. While lithium remains
the gold standard in the maintenance treatment of bipolar disorders, valproate,
olanzapine, lamotrigine, aripiprazole, and quetiapine have been shown efficacious
for this indication, with quetiapine possessing the broadest approval status of all
drugs for the different treatment phases of this illness. Despite this progress
there remains a huge demand regarding new compounds for nearly every area in the
psychopharmacological treatment of bipolar disorders. In addition new
methodological approaches regarding the proof of effectiveness in clinical practice
are urgently needed.

Severus, W. E., et al. (2010). "In search of optimal lithium levels and olanzapine
doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the
maintenance study by Tohen et al. 2005." Eur Psychiatry 25(8): 443-449.
PURPOSE: The aim of this study was to investigate whether lower lithium
levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes
in patients with bipolar I disorder. METHODS: A post-hoc analysis of the
olanzapine-lithium-maintenance study [31] was performed using proportional hazards
Cox regression models and marginal structural models (MSMs), adjusting for non-
random assignments of dose during treatment. RESULTS: The LoLi group (<0.6 mmol/L)
had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96,
p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined
medium (0.6-0.79 mmol/L) and high lithium level (>/=0.8 mmol/L) groups. There was
no significant difference in risk between the two higher lithium level groups (0.6-
0.79 mmol/L; >/=0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive
(HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly
increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher
olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically
significant difference in risk for manic/mixed episodes between the two groups
(HR=0.94, p=0.895). CONCLUSION: Lithium levels>/=0.6 mmol/L and olanzapine
doses>/=10mg/day may be necessary for optimal protection against manic/mixed or
depressive episodes, respectively in patients with bipolar I disorder.

Shahjouei, S., et al. (2016). "Potential Roles of Adropin in Central Nervous

System: Review of Current Literature." Front Mol Biosci 3: 25.
Adropin is a 4.9 kDa peptide that is important for maintenance of metabolic
and non-metabolic homeostasis. It regulates glucose and fatty acid metabolism and
is involved in endothelial cell function and endothelial nitric oxide (NO) synthase
bioactivity as well as physical activity and motor coordination. Adropin is
expressed in many tissues and organs including central nervous system (CNS). This
peptide plays a crucial role in the development of various CNS disorders such as
stroke, schizophrenia, bipolar disorder as well as Alzheimer's, Parkinson's, and
Huntington's diseases. In this comprehensive review, the potential roles of adropin
in cellular signaling pathways that lead to pathogenesis and/or treatment of CNS
disorders will be discussed.

Shan, G. W., et al. (2016). "Long term use of lithium and factors associated with
treatment response among patients with bipolar disorder." Psychiatr Danub 28(2):
146-153.
BACKGROUND: Lithium has been the gold standard in treating bipolar disorder.
In recent years, the use of lithium seems to be diminished although it is well
tolerated among the bipolar disorder patients. SUBJECTS AND METHODS: This study
aimed to evaluate the efficacy and tolerability of lithium as well as to determine
factors associated with lithium response among patient with bipolar disorder. A
retrospective study was done in a tertiary care hospital in Malaysia which included
47 bipolar disorder patients that were prescribed with lithium maintenance therapy
in the time frame of January 2009 until December 2013. RESULTS: Of all the baseline
characteristics tested, only psychotic feature differentiated lithium monotherapy
group and combination therapy group significantly (chi(2)=4.732, p=0.03). When
compared to period before lithium maintenance, all outcome measures (i.e. annual
relapse rate, proportion time spent ill and duration of mood episode) showed
significant improvement after lithium maintenance in both treatment groups. Lithium
discontinuation only occurred in five cases of adverse effects. Predominant
depressive mood episode before lithium maintenance (OR=0.159, p=0.033) and first
euthymic interval after lithium maintenance (OR=1.109, p=0.047) significantly
predicted lithium response. DISCUSSION: Lithium significantly reduced the frequency
and time spent in relapse in patients with bipolar disorder. Predominant depressive
mood polarity before lithium maintenance and longer first euthymic interval after
lithium maintenance had been identified to predict lithium response significantly.

Shao, L., et al. (2016). "Deficits in axon-associated proteins in prefrontal white

matter in bipolar disorder but not schizophrenia." Bipolar Disord 18(4): 342-351.
OBJECTIVES: Brain imaging studies have implicated white matter dysfunction in
the pathophysiology of both bipolar disorder (BD) and schizophrenia (SCZ). However,
the contribution of axons to white matter pathology in these disorders is not yet
understood. Maintenance of neuronal function is dependent on the active transport
of biological material, including synaptic proteins, along the axon. In this study,
the expression of six proteins associated with axonal transport of synaptic cargoes
was quantified in postmortem samples of prefrontal white matter in subjects with
BD, those with SCZ, and matched controls, as a measure of axonal dysfunction in
these disorders. METHODS: Levels of the microtubule-associated proteins beta-
tubulin and microtubule-associated protein 6 (MAP6), the motor and accessory
proteins kinesin-1 and disrupted-in-schizophrenia 1 (DISC1), and the synaptic
cargoes synaptotagmin and synaptosomal-associated protein-25 (SNAP-25) were
quantified in white matter adjacent to the dorsolateral prefrontal cortex in
subjects with BD (n = 34), subjects with SCZ (n = 35), and non-psychiatric controls
(n = 35) using immunoblotting and an enzyme-linked immunosorbent assay (ELISA).
RESULTS: Protein expression of beta-tubulin, kinesin-1, DISC1, synaptotagmin, and
SNAP-25 was significantly lower in subjects with BD compared to controls. Levels of
axon-associated proteins were also lower in subjects with SCZ, but failed to reach
statistical significance. CONCLUSIONS: These data provide evidence for deficits in
axon-associated proteins in prefrontal white matter in BD. Findings are suggestive
of decreased axonal density or dysregulation of axonal function in this disorder.

Sharma, V. (2011). "Considerations in the pharmacotherapy of bipolar disorder

during and after pregnancy." Curr Drug Saf 6(5): 318-323.
There are conflicting data on the course of bipolar disorder during pregnancy
but childbirth is generally considered a time of high risk for the onset or
exacerbation of mood and psychotic episodes in women with bipolar disorder. Despite
the increasing use of psychotropic drugs in women with psychiatric disorders, there
is a paucity of information in the pharmacological treatment of bipolar disorder
during and after pregnancy. Optimal drug treatment requires an understanding of the
illness course prior to, during, and after pregnancy; bipolar disorder type and
dominant polarity, psychiatric comorbidity, physical health status, prior response
to psychotropic drugs, effectiveness of medications in the acute and preventative
treatment of mood episodes, side effect profile including teratogenicity, and
finally family history of psychiatric illness. For women who discontinue
psychotropic drugs abruptly upon finding out about the pregnancy, the withdrawal
symptoms of medications should be distinguished from the symptoms of the disorder.
Compatibility of drugs with breastfeeding is another important consideration.
Antidepressants should be avoided as much as possible due to their association with
manic switches, rapid cycling, and suicidality. An important aspect of
pharmacotherapy in women with a personal or family history of bipolar I disorder or
postpartum psychosis should be the management of insomnia that can either be an
early symptom of, or a trigger for postpartum manic/mixed or psychotic episodes.
Whereas polypharmacy may be unavoidable, every effort should be made to keep the
overall number of medications and dosages to a minimum.

Sheaves, B., et al. (2016). "Insomnia, Nightmares, and Chronotype as Markers of

Risk for Severe Mental Illness: Results from a Student Population." Sleep 39(1):
173-181.
STUDY OBJECTIVES: To group participants according to markers of risk for
severe mental illness based on subsyndromal symptoms reported in early adulthood
and evaluate attributes of sleep across these risk categories. METHODS: An online
survey of sleep and psychiatric symptomatology (The Oxford Sleep Survey) was
administered to students at one United Kingdom university. 1403 students
(undergraduate and postgraduate) completed the survey. The median age was 21
(interquartile range = 20-23) and 55.60% were female. The cross-sectional data were
used to cluster participants based on dimensional measures of psychiatric symptoms
(hallucinations, paranoia, depression, anxiety, and (hypo)mania). High, medium, and
low symptom groups were compared across sleep parameters: insomnia symptoms,
nightmares, chronotype, and social jet lag. RESULTS: Insomnia symptoms, nightmares
frequency, and nightmare-related distress increased in a dose-response manner with
higher reported subsyndromal psychiatric symptoms (low, medium, and high). The
high-risk group exhibited a later chronotype (mid sleep point for free days) than
the medium- or low-risk group. The majority of participants (71.7%) in the high-
risk group screened positive for insomnia and the median nightmare frequency was
two per 14 days (moderately severe pathology). CONCLUSIONS: Insomnia, nightmares,
and circadian phase delay are associated with increased subsyndromal psychiatric
symptoms in young people. Each is a treatable sleep disorder and might be a target
for early intervention to modify the subsequent progression of psychiatric
disorder.

Shimazu, K., et al. (2011). "Family psychoeducation for major depression:

randomised controlled trial." Br J Psychiatry 198(5): 385-390.
BACKGROUND: The value of family psychoeducation for schizophrenia has been
well established, and indications for its use have recently expanded to include
bipolar affective disorder. However, no study to date has adequately examined its
use in depression. AIMS: To examine family psychoeducation in the maintenance
treatment of depression and to investigate the influence of the family's expressed
emotion (EE) on its effectiveness. METHOD: Of 103 patients diagnosed with major
depression and their primary family members, 57 pairs provided written informed
consent. The pairs were randomly allocated to the intervention (n = 25) or control
(n = 32). One family in the intervention group and two in the control group
withdrew their consent after randomisation. The intervention group underwent four
psychoeducation sessions consisting of didactic lectures about depression and group
problem-solving focusing on how to cope in high-EE situations. Patients did not
attend these sessions. Patients in both the intervention and control groups
received treatment as usual. The families' EE levels were evaluated through Five-
Minute Speech Samples. The primary outcome was relapse. RESULTS: Time to relapse
was statistically significantly longer in the psychoeducation group than in the
control group (Kaplan-Meier survival analysis, P = 0.002). The relapse rates up to
the 9-month follow-up were 8% and 50% respectively (risk ratio 0.17, 95% CI 0.04-
0.66; number needed to treat 2.4, 95% CI 1.6-4.9). In Cox proportional hazard
analysis, baseline EE did not moderate the effectiveness of the intervention.
CONCLUSIONS: Family psychoeducation is effective in the prevention of relapse in
adult patients with major depression.

Shin, Y. C., et al. (2013). "Korean medication algorithm for bipolar disorder:
second revision." Asia Pac Psychiatry 5(4): 301-308.
INTRODUCTION: The Feasibility Study of the Korean Medication Algorithm
Project for Bipolar Disorder 2002 (KMAP-BP 2002) revealed its clinical usefulness
in 2005. Since much more data had become available since 2002, it was revised in
2006 as KMAP-BP 2006. For the same reason, revision of KMAP-BP 2006 is now
necessary. METHODS: The questionnaire, amended on the basis of KMAP-BP 2006 and new
data, was sent to 94 experts, 65 of whom replied. RESULTS: In an acute manic
episode, a combination of a mood stabilizer (MS) with an atypical antipsychotic
(AAP) is recommended as first-line strategy. Monotherapy with MS is first-line in a
hypomanic episode. Triple combination of a MS, an AAP, and an antidepressant (AD),
is the first-line strategy in non-psychotic severe depression. Also MS+AAP and
MS+AD are recommended as first-line. In psychotic bipolar depression, MS+AAP+AD,
MS+AAP and AAP+AD are first-line strategies. In bipolar depression, lithium,
lamotrigine and valproic acid are selected as first-line MS and quetiapine,
olanzapine and aripiprazole are preferred antipsychotics. In maintenance treatment,
a combination of MS with AAP and monotherapy of MS are recommended as first-line.
DISCUSSION: In treating bipolar disorder, even the first step of treatment, the
expert consensus has changed from our studies in 2002 and 2006.

Shulman, K. I. (2010). "Lithium for older adults with bipolar disorder: Should it
still be considered a first-line agent?" Drugs Aging 27(8): 607-615.
The use of lithium carbonate for the treatment of bipolar disorder in older
adults is decreasing at a significant rate. This change in prescription pattern is
occurring at a time when all evidence-based treatment guidelines and systematic
reviews still recommend lithium as a first-line treatment for bipolar disorder.
Despite having the strongest evidence base for effectiveness, lithium does pose
significant concerns in the older population, including the risk of drug
interactions that cause toxicity associated with decreased creatinine clearance.
The evidence for lithium's impact on chronic renal disease is still controversial
and is reviewed in this article. Mixed evidence exists regarding the impact of
lithium on suicide risk, although there is a consensus that it does have protective
properties through its mood-stabilizing effect. Because of the very limited
research base regarding the use of lithium in old age, guidelines for dosing and
maintenance of serum concentrations are not well established, and this may be
leading to increased episodes of lithium toxicity. At the same time that these
legitimate concerns about lithium are being highlighted, evidence has accumulated
that suggests that lithium may have neuroprotective properties. Its action of
inhibiting the enzyme glycogen synthase kinase-3 may be responsible in part for a
decrease in the induction of amyloid beta peptide and hyperphosphorylated tau
protein, which have been implicated in the development of Alzheimer's disease. Very
little evidence supports use of alternatives to lithium such as other mood-
stabilizing agents, including atypical antipsychotics, in older adults. Thus,
before we abandon lithium as a first-line agent, we should ensure that the
guidelines for lithium treatment are safe, practical and effective. Newer agents
must be appropriately tested in older adults before replacing this longstanding
first-line treatment for bipolar disorder.

Sidor, M. M. and G. M. MacQueen (2012). "An update on antidepressant use in bipolar

depression." Curr Psychiatry Rep 14(6): 696-704.
The effective treatment of depression in people with bipolar disorder remains
a clinical challenge. The role of antidepressant medication in treating bipolar
depression has been controversial. While early studies and meta-analyses supported
a role for antidepressant medication, more recent, high quality randomized
controlled trials in bipolar depression have generally not demonstrated efficacy
for antidepressant medications. Although the risk of affective switch and long-term
de-stabilization remains a concern when using antidepressant medications in bipolar
disorder, the magnitude of this risk has been difficult to ascertain with
confidence. Maintenance use of antidepressant medication has generally not
demonstrated a favorable risk-benefit ratio. Future studies should explore the
patient characteristics and response patterns that predict a more favorable
response profile to antidepressants amongst patients with bipolar disorder so that
the medications can be rationally used in those who are most likely to benefit.

Siebel, A. M., et al. (2014). "Pharmacological and toxicological effects of lithium

in zebrafish." ACS Chem Neurosci 5(6): 468-476.
Lithium is the paradigmatic treatment for bipolar disorder and has been
widely used as a mood stabilizer due to its ability to reduce manic and depressive
episodes, efficiency in long-term mood stabilization, and effectiveness in reducing
suicide risks. Despite many decades of clinical use, the molecular targets of
lithium are not completely understood. However, they are credited at least
partially to glycogen synthase kinase 3 (GSK3) inhibition, mimicking and
exacerbating Wnt signaling pathway activation. There has been a great effort to
characterize lithium cellular and system actions, aiming to improve treatment
effectiveness and reduce side effects. There is also a growing concern about
lithium's impact as an environmental contaminant and its effects on development. In
this scenario, zebrafish is a helpful model organism to gather more information on
lithium's effects in different systems and developmental stages. The rapid external
development, initial transparency, capacity to easily absorb substances, and little
space required for maintenance and experimentation, among other advantages, make
zebrafish a suitable model. In addition, zebrafish has been established as an
effective model organism in behavioral and neuropharmacological studies, reacting
to a wide range of psychoactive drugs, including lithium. So far only a limited
number of studies evaluated the toxicological impact of lithium on zebrafish
development and demonstrated morphological, physiological, and behavioral effects
that may be informative regarding human findings. Further studies dedicated to
characterize and evaluate the underlying mechanisms of the toxic effects and the
potential impact of exposure on developing and adult individuals are necessary to
establish safe clinical management guidelines for women with bipolar disorder of
childbearing age and safety disposal guidelines for pharmaceutical neuroactive
compounds.

Siegel, M., et al. (2012). "Electroconvulsive therapy in an adolescent with autism

and bipolar I disorder." J ECT 28(4): 252-255.
 OBJECTIVES: We report a positive response to electroconvulsive therapy in a
severely functionally impaired adolescent with autistic disorder and classic
bipolar I disorder, including an episodic pattern of decreased need for sleep,
hypersexuality, expansive and agitated affect, aggression, self-injury, and
property destruction. METHODS: After ineffective trials of mood stabilizers and
antipsychotics as well as inability to sustain a positive response to lithium due
to medication noncompliance, a course of acute and maintenance electroconvulsive
therapy was attempted. RESULTS: A marked and sustained improvement across all
symptom categories, as measured by directly observed frequency counts of target
behaviors in an inpatient setting, was obtained. CONCLUSIONS: Electroconvulsive
therapy should be considered a potentially useful intervention in cases of children
with autistic disorder and a severe comorbid affective disorder.

Singh, J., et al. (2012). "Antipsychotics in the treatment of bipolar disorder."

Handb Exp Pharmacol(212): 187-212.
Atypical antipsychotics have an important role in the acute and maintenance
treatment of bipolar disorder. While robust evidence supports the efficacy of these
agents in the treatment of mania and in the prevention of manic relapse, few
atypical antipsychotics have shown efficacy in the treatment or prevention of
depressive episodes. These agents pose a lower risk of extrapyramidal side effects
compared to typical neuroleptics, but carry a significant liability for weight gain
and other metabolic side effects such as hyperglycemia and hyperlipidemia. More
comparative effectiveness studies are needed to assess the optimal treatment
regimens, including the relative benefits and risks of antipsychotics versus mood
stabilizers. The exploration of the molecular mechanisms of antipsychotics has
helped to shed further light on the underlying neurobiology of bipolar disorder,
since these compounds target systems thought to be key to the pathophysiology of
bipolar disorder. In addition to modulating monoaminergic neurotransmission,
atypical antipsychotics appear to share properties with mood-stabilizing agents
known to alter intracellular signal transduction leading to changes in neuronal
activity and gene expression. Atypical antipsychotic drugs have been shown to
exhibit neuroprotective properties that are mediated by upregulation of trophic and
cellular resilience factors. Building on our understanding of existing
therapeutics, especially as it relates to underlying disease pathology, newer
"plasticity enhancing" strategies hold promise for future treatments of bipolar
disorder.

Sipe, W. E. and S. J. Eisendrath (2012). "Mindfulness-based cognitive therapy:

theory and practice." Can J Psychiatry 57(2): 63-69.
Mindfulness-based cognitive therapy (MBCT) incorporates elements of
cognitive-behavioural therapy with mindfulness-based stress reduction into an 8-
session group program. Initially conceived as an intervention for relapse
prevention in people with recurrent depression, it has since been applied to
various psychiatric conditions. Our paper aims to briefly describe MBCT and its
putative mechanisms of action, and to review the current findings about the use of
MBCT in people with mood and anxiety disorders. The therapeutic stance of MBCT
focuses on encouraging patients to adopt a new way of being and relating to their
thoughts and feelings, while placing little emphasis on altering or challenging
specific cognitions. Preliminary functional neuroimaging studies are consistent
with an account of mindfulness improving emotional regulation by enhancing cortical
regulation of limbic circuits and attentional control. Research findings from
several randomized controlled trials suggest that MBCT is a useful intervention for
relapse prevention in patients with recurrent depression, with efficacy that may be
similar to maintenance antidepressants. Preliminary studies indicate MBCT also
shows promise in the treatment of active depression, including treatment-resistant
depression. Pilot studies have also evaluated MBCT in bipolar disorder and anxiety
disorders. Patient and clinician resources for further information on mindfulness
and MBCT are provided.
Sit, D., et al. (2011). "Menstrual effects on mood symptoms in treated women with
bipolar disorder." Bipolar Disord 13(3): 310-317.
OBJECTIVES: Reports suggest women with bipolar disorder (BD) have high rates
of perimenstrual mood worsening. In this prospective study, the authors compared
healthy controls and depressed and euthymic BD patients on medications on mood
levels, psychosocial function, and physical symptoms in the late luteal versus the
early follicular phase. METHODS: At baseline, the lifetime diagnosis of bipolar I
disorder or bipolar II disorder, current mood episode, and absence of premenstrual
dysphoric disorder in controls were confirmed with the Structured Clinical
Interview for DSM-IV Disorders. Subjects were assessed across three menstrual
cycles during the late luteal and early follicular phases. Clinicians administered
the Structured Interview Guide for the Hamilton Depression Rating Scale and the
Mania Rating Scale to assess levels of depression and hypomania/mania,
respectively. Subjects completed self-report ratings on psychosocial function and
perceived stress and tracked daily mood and physical symptoms on the National
Institute of Mental Health LifeChart and the Daily Rating Form. Ovulation was
verified objectively with mid-cycle luteinizing hormone urine dipsticks and serum
progesterone levels. RESULTS: The sample characteristics were similar among the
three patient groups of healthy controls (n = 10), BD-euthymic (n = 6), and BD-
depressed (n = 5). The two-way analysis of variance indicated a significant
difference among the diagnostic groups on depression scores, psychosocial
functioning, and levels of perceived stress. There was no significant difference
for menstrual phase or the interaction of menstrual phase by diagnostic group.
CONCLUSIONS: Mood symptom level, psychosocial functioning, perceived stress, and
physical discomfort were unrelated to menstrual phase in patients with BD.
Appropriate maintenance treatment may prevent menstrual related mood symptoms. Use
of an objective marker of ovulation is critical for research involving menstrual
related outcomes.

Smith, K. R., et al. (2014). "Psychiatric risk factor ANK3/ankyrin-G nanodomains

regulate the structure and function of glutamatergic synapses." Neuron 84(2): 399-
415.
Recent evidence implicates glutamatergic synapses as key pathogenic sites in
psychiatric disorders. Common and rare variants in the ANK3 gene, encoding ankyrin-
G, have been associated with bipolar disorder, schizophrenia, and autism. Here we
demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and
maintenance of spine morphology. Using superresolution microscopy we find that
ankyrin-G forms distinct nanodomain structures within the spine head and neck. At
these sites, it modulates mushroom spine structure and function, probably as a
perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes
ankyrin-G accumulation in distinct spine subdomains, where it differentially
regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic
nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having
location-specific functions and open directions for basic and translational
investigation of psychiatric risk molecules.

Soehner, A. M., et al. (2014). "Prevalence and clinical correlates of co-occurring

insomnia and hypersomnia symptoms in depression." J Affect Disord 167: 93-97.
BACKGROUND: The aim was to examine the prevalence and consequences of co-
occurring insomnia and hypersomnia symptoms in depressed adults drawn from a
representative sample of the U.S. population. METHOD: Data from 687 National
Comorbidity Survey Replication (NCS-R) respondents meeting criteria for a major
depressive episode (MDE) in the past year were included. Respondents completed
clinical interviews that assessed 12-month DSM-IV disorders, impairment, mental
health treatment, and depressive symptom severity. Outcomes were compared between
respondents who experienced insomnia symptoms-only (N=404), hypersomnia symptoms-
only (N=44), both insomnia and hypersomnia symptoms (N=184) and no sleep problems
(N=55) during an MDE. RESULTS: Insomnia and hypersomnia symptoms co-occurred in
27.7% of respondents with past-year MDEs, most frequently in bipolar spectrum
disorders and major depressive disorder with dysthymia. Similar to the insomnia-
only group, respondents with co-occurring sleep disturbances had more severe
depression, and higher rates of past-year impulse control disorders and suicide
planning. Similar to the hypersomnia-only group, respondents with co-occurring
sleep disturbances had higher rates of past-year drug use disorders and suicide
attempts. Compared to the insomnia-only and no sleep problem groups, respondents
with both sleep disturbances were more frequently in mental health treatment,
seeing a general practitioner, and taking antidepressants. LIMITATIONS: The NCS-R
is cross-sectional and did not evaluate sleep disorder diagnoses. CONCLUSIONS: Co-
occurring insomnia and hypersomnia symptoms were associated with a more severe MDE.
Further research is warranted to more fully understand the joint presentation of
insomnia and hypersomnia in depression.

Sogawa, R., et al. (2016). "Safety of Long-term Use of Lamotrigine for the
Treatment of Psychiatric Disorders." Clin Neuropharmacol 39(6): 295-298.
OBJECTIVES: Lamotrigine (LTG) is a drug commonly used to treat epilepsy and
can also be used to manage mood disorders, such as bipolar disorder. One of the
most dangerous adverse effects of LTG is skin rash, which can make early cessation
necessary. Here, we examine the adverse effects associated with long-term use of
LTG for the treatment of mood disorders. METHODS: Data were obtained from the
medical records of 101 psychiatric patients who were prescribed long-term treatment
with LTG. Patients were retrospectively divided into those who discontinued
treatment within 6 months and those who continued for longer, and the groups were
compared for adverse effects. We also compared the incidence of adverse effects in
high and low doses. RESULTS: Fifty-four patients continued LTG treatment for 6
months or longer; 47 discontinued within 6 months. A history of allergy was more
prevalent among the patients who discontinued treatment early than in those who
continued. Of the patients who continued treatment for 6 months or longer, only 2
later discontinued treatment because of adverse effects. Lamotrigine monotherapy
showed no difference in the incidence of adverse effects for different doses of LTG
(>200 mg = 4.8% vs >100 mg, </=200 mg = 7.7%; P = 1, vs >50 mg, </=100 mg = 0%; P =
1 vs </=50 mg = 0%; P = 1). CONCLUSIONS: Clinicians must be mindful of the adverse
effects occurring early during the titration phase. However, long-term use of LTG
was very well tolerated, even at high maintenance doses.

Song, H. R., et al. (2016). "Current prescription pattern of maintenance treatments

for bipolar patients in Korea: A focus on the transition from acute treatments."
Psychiatry Clin Neurosci 70(1): 42-50.
AIMS: We examined prescription patterns in maintenance treatment for
recovered bipolar patients and compared these with acute treatments. METHODS: Using
retrospective methods, the bipolar patients in clinical recovery (Clinical Global
Impression Bipolar Version score </= 2 for 6 months) after acute episode were
selected. We reviewed differences between prescription patterns at remission and
after a maintenance period of at least 6 months. RESULTS: A total of 340 bipolar
disorder patients were selected. During the maintenance period, more than half of
the patients (192, 56.5%) took a mood stabilizer (MS) + antipsychotic (AP)
combination. Among the MS, valproate (149, 43.8%) was most prescribed, and lithium
(98, 28.8%) was second, but as patients moved into maintenance treatment, lithium
use decreased, and the use of lamotrigine (86, 25.3%) increased. Preferred AP were
quetiapine (125, 36.8%), aripiprazole (67, 19.7%), risperidone (48, 14.1%), and
olanzapine (39, 11.5%). The use of olanzapine in maintenance was greatly decreased
compared with that during acute treatment (67, 19.7%). Most patients did not take
an antidepressant (AD), but the proportion using one or more AD was increased
during maintenance (17.9% to 30.3%), and bupropion (28, 8.2%) was the preferred AD.
Doses were decreased in all drugs, but lamotrigine was maintained at a dose of
133.2 +/- 68.5 mg/day. CONCLUSIONS: The most common prescription combination for
bipolar maintenance treatment was MS + AP. The use of AP was decreased, whereas the
use of AD in combination with MS and/or AP was increased. The doses of MS and AP
were generally decreased during the maintenance periods, with the exception of
lamotrigine.

Soreca, I. (2014). "Circadian rhythms and sleep in bipolar disorder: implications

for pathophysiology and treatment." Curr Opin Psychiatry 27(6): 467-471.
PURPOSE OF REVIEW: Multiple lines of evidence support the conceptualization
of bipolar disorder as a disorder of circadian rhythms. Considering bipolar
disorder in the framework of circadian disturbances also helps understand the
clinical phenomenology pointing toward a multisystemic involvement. RECENT
FINDINGS: Patients with bipolar disorder show altered rhythmicity in body
temperature and melatonin rhythms, high day-to-day variability in activity and
sleep timing, persistent disturbances of sleep or wake cycles, including
disturbances of sleep continuity. The internal clocks are, indeed, responsible for
regulating a variety of physiologic functions, including appetitive behaviors,
cognitive functions and metabolism. SUMMARY: An underlying circadian pathology in
bipolar disorder is a unifying explicatory model for the high psychiatric and
medical comorbidity observed during the long-term course of the disorder. This
model also provides a rationale for therapeutic interventions aimed at re-
entraining the internal clock.

Soreca, I., et al. (2016). "The association between meal timing and frequency with
cardiometabolic profile in patients with bipolar disorder." Acta Psychiatr Scand
133(6): 453-458.
OBJECTIVE: The goal of this study was to explore the association of timing of
and frequency of meals with markers of cardiometabolic risk in patients with
bipolar disorder in out-patient maintenance treatment. METHODS: We used Pittsburgh
Sleep Diary and actigraphy measures for individuals with bipolar I disorder. Linear
and logistic regression analyses were used to determine whether dinnertime,
instability of dinnertime, and/or interval between meals were associated with
metabolic syndrome and its components. RESULTS: Later dinnertime was associated
with greater waist circumference (beta = 0.25, P = 0.02) after adjusting for age,
sex, dinner-to-bed interval, and sleep duration. Longer breakfast-to-lunch
intervals were also associated with greater waist circumferences (beta =-.35, P = .
002) after adjusting for age, sex, and sleep duration. Neither instability of
dinnertime nor number of meals per day was associated with the metabolic syndrome
or its components. CONCLUSION: Weight gain is often perceived as inevitable side-
effect of medications. While patients often need to be on medication to function, a
more careful lifestyle assessment with attention to social rhythms and timing of
activities may be critical not only for mood stability, but also to reduce
cardiovascular risk.

Soriano-Barcelo, J., et al. (2015). "A case with reversible neurotoxicity after 2
years of dementia secondary to maintenance lithium treatment." J Psychiatr Pract
21(2): 154-159.
Chronic neurotoxicity caused by lithium salts can be reversible or
irreversible and may appear after years of treatment, even at serum levels
considered within the usual therapeutic range. The authors present the case of a
patient with bipolar disorder who developed dementia at the age of 54 after being
treated with lithium carbonate at therapeutic levels for 4 years. Nevertheless,
lithium treatment was continued. At age 56, the patient presented with an acute
encephalopathy caused by toxic lithium levels, which resolved only after lithium
carbonate was discontinued. Full recovery from the dementia, which had started 2
years earlier, occurred only after cessation of lithium. The authors conclude that
when patients treated with lithium develop subacute cognitive impairment, the
possibility of lithium toxicity should be considered, even if the serum levels are
considered within the therapeutic range. A long duration of neurotoxicity
associated with lithium treatment does not necessarily indicate an irreversible
prognosis.

Squassina, A., et al. (2010). "Pharmacogenomics of mood stabilizers in the

treatment of bipolar disorder." Hum Genomics Proteomics 2010: 159761.
Bipolar disorder (BD) is a chronic and often severe psychiatric illness
characterized by manic and depressive episodes. Among the most effective
treatments, mood stabilizers represent the keystone in acute mania, depression, and
maintenance treatment of BD. However, treatment response is a highly heterogeneous
trait, thus emphasizing the need for a structured informational framework of
phenotypic and genetic predictors. In this paper, we present the current state of
pharmacogenomic research on long-term treatment in BD, specifically focusing on
mood stabilizers. While the results provided so far support the key role of genetic
factors in modulating the response phenotype, strong evidence for genetic
predictors is still lacking. In order to facilitate implementation of
pharmacogenomics into clinical settings (i.e., the creation of personalized
therapy), further research efforts are needed.

Srivastava, S., et al. (2012). "Pilot study of the efficacy of double-blind,

placebo-controlled one-week olanzapine stabilization therapy in heterogeneous
symptomatic bipolar disorder patients." J Psychiatr Res 46(7): 920-926.
BACKGROUND: Olanzapine has demonstrated efficacy in acute mania and bipolar I
disorder (BDI) maintenance, but efficacy in brief therapy in more diverse
populations, including patients with bipolar II disorder (BDII)/bipolar disorder
not otherwise specified (BDNOS) with syndromal/subsyndromal depressive/mood
elevation symptoms and taking/not taking concurrent medications remains to be
established. METHODS: Fifty adult outpatients (24 BD1, 22 BDII, 4 BDNOS, mean +/-
SD age 40.8 +/- 11.5 years, 28.1% female, already taking 1.1 +/- 1.2 [median 1]
prescription psychotropics) with 17-item Hamilton Depression Rating Scale (HDRS)
>/=10 and/or Young Mania Rating Scale (YMRS) >/=10 and </=24, were randomized to
double-blind olanzapine (2.5-20 mg/day) versus placebo for one week. RESULTS: Among
45 patients with post-baseline ratings, olanzapine (9.0 +/- 5.8 mg/day, n = 23)
compared to placebo (n = 22) tended to yield greater Clinical Global Impressions-
Bipolar Version-Overall Severity of Illness (-1.4 +/- 0.9 versus -0.8 +/- 1.1, p =
0.08) and Hamilton Anxiety Scale (-7.9 +/- 6.3 versus -3.8 +/- 6.1, p = 0.07)
improvements, and YMRS/HDRS remission rate (47.8% versus 22.7%, p = 0.08), but
significantly increased median weight (+2 versus -1 lbs, p = 0.001), and rates of
excessive appetite (54.2% versus 22.7%, p = 0.04) and tremor (50.0% versus 9.1% p =
0.004). Number Needed to Treat and 95% Confidence Interval for YMRS/HDRS remission
were 4 (1-infinity). Numbers Needed to Harm for excessive appetite and tremor were
4 (1-21) and 3 (1-6), respectively. CONCLUSIONS: Olanzapine tended to yield
affective improvement and significantly increased weight, appetite, and tremor.
Larger controlled studies appear feasible and warranted to assess brief olanzapine
therapy in heterogeneous symptomatic bipolar disorder patients.

St-Amand, J., et al. (2013). "Sleep disturbances in bipolar disorder during

remission." J Affect Disord 146(1): 112-119.
BACKGROUND: While sleep disturbances associated with bipolar disorder's
depression and mania phases are well documented, the literature regarding sleep
during remission phases is less consistent. The present study's aim was to describe
the nature and severity of sleep difficulties in individuals with bipolar disorder
(BD) during remission phases. METHODS: Fourteen participants with BD were compared
to 13 participants with primary insomnia and 13 without mental health disorders or
insomnia on different sleep and daytime functioning parameters using actigraphy,
sleep diaries and self-report measures. RESULTS: Results suggest that sleep of
individuals with BD was similar to that of individuals without mental health
disorders or insomnia, but differed from that of individuals with insomnia.
Nevertheless, participants with BD still presented sleep complaints and, like
individuals with insomnia, were less active in the daytime, carried on their daily
activities at more variable times from day to day, and reported more daytime
sleepiness. LIMITATIONS: Patients were taking medications and the limited sample
size did not permit comparison of sleep parameters between bipolar I and bipolar II
patients. CONCLUSIONS: Psychological interventions aimed at encouraging the
adoption of more stable sleep and daily routines might be helpful in helping
individuals with BD cope more efficiently with some of these complaints.

Staufenbiel, S. M., et al. (2013). "Hair cortisol, stress exposure, and mental
health in humans: a systematic review." Psychoneuroendocrinology 38(8): 1220-1235.
The deleterious effects of chronic stress on health and its contribution to
the development of mental illness attract broad attention worldwide. An important
development in the last few years has been the employment of hair cortisol analysis
with its unique possibility to assess the long-term systematic levels of cortisol
retrospectively. This review makes a first attempt to systematically synthesize the
body of published research on hair cortisol, chronic stress, and mental health. The
results of hair cortisol studies are contrasted and integrated with literature on
acutely circulating cortisol as measured in bodily fluids, thereby combining
cortisol baseline concentration and cortisol reactivity in an attempt to understand
the cortisol dynamics in the development and/or maintenance of mental illnesses.
The studies on hair cortisol and chronic stress show increased hair cortisol levels
in a wide range of contexts/situations (e.g. endurance athletes, shift work,
unemployment, chronic pain, stress in neonates, major life events). With respect to
mental illnesses, the results differed between diagnoses. In major depression, the
hair cortisol concentrations appear to be increased, whereas for bipolar disorder,
cortisol concentrations were only increased in patients with a late age-of-onset.
In patients with anxiety (generalized anxiety disorder, panic disorder), hair
cortisol levels were reported to be decreased. The same holds true for patients
with posttraumatic stress disorder, in whom - after an initial increase in cortisol
release - the cortisol output decreases below baseline. The effect sizes are
calculated when descriptive statistics are provided, to enable preliminary
comparisons across the different laboratories. For exposure to chronic stressors,
the effect sizes on hair cortisol levels were medium to large, whereas for
psychopathology, the effect sizes were small to medium. This is a first implication
that the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in the
development and/or maintenance of psychopathology may be more subtle than it is in
healthy but chronically stressed populations. Future research possibilities
regarding the application of hair cortisol research in mental health and the need
for multidisciplinary approaches are discussed.

Steinan, M. K., et al. (2014). "Cognitive behavioral therapy for insomnia in

euthymic bipolar disorder: study protocol for a randomized controlled trial."
Trials 15: 24.
BACKGROUND: Patients with bipolar disorder experience sleep disturbance, even
in euthymic phases. Changes in sleep pattern are frequent signs of a new episode of
(hypo)mania or depression. Cognitive behavioral therapy for insomnia (CBT-I) is an
effective treatment for primary insomnia, but there are no published results on the
effects of CBT-I in patients with bipolar disorder. In this randomized controlled
trial, we wish to compare CBT-I and treatment as usual with treatment as usual
alone to determine its effect in improving quality of sleep, stabilizing minor mood
variations and preventing new mood episodes in euthymic patients with bipolar
disorder and comorbid insomnia. METHODS: Patients with euthymic bipolar I or II
disorder and insomnia, as verified by the Structured Clinical Interview for DSM
Disorders (SCID-1) assessment, will be included. The patients enter a three-week
run-in phase in which they complete a sleep diary and a mood diary, are monitored
for seven consecutive days with an actigraph and on two of these nights with
polysomnography in addition before randomization to an eight-week treatment trial.
Treatment as usual consists of pharmacological and supportive psychosocial
treatment. In this trial, CBT-I will consist of sleep restriction, psychoeducation
about sleep, stabilization of the circadian rhythm, and challenging and correcting
sleep state misperception, in three to eight sessions. DISCUSSION: This trial could
document a new treatment for insomnia in bipolar disorder with possible effects on
sleep and on stability of mood. In addition, more precise information can be
obtained about the character of sleep disturbance in bipolar disorder. TRIAL
REGISTRATION: ClinicalTrials.gov: NCT01704352.

Steinan, M. K., et al. (2016). "Delayed sleep phase: An important circadian subtype
of sleep disturbance in bipolar disorders." J Affect Disord 191: 156-163.
BACKGROUND: Theoretical models of Bipolar Disorder (BD) highlight that sleep
disturbances may be a marker of underlying circadian dysregulation. However, few
studies of sleep in BD have reported on the most prevalent circadian sleep
abnormality, namely Delayed Sleep Phase (DSP). METHODS: A cross-sectional study of
404 adults with BD who met published clinical criteria for insomnia, hypersomnia or
DSP, and who had previously participated in a study of sleep in BD using a
comprehensive structured interview assessment. RESULTS: About 10% of BD cases with
a sleep problem met criteria for a DSP profile. The DSP group was younger and had a
higher mean Body Mass Index (BMI) than the other groups. Also, DSP cases were
significantly more likely to be prescribed mood stabilizers and antidepressant than
insomnia cases. An exploratory analysis of selected symptom item ratings indicated
that DSP was significantly more likely to be associated with impaired energy and
activity levels. LIMITATIONS: The cross-sectional design precludes examination of
longitudinal changes. DSP is identified by sleep profile, not by diagnostic
criteria or objective sleep records such as actigraphy. The study uses data from a
previous study to identify and examine the DSP group. CONCLUSIONS: The DSP group
identified in this study can be differentiated from hypersomnia and insomnia groups
on the basis of clinical and demographic features. The association of DSP with
younger age, higher BMI and impaired energy and activity also suggest that this
clinical profile may be a good proxy for underlying circadian dysregulation.

Steinan, M. K., et al. (2016). "Sleep problems in bipolar disorders: more than just
insomnia." Acta Psychiatr Scand 133(5): 368-377.
OBJECTIVE: Sleep problems in bipolar disorder (BD) are common, but reported
rates vary from 10% to 80%, depending on definitions, methodologies and management
of potential confounding factors. This multicenter study seeks to address these
issues and also compares BD cases with Hypersomnia as well as the more commonly
investigated Insomnia and No Sleep Problem groups. METHOD: A cross-sectional
comparison of sleep profiles in 563 BD I and II individuals who participated in a
structured assessment of demographic, clinical, illness history and treatment
variables. RESULTS: Over 40% cases met criteria for Insomnia and 29% for
Hypersomnia. In univariate analysis, Insomnia was associated with BD II depression
whilst Hypersomnia was associated with BD I depression or euthymia. After
controlling for confounders and covariates, it was demonstrated that Hypersomnia
cases were significantly more likely to be younger, have BD I and be prescribed
antidepressants whilst Insomnia cases had longer illness durations and were more
likely to be prescribed benzodiazepines and hypnotics. CONCLUSION: Whilst Insomnia
symptoms are common in BD, Hypersomnia is a significant, frequently underexplored
problem. Detailed analyses of large representative clinical samples are critical to
extending our knowledge of differences between subgroups defined by sleep profile.

Strejilevich, S., et al. (2010). "[2nd Argentine consensus on the treatment of

bipolar disorders 2010]." Vertex 21 Suppl II Consenso: 3-55.
The consensus guidelines of Argentine experts in the treatment of bipolar
disorders are the result of three days of work of the 9 main local experts under
the organization of the Argentine Association of Mood Disorders (ASATHU). This work
is an update of the guidelines published on this journal in 2006. It was adopted a
mixed criterion for its preparation: all the recent data of the evidence medicine
based published until now were discussed and were balanced with the knowledge
acquired from clinical experience of the local experts on the bipolar field. It
presents general recommendations and suggested therapeutic sequences for
maintenance, manic/hypomanic or mixed episode and depressive episode treatments.
Bipolar disorders have been divided according to the international classifications
in type I and II; with or without rapid cycling. This work also includes a series
of recommendations for early and differential diagnosis of bipolar disorders.
Styczen, K., et al. (2015). "[The place of quetiapine extended release in the
treatment of mental disorders]." Psychiatr Pol 49(1): 67-80.
This article presents a summary of available data on the use of quetiapine
extended release (QUE-XR). QUE-XR is an example of an atypical antipsychotic drug
that can be used in a single dose, thereby simplifying the treatment regimen. From
the therapeutic standpoint, this issue is of paramount importance, since
approximately 50% of patients have adherence issues. Therefore, availability of the
drug which is comfortable in administration can significantly improve treatment
outcomes. Due to its antipsychotic, antidepressive, mood stabilizing and anxiolytic
efficacy, QUE-XR seems to be a promising drug with potentially broad spectrum of
indications (in patients with schizophrenia, bipolar disorder, major depression and
some anxiety disorders - both in the acute phase of treatment, and the maintenance
treatment). Notably, QUE-XR seems to ameliorate sleep disturbances, and it may also
improve patients' quality of life (as suggested by some studies). Due to the simple
dosing regimen of QUE-XR, conducting therapy with this drug may contribute to the
improvement of compliance. Yet, the primary clinical criterion for selection of the
type of formulation of quetiapine should be the individual preferences of the
patient, and the knowledge and experience of the treating physician.

Suganthi, M., et al. (2012). "In vitro mechanisms involved in the regulation of
cell survival by lithium chloride and IGF-1 in human hormone-dependent breast
cancer cells (MCF-7)." Toxicol Lett 214(2): 182-191.
Lithium, the lightest of all solid elements, has been used for the treatment
of bipolar disorder since 1970s and prescribed to millions of women worldwide.
Lithium chloride (LiCl) has been considered to be a potent inhibitor of glycogen
synthase kinase-3beta (GSK-3beta), a serine/threonine kinase that is involved in
the control of cell proliferation, differentiation, and apoptosis. In addition,
GSK-3beta has been found to be inhibited endogenously by insulin-like growth
factor-1 (IGF-1), a potent mitogen that plays an important role in the survival,
growth, and differentiation of normal and neoplastic cells. Although both IGF-1 and
LiCl have the ability to inhibit GSK-3beta, the specific signaling difference that
mediates the survival of breast cancer cells was not clear. Therefore, in the
present study, MCF-7 cells (human breast cancer cells) were treated with or without
IGF-1 or LiCl in the presence or absence of LY294002 or PD98059 (pharmacological
inhibitors) for 24h. As the expression of signaling proteins is crucial in the
maintenance of cell survival and apoptosis, we analyzed the cells using
immunoblotting procedure. In summary, our results have shown that LiCl and IGF-1
mediates cell survival by inhibiting GSK-3beta but differ in their mechanisms. IGF-
1 involves PI3K/Akt or MAPK pathways whereas LiCl is completely independent of
these pathways. IGF-1 upregulates anti-apoptotic proteins whereas LiCl
downregulates apoptotic proteins in order to maintain cell survival.

Suppes, T., et al. (2013). "Maintenance treatment with quetiapine when combined
with either lithium or divalproex in bipolar I disorder: analysis of two large
randomized, placebo-controlled trials." Depress Anxiety 30(11): 1089-1098.
BACKGROUND: To determine the efficacy and safety of quetiapine combined with
lithium or divalproex for preventing mood events in patients with bipolar I
disorder. In this pooled analysis of two similar long-term studies (D1447C00126
[NCT00107731] and D1447C00127 [NCT00081380]), lithium and divalproex treatment
groups were analyzed separately. METHODS: Patients received open-label quetiapine
(400-800 mg/d) plus lithium or divalproex to achieve >/=12 weeks of clinical
stability before being randomized to double-blind combination treatment with
quetiapine (400-800 mg/d) or placebo plus lithium or divalproex for up to 104
weeks. The primary endpoint was time to first mood event postrandomization
following open stabilization. RESULTS: Of 3,414 patients in the stabilization
phase, 1,326 were randomized. There were no differences in the risk of recurrence
of mood, mania, or depression between quetiapine plus lithium or quetiapine plus
divalproex. Among patients co-treated with placebo and lithium, the risk of
recurrence of a mania event was significantly higher than among patients co-treated
with placebo and divalproex. In patients with an index episode of mania, placebo
plus lithium was associated with a significantly higher risk of recurrence of a
mania event than placebo plus divalproex. Safety data were generally consistent
with recognized safety profiles. CONCLUSIONS: In patients with bipolar I disorder
previously stabilized on quetiapine and lithium or divalproex, maintenance therapy
with quetiapine significantly increased the time to recurrence of a mood event
(mania or depression) versus placebo, regardless of whether it was combined with
lithium or divalproex.

Swann, A. C. (2010). "Approaches to preventing relapse in bipolar disorder:

addressing nonadherence and prodromal symptoms." J Clin Psychiatry 71(12): e35.
The goals of maintenance treatment for euthymic patients with bipolar
disorder are to prevent recurrence of acute episodes and to optimize the patient's
adaptive functioning. Although medications are the primary treatment for preventing
relapse, patient outcomes can be enhanced through the use of psychosocial
interventions that address barriers to treatment success such as nonadherence to
medication and lack of patient or caregiver understanding of the illness. Patients
can learn to take an active and responsible role in managing their illness,
including monitoring their symptoms to recognize prodromal signs of relapse,
protecting daily social rhythms and routines, and maintaining healthy activities.

Sylvia, L. G., et al. (2012). "Sleep disturbance in euthymic bipolar patients." J

Psychopharmacol 26(8): 1108-1112.
Sleep disturbance is a common feature during mood episodes in bipolar
disorder. The aim of this study was to investigate the prevalence of such symptoms
among euthymic bipolar patients, and their association with risk for mood episode
recurrence. A cohort of bipolar I and II subjects participating in the Systematic
Treatment Enhancement Program for Bipolar Disorder who were euthymic for at least 8
weeks were included in this analysis. Survival analysis was used to examine the
association between sleep disturbance on the Montgomery-Asberg Depression Rating
Scale (MADRS) and recurrence risk. A total of 73/483 bipolar I and II subjects
reported at least mild sleep disturbance (MADRS sleep item >/=2) for the week prior
to study entry. The presence of sleep problems was associated with a history of
psychosis, number of previous suicide attempts, and anticonvulsant use. Sleep
disturbance at study entry was significantly associated with risk for mood episode
recurrence. Sleep disturbance is not uncommon between episodes for individuals with
bipolar disorder and may be associated with a more severe course of illness. This
suggests that sleep disturbance is an important prodromal symptom of bipolar
disorder and should be considered a target for pharmacologic or psychosocial
maintenance treatment.

Takeshima, M. (2016). "Treating mixed mania/hypomania: a review and synthesis of

the evidence." CNS Spectr: 1-9.
The DSM-5 incorporates a broad concept of mixed states and captured >/=3
nonoverlapping symptoms of the opposite polarity using a "with mixed features"
specifier to be applied to manic/hypomanic and major depressive episodes.
Pharmacotherapy of mixed states is challenging because of the necessity to treat
both manic/hypomanic and depressive symptoms concurrently. High-potency
antipsychotics used to treat manic symptoms and antidepressants can potentially
deteriorate symptoms of the opposite polarity. This review aimed to provide a
synthesis of the current evidence for pharmacotherapy of mixed states with an
emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized
controlled trials (RCTs) that were at least moderately sized, included a placebo
arm, and contained information on acute-phase and maintenance treatments of adult
patients with mixed episodes or mania/hypomania with significant depressive
symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from
RCTs for acute manic and mixed episodes of bipolar I disorder; only two
prospectively examined efficacy for mixed mania/hypomania specifically.
Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the
strongest evidence of efficacy in acute-phase treatment. Quetiapine and
divalproex/valproate were also efficacious. Combination therapies with these
atypical antipsychotics and mood stabilizers can be considered in severe cases.
Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed
the strongest evidence of efficacy in maintenance treatment. Lithium and
lamotrigine may be beneficial given their preventive effects on suicide and
depressive relapse. Further prospective studies primarily focusing on mixed states
are needed.

Talbot, L. S., et al. (2012). "A test of the bidirectional association between
sleep and mood in bipolar disorder and insomnia." J Abnorm Psychol 121(1): 39-50.
The present study investigates sleep, mood, and the proposed bidirectional
relationship between the two in psychiatric disorders. Participants with
interepisode bipolar disorder (n = 49), insomnia (n = 34), and no psychiatric
history (n = 52) completed seven consecutive days of sleep diaries and mood
measures. The interepisode bipolar and insomnia participants exhibited greater
sleep disturbance than the healthy control individuals. Negative mood was equally
heightened in both interepisode bipolar disorder and insomnia, and there were no
differences between the three groups in positive mood. Total wake time was
associated with next morning negative mood in bipolar disorder, whereas evening
negative mood was associated with subsequent total wake time in both bipolar
disorder and insomnia. Additionally, positive mood was associated with subsequent
total wake time for the insomnia group. Results support the theory that disruptions
in nighttime sleep and daytime mood may be mutually maintaining and suggest the
potential importance of transdiagnostic or universal processes.

Tang, C. H., et al. (2010). "One-year post-hospital medical costs and relapse rates
of bipolar disorder patients in Taiwan: a population-based study." Bipolar Disord
12(8): 859-865.
OBJECTIVES: We examined a nationwide population-based dataset of patients
with bipolar disorder (BD) hospitalized in Taiwan, with our analyses focusing on
one-year medical costs and relapse rates. METHODS: The data for this study,
covering the years 2006 and 2007, were obtained from the Taiwan National Health
Insurance (NHI) claims database. The study sample comprised BD patients who were
discharged from hospitals between January 1 and December 31, 2006. Annual medical
costs and relapse rates were described; the Kaplan-Meier method and the generalized
linear models were carried out to examine the risk factors associated with cases of
relapse. RESULTS: The annual medical costs associated with relapses among the study
sample were found to be approximately 7.6 times the average per-capita NHI
expenditure in Taiwan in 2006 (US$4,354 versus US$574), with a one-year relapse
rate of 55%. Those patients between 20 and 60 years old with a medication
possession ratio of <80 and with depressive episodes during the recruitment period
were identified as being at risk of relapse. CONCLUSION: Bipolar disorder, which is
a very costly disease, is associated with both poor medication adherence rates and
frequent recurrences. Targeting drug adherence issues during maintenance treatment
may well provide a valuable opportunity to reduce the risk of such recurrences.

Tarazi, F. I. and J. C. Neill (2013). "The preclinical profile of asenapine:

clinical relevance for the treatment of schizophrenia and bipolar mania." Expert
Opin Drug Discov 8(1): 93-103.
INTRODUCTION: Asenapine is a novel antipsychotic drug approved for the
treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar
I disorder, as a maintenance treatment of schizophrenia and as an adjunctive
therapy with lithium or valproate for the acute treatment of manic or mixed
episodes associated with bipolar I disorder in adults. AREAS COVERED: This review
focuses on the preclinical profile of asenapine. It analyzes the pharmacological,
neurochemical, behavioral, and molecular mechanisms of asenapine and their
contribution to the beneficial therapeutic advantages of the drug as reported in
published preclinical and clinical studies, product labels, and poster
presentations. EXPERT OPINION: Asenapine exhibits a broad pharmacological profile
that targets a wide range of neurotransmitter receptors with variable affinities.
The drug preferentially increases dopamine, norepinephrine, and acetylcholine
levels in cortical and limbic brain areas. It also potentiates cortical
glutamatergic neurotransmission, and is active in behavioral animal models
predictive of antipsychotic, antidepressant, and pro-cognitive activities. Chronic
administration of asenapine alters the abundance of dopamine, serotonin, glutamate,
adrenergic, and cholinergic receptor subtypes in different brain regions. These
action mechanisms of asenapine might contribute to its unique psychopharmacological
properties in the improved treatment of schizophrenia and other psychotic
disorders.

Tarazi, F. I. and S. M. Stahl (2012). "Iloperidone, asenapine and lurasidone: a

primer on their current status." Expert Opin Pharmacother 13(13): 1911-1922.
INTRODUCTION: Three newer atypical antipsychotic drugs were FDA-approved in
2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The
three drugs are indicated for the treatment of acute schizophrenia. Asenapine is
also approved for treatment of manic or mixed episodes associated with bipolar I
disorder, for the maintenance treatment of schizophrenia and as an adjunctive
therapy with lithium or valproate for the acute treatment of manic or mixed
episodes associated with bipolar I disorder in adults. AREAS COVERED: This review
compares and contrasts the current preclinical, clinical, safety and tolerability
profiles of the three newer drugs, as reported in published preclinical and
clinical studies, product labels, poster presentations and press releases. EXPERT
OPINION: Preclinical studies have reported that the three drugs have variable
affinities for a wide range of neurotransmitter receptors, and are active in animal
models predictive of antipsychotic activity. Asenapine is the first antipsychotic
to be administered sublingually, whereas iloperidone requires titration to minimize
orthostatic hypotension. Asenapine and lurasidone are associated with dose-related
akathisia, whereas iloperidone is not. The three drugs appear to have relatively
benign metabolic profiles. The availability of the three novel antipsychotics
should provide additional options for improved treatment of schizophrenia and other
psychotic disorders.

Teh, A. W., et al. (2012). "Electroanatomic remodeling of the left atrium in

paroxysmal and persistent atrial fibrillation patients without structural heart
disease." J Cardiovasc Electrophysiol 23(3): 232-238.
INTRODUCTION: The nature of the atrial substrate thought to contribute toward
maintaining atrial fibrillation (AF) outside the pulmonary veins remains poorly
defined. Therefore, our objective was to determine whether patients with paroxysmal
and persistent AF have an abnormal electroanatomic substrate within the left atrium
(LA). METHODS AND RESULTS: Thirty-one patients with AF (17 paroxysmal AF and 14
persistent AF) were compared with 15 age-matched controls with left-sided
supraventricular tachycardia (SVT). High-density 3-dimensional electroanatomic maps
were created and the LA was divided into 8 segments for regional analysis. Bipolar
voltage, conduction, and effective refractory periods (ERPs) of the posterior LA,
left atrial appendage (LAA), and distal coronary sinus (CSd) and percentage complex
signals were assessed. In the majority of LA regions, compared with controls, AF
patients had: (1) lower mean voltage and a higher percentage low voltage; (2)
slower conduction; and (3) more prevalent complex signals. Many of these changes
were more marked in the persistent than the paroxysmal AF group. CONCLUSIONS:
Patients with AF have lower regional voltage, increased proportion of low voltage,
slowed conduction, and increased proportion of complex signals compared to
controls. Many of these changes are more pronounced in persistent AF patients,
suggesting there may be a progressive nature to the changes. Differences occurred
in the absence of structural heart disease. These substrate abnormalities provide
further insight into the progressive nature of atrial remodeling and the mechanisms
involved in maintenance of AF.
Terrillion, C. E., et al. (2017). "Reduced levels of Cacna1c attenuate mesolimbic
dopamine system function." Genes Brain Behav.
Genetic variation in CACNA1C, which codes for the L-type calcium channel
(LTCC) Cav 1.2, is associated with clinical diagnoses of bipolar disorder,
depression, and schizophrenia. Dysregulation of the mesolimbic dopamine (DA) system
is linked to these syndromes and LTCCs are required for normal DAergic
neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens
(NAc). It is unclear, however, how variations in CACNA1C genotype, and potential
subsequent changes in expression levels in these regions, modify risk. Using
constitutive and conditional knockout mice, and treatment with the LTCC antagonist
nimodipine, we examined the role of Cacna1c in DA-mediated behaviors elicited by
psychomotor stimulants. Using fast-scan cyclic voltammetry (FSCV), DA release and
reuptake in the NAc were measured. We find that subsecond DA release in Cacna1c
haploinsufficient mice lacks normal sensitivity to inhibition of the DA transporter
(DAT). Constitutive haploinsufficiency of Cacna1c led to attenuation of
hyperlocomotion following acute administration of stimulants specific to DAT, and
locomotor sensitization of these mice to the DAT antagonist GBR12909 did not reach
the same level as wild type mice. The maintenance of sensitization to GBR12909 was
attenuated by administration of nimodipine. Sensitization to GBR12909 was
attenuated in mice with reduced Cacna1c selectively in the VTA but not in the NAc.
Our findings reveal that Cacna1c is crucial for normal behavioral responses to DA
stimulants and that its activity in the VTA is required for behavioral
sensitization. Cacna1c likely exerts these effects through modifications to
presynaptic mesolimbic DA system function.

Thase, M. E. (2012). "Bipolar disorder maintenance treatment: monitoring

effectiveness and safety." J Clin Psychiatry 73(4): e15.
Bipolar disorder is a chronic illness that requires long-term treatment, the
goal of which is to shorten or prevent mood episodes without increasing cycle
frequency, thereby increasing the length of well periods. Treatment guidelines
recommend mood stabilizers as first-line medications, and several atypical
antipsychotics are also approved as monotherapy or as adjuncts to mood stabilizers
for maintenance treatment. Combination therapy with 2 mood stabilizers or with a
mood stabilizer and an antipsychotic may be necessary to achieve or maintain
remission of the patient's symptoms. When treating patients with mood stabilizers
and atypical antipsychotics during the maintenance phase, physicians should
systematically monitor for adverse effects, particularly weight gain, and
tolerability issues, and address those issues in a timely manner in order to
enhance treatment adherence and improve patient outcomes.

Thirthalli, J., et al. (2012). "Electroconvulsive therapy (ECT) in bipolar

disorder: A narrative review of literature." Asian J Psychiatr 5(1): 11-17.
In many countries including India electroconvulsive therapy (ECT) is
frequently used to treat different phases of bipolar disorder. The response to ECT
is impressive in mania, depression and in mixed affective states. Preliminary
evidence also suggests benefit from maintenance ECT in bipolar disorder. However,
most of the literature on efficacy and adverse effects comes from case series,
retrospective reports and open trials - controlled trials have been few and far
between. Official guidelines recommend the use of ECT only when there is a dire
emergency or when all other options have been exhausted. Concurrent use of lithium
and antiepileptic drugs along with ECT is common in clinical practice. While such
practice appears to be largely safe, one should be mindful about dose of lithium
and possible interference of antiepileptic drugs with efficacy of ECT. The use of
suprathreshold bilateral ECT and bifrontal placement of electrodes may confer some
advantage over other methods.

Tidey, J. W. and M. E. Miller (2015). "Smoking cessation and reduction in people

with chronic mental illness." BMJ 351: h4065.
 The high prevalence of cigarette smoking and tobacco related morbidity and
mortality in people with chronic mental illness is well documented. This review
summarizes results from studies of smoking cessation treatments in people with
schizophrenia, depression, anxiety disorders, and post-traumatic stress disorder.
It also summarizes experimental studies aimed at identifying biopsychosocial
mechanisms that underlie the high smoking rates seen in people with these
disorders. Research indicates that smokers with chronic mental illness can quit
with standard cessation approaches with minimal effects on psychiatric symptoms.
Although some studies have noted high relapse rates, longer maintenance on
pharmacotherapy reduces rates of relapse without untoward effects on psychiatric
symptoms. Similar biopsychosocial mechanisms are thought to be involved in the
initiation and persistence of smoking in patients with different disorders. An
appreciation of these common factors may aid the development of novel tobacco
treatments for people with chronic mental illness. Novel nicotine and tobacco
products such as electronic cigarettes and very low nicotine content cigarettes may
also be used to improve smoking cessation rates in people with chronic mental
illness.

Toffol, E., et al. (2015). "Lithium is associated with decrease in all-cause and
suicide mortality in high-risk bipolar patients: A nationwide registry-based
prospective cohort study." J Affect Disord 183: 159-165.
BACKGROUND: Mortality rates, in particular due to suicide, are especially
high in bipolar patients. This nationwide, registry-based study analyses the
associations of medication use with hospitalization due to attempted suicides,
deaths from suicide, and overall mortality across different psychotropic agents in
bipolar patients. METHOD: Altogether 826 bipolar patients hospitalized in Finland
between 1996-2003 because of a suicide attempt were followed-up for a mean of 3.5
years. The relative risk of suicide attempts leading to hospitalization, completed
suicide, and overall mortality during lithium vs. no-lithium, antipsychotic vs. no-
antipsychotic, valproic acid vs. no-valproic acid, antidepressant vs. no-
antidepressant and benzodiazepine vs. no-benzodiazepine treatment was measured.
RESULTS: The use of valproic acid (RR=1.53, 95% CI: 1.26-1.85, p<0.001),
antidepressants (RR=1.49, 95% CI: 1.23-1.8, p<0.001) and benzodiazepines (RR=1.49,
95% CI: 1.23-1.80, p<0.001) was associated with increased risk of attempted
suicide. Lithium was associated with a (non-significantly) lower risk of suicide
attempts, and with significantly decreased suicide mortality in univariate
(RR=0.39, 95% CI: 0.17-0.93, p=0.03), Cox (HR=0.37, 95% CI: 0.16-0.88, p=0.02) and
marginal structural models (HR=0.31, 95% CI: 0.12-0.79, p=0.02). Moreover, lithium
was related to decreased all-cause mortality by 49% (marginal structural models).
LIMITATIONS: Only high-risk bipolar patients hospitalized after a suicide attempt
were studied. Diagnosis was not based on standardized diagnostic interviews;
treatment regimens were uncontrolled. CONCLUSIONS: Maintenance therapy with
lithium, but not with other medications, is linked to decreased suicide and all-
cause mortality in high-risk bipolar patients. Lithium should be considered for
suicide prevention in high-risk bipolar patients.

Tohen, M., et al. (2016). "Analysis of bipolar maintenance treatment with lithium
versus olanzapine utilizing Multi-state Outcome Analysis of Treatments (MOAT)."
Bipolar Disord 18(3): 282-287.
OBJECTIVES: Survival analysis has superseded most other analytic techniques
for maintenance treatment studies over recent decades, despite providing results
based solely on a single time-point predefined event. The aim of the present study
was to develop the Multi-state Outcome Analysis of Treatments (MOAT), to provide
more pragmatic information for clinicians and investigators in guiding maintenance
treatment decisions. The present study was one of two published studies on the
development of MOAT procedures, involving a one-year comparison of olanzapine
versus lithium in recently manic patients. METHODS: MOAT partitions total survival
time into clinically distinct periods that are operationally defined by cut points
on established rating scales. For bipolar disorders, the clinical states are
remission, subsyndromal and syndromal mania, mixed states, and subsyndromal and
syndromal depression. RESULTS: MOAT re-analyses of the clinical trial revealed
clinically important findings not identified when utilizing Kaplan-Meier survival
analyses. Compared to patients treated with lithium, patients taking olanzapine
experienced significantly more time in subsyndromal depression. Patients taking
lithium spent significantly more time in mixed states than did patients taking
olanzapine. CONCLUSIONS: MOAT provided detailed information on treatment outcomes
that was not provided by Kaplan-Meier survival analysis. Its capability to identify
and aggregate time in different clinical states of bipolar disorder may aid in
identifying drug effects that are important in selecting and conducting maintenance
treatment.

Tohen, M., et al. (2012). "Variables as mediators or moderators in predicting

relapse to any type of mood episode in a bipolar maintenance study." J Clin
Psychiatry 73(7): e913-917.
OBJECTIVE: Post hoc mediator/moderator analyses were designed to identify
risk factors and their relationships in predicting relapse in olanzapine- or
lithium-treated bipolar patients with an index manic or mixed episode. The aim was
to identify moderators that precede and influence other variables to affect relapse
and mediators that explain how or why a second variable affects relapse. METHOD: We
examined DSM-IV-diagnosed bipolar I disorder patients who met symptomatic remission
criteria of an index manic or mixed (6.3%) episode after acute (6-12 weeks), open-
label, combined therapy with olanzapine (5-20 mg/d; mean dose = 13.5 mg/d) plus
lithium (300-1,800 mg/d; mean dose = 1,003.3 mg/d) followed by double-blind
randomization to lithium (n = 214) or olanzapine (n = 217) for up to 52 weeks. The
study started on August 5, 1999, and finished on June 14, 2002. Mediator/moderator
analyses with alpha cut at .05 were used to understand how variables work together
to impact rate of relapse. RESULTS: For lithium-treated patients, variables
identified for relapse were country of residence, smoking status, previous episode
history, and previous lithium use. For olanzapine-treated patients, risk factors
included smoking status, previous episode history, amount of time patients had a
21-Item Hamilton Depression Rating Scale (HDRS-21) score </= 8 at pre-
randomization, and HDRS-21 score at randomization. For lithium-treated patients, no
mediators/moderators were identified among relapse variables. For olanzapine-
treated patients, several baseline variables--such as previous number of mood
episodes (manic or depressive)--operate through severity of depressive symptoms
prior to remission (mediator) to affect relapse rate. On the other hand, the effect
of the patient's pre-remission depressive symptoms on outcome is moderated by the
polarity of the first episode, whether manic, depressive, or mixed. CONCLUSIONS:
Mediators and moderators may provide valuable information in the treatment planning
of patients with bipolar disorder and potentially influence treatment outcomes.

Trankner, A., et al. (2013). "A critical review of the recent literature and
selected therapy guidelines since 2006 on the use of lamotrigine in bipolar
disorder." Neuropsychiatr Dis Treat 9: 101-111.
The anticonvulsant drug lamotrigine (LTG), a sodium channel blocker and
inhibitor of glutamate release, has been found to have antidepressant effects in
the treatment of bipolar disorder. It is recommended by certain therapy guidelines
as a first-line agent for acute and maintenance therapy in bipolar depression, but
there have been only some promising results of placebo-controlled trials on its
acute antidepressant effects, and the recommendation in therapy guidelines has been
reconsidered. On the contrary, positive results for maintenance therapy could be
confirmed, and LTG is still a well-tolerated option, especially in patients with
predominant depressive episodes. Antimanic effects are not shown in the literature,
and its use is not advised in any guidelines that were examined. In conclusion, the
findings of the present review article on treatment guidelines for bipolar disorder
question the role of LTG in acute depressive states, and critically discusses its
use, particularly in acute depressive states.
Tsai, A. C., et al. (2011). "Aripiprazole in the maintenance treatment of bipolar
disorder: a critical review of the evidence and its dissemination into the
scientific literature." PLoS Med 8(5): e1000434.
BACKGROUND: Aripiprazole, a second-generation antipsychotic medication, has
been increasingly used in the maintenance treatment of bipolar disorder and
received approval from the U.S. Food and Drug Administration for this indication in
2005. Given its widespread use, we sought to critically review the evidence
supporting the use of aripiprazole in the maintenance treatment of bipolar disorder
and examine how that evidence has been disseminated in the scientific literature.
METHODS AND FINDINGS: We systematically searched multiple databases to identify
double-blind, randomized controlled trials of aripiprazole for the maintenance
treatment of bipolar disorder while excluding other types of studies, such as open-
label, acute, and adjunctive studies. We then used a citation search to identify
articles that cited these trials and rated the quality of their citations. Our
evidence search protocol identified only two publications, both describing the
results of a single trial conducted by Keck et al., which met criteria for
inclusion in this review. We describe four issues that limit the interpretation of
that trial as supporting the use of aripiprazole for bipolar maintenance: (1)
insufficient duration to demonstrate maintenance efficacy; (2) limited
generalizability due to its enriched sample; (3) possible conflation of iatrogenic
adverse effects of abrupt medication discontinuation with beneficial effects of
treatment; and (4) a low overall completion rate. Our citation search protocol
yielded 80 publications that cited the Keck et al. trial in discussing the use of
aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse
events reported and four (5%) mentioned study limitations. CONCLUSIONS: A single
trial by Keck et al. represents the entirety of the literature on the use of
aripiprazole for the maintenance treatment of bipolar disorder. Although careful
review identifies four critical limitations to the trial's interpretation and
overall utility, the trial has been uncritically cited in the subsequent scientific
literature. Please see later in the article for the Editors' Summary.

Uguz, F. (2016). "Prophylactic use of olanzapine and quetiapine from pregnancy to

the postpartum period in women with bipolar disorder: a case series." J Matern
Fetal Neonatal Med: 1-3.
The management of bipolar disorder in pregnant and postpartum women is one of
the most difficult issues in clinical practice. Data on the efficacy of mood
stabilizers, except lithium and antipsychotics, in the maintenance treatment of
bipolar disorders during pregnancy and postpartum period are very limited. This
report presents results of prophylaxis with olanzapine and quetiapine with regard
to affective episodes in pregnancy to the postpartum period.

Unholzer, S. and E. Haen (2015). "Retrospective analysis of therapeutic drug

monitoring data for treatment of bipolar disorder with lamotrigine."
Pharmacopsychiatry 48(6): 211-214.
INTRODUCTION: Lamotrigine is licensed for treatment of epilepsy and
prevention or at least delay of depressive episodes in bipolar disorder. The
accepted therapeutic reference range (TRR) of lamotrigine for anticonvulsant
treatment is 3 000-14 000 ng/ml. This TRR is often used for the therapy of bipolar
disorders as well. This work presents serious doubts about this approach. METHODS:
KONBEST, a large TDM database containing patients' characteristics including
diagnoses, doses, comedication and serum concentrations, was analyzed. Out of a
total of 3 459 lamotrigine samples, 360 patients suffered from bipolar disorder. 82
of them benefitted from therapy with lamotrigine as judged by the clinical global
impression of improvement (CGI-I) scale. Patients with a score of minimally (3),
much (2) or very much improved (1) were considered as responders. RESULTS: The
recommended lamotrigine maintenance dose for bipolar disorder is 200 mg/day; the
doses prescribed in our samples ranged from 25 to 450 mg/day. Only 32
concentrations (39.0%) fitted into the TRR recommended for therapy of epilepsy; 50
(61.0%) did not reach it, none exceeded it. The lowest concentration was 177 ng/ml,
the highest 11 871 ng/ml. A mean lamotrigine serum concentration of 3 341+/-2 563
ng/ml (x+/-SD) was detected in the patients who benefitted. DISCUSSION: The authors
conclude that in bipolar disorder lower lamotrigine serum concentrations lead to
therapeutic benefit.

Vai, B., et al. (2014). "Corticolimbic connectivity as a possible biomarker for

bipolar disorder." Expert Rev Neurother 14(6): 631-650.
Bipolar disorder is a severe, disabling and life-threatening illness, which
affects nearly 2% of the general population. The identification of reliable and
objective biomarkers may aid early diagnosis and optimize treatment efficacy.
Through a careful overview of the neuroimaging studies which investigated the
structural, functional, and effective connectivity in bipolar disorder, we explored
the role of a disconnected cortico-limbic circuitry in the development and
maintenance of the disorder. This review offers perspectives and suggestions for
future research, in order to propose the corticolimbic disconnection as a
neurobiological underpinning and biomarker for bipolar psychopathology.

van Lammeren, A., et al. (2011). "[Mania in late life: bipolar disorder as
diagnosis by exclusion]." Tijdschr Psychiatr 53(11): 813-823.
BACKGROUND: The underlying cause of mania in later life can be an early- or
late-onset bipolar disorder or it can be a mood disorder arising from a physical
illness, also known as 'a secondary mania'. Thorough diagnostic tests are needed to
differentiate between the two types of mania. AIM: To discuss the epidemiology,
presentation, diagnostic considerations and treatment options when a mania develops
in later life. METHOD: The literature was studied systematically with the help of
PubMed, the Cochrane Library, specialist manuals, Dutch guidelines and references.
RESULTS: So far, research into the incidence and prevalence of a mania in later
life has been very limited. In making a differential diagnosis of this kind of
mania the clinician has to consider not only the possibility of a bipolar disorder,
severe depression or psychosis but also the possibility of delirium, dementia or
secondary mania. According to some researchers, a mania can be caused by various
neurological, systemic and pharmacological factors. Patients should be given
somatic screening, including brain imaging. Lithium and antipsychotics are the
agents of choice for treating a mania occurring as part of a bipolar disorder as
well as for treating a secondary mania. CONCLUSION: Epidemiologic research into
late-onset mania is limited. In older patients it is important to identify -or rule
out- somatic causes (secondary mania, dementia, delirium). Symptomatic treatment is
more or less on the same lines as the treatment for mania in young adults. In cases
of secondary mania maintenance treatment is not always necessary, but must be
considered if risk factors for bipolar disorder are present.

van Melick, E. J., et al. (2013). "Age as a determinant of instability of serum

lithium concentrations." Ther Drug Monit 35(5): 643-648.
BACKGROUND: Lithium is used both in bipolar disorder and as augmentation in
treatment-resistant unipolar depression. Long-term treatment is often indicated.
Pharmacokinetic and pharmacodynamic changes in older age, as well as increasing
comorbidities and polypharmacy, could result in instability of serum lithium
concentrations. In this study, several parameters, considered proxy for
instability, were compared between age groups. These parameters were derived from
studies involving oral anticoagulants. METHODS: A retrospective study (1995-2004)
was conducted using serum lithium concentrations from the laboratories of 3
hospitals in the Netherlands; 759 patients treated with lithium, 40 years or older,
with at least 2 years' follow-up were identified. They were divided into 4 age
groups: 40-49, 50-59, 60-69, and 70+ years; the youngest group was used as a
reference group. The variance growth rate and percentage of time below, in, and
above treatment range are all proxies for instability. They were analyzed between
the age categories. RESULTS: There was no significant difference for these
variables between the reference group and the older age groups. In a subgroup of
454 patients, the parameters considered as proxy for instability during titration,
number of days and number of serum lithium concentration measurements during
titration, were evaluated; no significant difference was found between the age
groups. In a small group of 117 patients, titration and maintenance treatment for
at least 2 years could be analyzed separately. Also in this group, there was no
difference between the age groups. CONCLUSIONS: Age is not a determinant of serum
lithium concentration instability. Therefore, age is not a reason to not initiate
or discontinue lithium therapy.

Van Meter, A., et al. (2011). "Examining the validity of cyclothymic disorder in a
youth sample." J Affect Disord 132(1-2): 55-63.
BACKGROUND: Four subtypes of bipolar disorder (BP) - bipolar I, bipolar II,
cyclothymia and bipolar not otherwise specified (NOS) - are defined in DSM-IV-TR.
Though the diagnostic criteria for each subtype are intended for both adults and
children, research investigators and clinicians often stray from the DSM when
diagnosing pediatric bipolar disorder (PBD) (Youngstrom, 2009), resulting in a lack
of agreement and understanding regarding the PBD subtypes. METHODS: The present
study uses the diagnostic validation method first proposed by Robins and Guze
(1970) to systematically evaluate cyclothymic disorder as a distinct diagnostic
subtype of BP. Using a youth (ages 5-17) outpatient clinical sample (n=827),
participants with cyclothymic disorder (n=52) were compared to participants with
other BP spectrum disorders and to participants with non-bipolar disorders.
RESULTS: Results indicate that cyclothymic disorder shares many characteristics
with other bipolar subtypes, supporting its inclusion on the bipolar spectrum.
Additionally, cyclothymia could be reliably differentiated from non-mood disorders
based on irritability, sleep disturbance, age of symptom onset, comorbid diagnoses,
and family history. LIMITATIONS: There is little supporting research on cyclothymia
in young people; these analyses may be considered exploratory. Gaps in this and
other studies are highlighted as areas in need of additional research. CONCLUSIONS:
Cyclothymic disorder has serious implications for those affected. Though it is
rarely diagnosed currently, it can be reliably differentiated from other disorders
in young people. Failing to accurately diagnose cyclothymia, and other subthreshold
forms of bipolar disorder, contributes to a significant delay in appropriate
treatment and may have serious prognostic implications.

Vancampfort, D., et al. (2015). "Could autonomous motivation hold the key to
successfully implementing lifestyle changes in affective disorders? A multicentre
cross sectional study." Psychiatry Res 228(1): 100-106.
There is a need for theoretically-based research on the motivational
processes linked to the adoption and maintenance of an active lifestyle in people
with affective disorders. Within the Self-Determination Theory (SDT) framework, we
investigated the SDT tenets in people with major depressive disorder or bipolar
disorder by examining the factor structure of the Behavioural Regulation in
Exercise Questionnaire-2 (BREQ-2) and by investigating associations between
motivation, the Positive and Negative Affect Scale (PANAS) and International
Physical Activity Questionnaire (IPAQ) scores. A total of 165 patients (105 female
symbol) (45.6 +/- 14.2 years) agreed to participate. An exploratory factor analysis
demonstrated sufficient convergence with the original factor for amotivation, and
external and introjected regulation. The items of identified and intrinsic
regulation loaded on the same factor, which was labelled autonomous regulation.
Significant correlations were found between the total IPAQ score and the subscales
amotivation, external regulation, introjected regulation and autonomous regulation.
The relative autonomy index (RAI) was associated with the PANAS scores. Differences
in RAI were found between physically inactive and active participants. Our results
suggest that in people with affective disorders the level of autonomous motivation
may play an important role in the adoption and maintenance of health promoting
behaviours.

Vancampfort, D., et al. (2016). "Autonomous motivation is associated with the

maintenance stage of behaviour change in people with affective disorders."
Psychiatry Res 240: 267-271.
The present study examined whether in people with affective disorders motives
for adopting and maintaining physical activity recommendations (as formulated by
the self-determination theory) differed across the stages of behaviour change
(identified by the transtheoretical model). A total of 165 (105female symbol)
persons (45.6+/-14.2years) with affective disorders [major depressive disorder
(n=96) or bipolar disorder (n=69)] completed the Behavioural Regulation in Exercise
Questionnaire-2 and the Patient-centred Assessment and Counselling for Exercise
questionnaire. Discriminant and multivariate analyses demonstrated that persons
with affective disorders at the early stages of change have less autonomous and
more controlled physical activity motives than those at the later stages. Our
results suggest that autonomous motivation may have an important role to play in
the maintenance of health recommendations in persons with affective disorders.
Longitudinal and intervention studies should be designed in people with affective
disorders to identify the causal pathways between motives for maintaining health
recommendations, effective changes in health behaviour and physical and mental
health outcomes.

Vancampfort, D., et al. (2016). "Top 10 research questions to promote physical

activity in bipolar disorders: A consensus statement from the International
Organization of Physical Therapists in Mental Health." J Affect Disord 195: 82-87.
BACKGROUND: Research has only recently started to consider the importance and
applicability of physical activity (PA) for people with bipolar disorder (BD). The
aim of the current study is to highlight 10 pertinent PA research questions in
people with BD. METHODS: The International Organization of Physical Therapy in
Mental Health executed a consultation with all National organizations (n=13) to
identify the most salient questions to guide future research on PA in BD. RESULTS:
We identified the following 10 questions: (1) What are the benefits of PA for
people with BD? (2) What are the most prominent safety issues for PA prescription
in BD? (3) What is the optimal PA prescription for people with BD? (4) What are the
key barriers to PA among people with BD? (5) What are the most effective
motivational strategies for ensuring PA adoption and maintenance in BD? (6) How do
we translate PA research into community practice? (7) If one treatment goal is
increased physical activity, what type of professionals are needed as part of a
multidisciplinary team? (8) How do we incorporate PA as a vital sign in clinical
practice? (9) How can we prevent sedentary behavior in BD? (10) What is the most
appropriate PA assessment method? LIMITATIONS: We did not consult people with BD.
CONCLUSIONS: Addressing these questions is critical for developing evidence-based
approaches for promoting and sustaining an active lifestyle in BD. Ultimately,
achieving this will reduce the burden of cardiovascular disease and improve the
quality of life of this population.

Vancampfort, D., et al. (2015). "Adopting and maintaining physical activity

behaviours in people with severe mental illness: The importance of autonomous
motivation." Prev Med 81: 216-220.
OBJECTIVE: Physical activity can improve the health of people with serious
mental illness (SMI) but many are inactive. Adopting theoretically-based research
considering the motivational processes linked to the adoption and maintenance of an
active lifestyle between different diagnostic groups of people with SMI can assist
in understanding physical activity in this group. Within the Self-Determination
Theory (SDT) and the Trans-Theoretical Model (TTM) (stages of change) frameworks,
we investigated differences in motives for physical activity between different
diagnostic groups. METHODS: All participants completed the Behavioral Regulation in
Exercise Questionnaire 2 (BREQ-2), the International Physical Activity
Questionnaire (IPAQ) and the Patient-centered Assessment and Counseling for
Exercise (PACE) questionnaire. RESULTS: Overall 294 persons with SMI (190female
symbol) (43.6 +/- 13.6 years) agreed to participate. People with affective
disorders had higher levels of introjected regulations than people with
schizophrenia. No significant differences were found for other motivational
regulations. Moreover, no significant differences were found according to gender,
setting and educational level. Multivariate analyses showed significantly higher
levels of amotivation and external regulations and lower levels of identified and
intrinsic regulations in the earlier stages of change. Strongest correlations with
the IPAQ were found for motivational regulations towards walking. CONCLUSIONS: Our
results suggest that in all people with SMI the level of identified and intrinsic
motivation may play an important role in the adoption and maintenance of health
promoting behaviours. The study provides a platform for future research to
investigate the relationships between autonomy support, motivational regulations
and physical and mental health variables within lifestyle interventions for this
population.

Vasudev, A., et al. (2011). "Tiagabine in the maintenance treatment of bipolar

disorder." Cochrane Database Syst Rev(12): CD005173.
BACKGROUND: Tiagabine, an anticonvulsant, has been reported to have efficacy
in prophylactic treatment of bipolar disorder in case reports and in case series.
OBJECTIVES: To assess the efficacy and acceptability of tiagabine, relative to
placebo, and other agents in the prevention or attenuation, or both, of episodes of
bipolar disorder in adults. The efficacy and acceptability of tiagabine were
considered in terms of mood symptoms, mortality, general health, social
functioning, adverse effects and overall acceptability to participants. SEARCH
METHODS: The Cochrane Collaboration Depression, Anxiety and Neurosis review group's
specialised registers (CCDANCTR-Studies and CCDANCTR-References) were searched to 1
October 2011. These registers contains relevant randomised controlled trials from:
The Cochrane Library (all years to date), EMBASE, (1974 to date) MEDLINE (1950 to
date) and PsycINFO (1967 to date). Reference lists of relevant papers and major
textbooks of affective disorder were examined. Authors, other experts in the field
and pharmaceutical companies were contacted for knowledge of suitable published or
unpublished trials. Specialist journals and conference proceedings were
handsearched. SELECTION CRITERIA: Randomised controlled trials of tiagabine versus
placebo, alternative mood stabilisers or antipsychotics, for the maintenance
treatment of bipolar disorder in adults, male and female, aged 18 to 74 years. DATA
COLLECTION AND ANALYSIS: Data were to be extracted from the original reports of
included studies independently by two authors. The main outcomes to be assessed
were:(1) the efficacy of tiagabine treatment in preventing or attenuating further
episodes of bipolar disorder, including its efficacy in rapid cycling disorder; (2)
the acceptability of tiagabine treatment to participants; (3) the prevalence of
side effects; and (4) mortality, if any, on tiagabine treatment.Outcomes concerning
relapse or recurrence were to be analysed excluding data from studies using
discontinuation protocols, which were to be analysed separately. Subgroup analyses
were to be performed to examine the effects of tiagabine treatment in rapid cycling
bipolar disorder and previous mood stabiliser non-responders. Data were to be
analysed using Review Manager 5. MAIN RESULTS: No randomised controlled trials of
tiagabine in the maintenance treatment of bipolar disorder were found. AUTHORS'
CONCLUSIONS: There is an insufficient methodologically rigorous evidence base to
draw any conclusions regarding the use of tiagabine in the maintenance treatment of
bipolar disorder. There is a need for randomised controlled trials examining the
therapeutic potential of this agent in bipolar disorder. There have been some
reports of syncope or seizures, or both, when tiagabine has been used for the acute
treatment of mania. It needs to be established if such adverse effects occur in the
maintenance phase as well.

Vasudev, K. and P. Sharma (2015). "Is Valproate Depressogenic in Patients Remitting

from Acute Mania? Case Series." Case Rep Psychiatry 2015: 456830.
Valproate is an effective antimanic agent and is recommended as a first-line
medication in the treatment of acute mania. Current evidence based guidelines
recommend that valproate should be given as a loading dose as it produces a rapid
antimanic and antipsychotic response with minimal side-effects. However, no clear
guidelines are available on the appropriate dosing or serum levels of valproate in
the continuation or maintenance phase of bipolar disorder. We present 4 clinical
cases to hypothesize that the higher doses of valproate, such as those used in the
treatment of acute mania, may cause a depressive switch. So consideration should be
given to reducing the dose of valproate if a patient develops depressive symptoms
following recovery from the manic episode, as a therapeutic strategy. The cases
also indicate that relatively lower doses and serum levels of valproate are
effective in the maintenance phase compared to those needed in the acute manic
phase of bipolar disorder. This is the first set of case series that questions the
depressogenic potential of valproate in patients remitting from an acute manic
episode. It highlights that different doses and serum levels of valproate may be
therapeutic in different phases of bipolar disorder.

Verhoeven, W. M., et al. (2013). "Phelan-McDermid syndrome: clinical report of a

70-year-old woman." Am J Med Genet A 161A(1): 158-161.
Phelan-McDermid or 22q13.3 deletion syndrome is characterized by global
intellectual disability, childhood hypotonia, severely delayed or absent speech,
features of autism spectrum disorder, without any major dysmorphisms or somatic
anomalies. It is typically diagnosed before adolescence and data about adult
patients are virtually absent. The expression of its phenotypical characteristics
appears to be linearly related to the deletion size. Here, an intellectually
disabled geriatric female patient is described with a long history of challenging
behaviors in whom Phelan-McDermid syndrome was demonstrated. Detailed analysis of
the patient's history and functioning resulted in a psychiatric diagnosis of
atypical bipolar disorder and her behavior significantly improved upon maintenance
treatment with a mood stabilizing agent. The present article confirms recent
findings that atypical bipolar disorder may be part of the psychopathological
phenotype of Phelan-McDermid syndrome, reason why careful etiological search is
warranted, also in the geriatric population.

Vieta, E. (2010). "Developing an individualized treatment plan for patients with

schizoaffective disorder: from pharmacotherapy to psychoeducation." J Clin
Psychiatry 71 Suppl 2: 14-19.
To develop an individualized treatment plan that addresses both psychotic and
affective symptoms in patients with schizoaffective disorder, clinicians can take
several steps. First, clinicians can confirm the diagnosis. In the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)
and in the International Classification of Diseases, Tenth Revision (ICD-10),
schizoaffective disorder is defined differently, but, diagnostically, the disorder
falls on a spectrum between bipolar disorder and schizophrenia and can be divided
into bipolar and depressive types. Next, clinicians can evaluate predictors of
outcome. Outcomes can be predicted by previous functioning, number of previous
episodes, persistence of psychotic symptoms, and level of cognitive impairment.
Then, clinicians can use evidence from clinical trials to guide selection of acute
and maintenance phase treatment. Although data are limited, direct and indirect
evidence from clinical trials support pharmacologic and psychoeducational
interventions. In bipolar type schizoaffective disorder, evidence supports the use
of an atypical antipsychotic and a mood stabilizer or atypical antipsychotic
monotherapy. In the depressive type of the disorder, the combination of an atypical
antipsychotic and an antidepressant is probably the best choice, but an atypical
antipsychotic and a mood stabilizer could also be used. In both types of the
disorder, patient psychoeducation can be beneficial in the maintenance phase of
treatment. Adherence to treatment is essential for optimal outcome, and, besides
patient psychoeducation, long-acting injectable antipsychotics and psychoeducation
for caregivers may also improve adherence. In refractory cases, electroconvulsive
therapy is an option.

Vieta, E. (2010). "Long-term treatment of bipolar depression and other issues." J

Clin Psychiatry 71(3): e07.
Bipolar disorder is a highly episodic illness, and many patients require
long-term or lifelong treatment to maintain a stable mood. Because depression is
the dominant pole of both bipolar I and bipolar II disorder, maintenance therapy
must prevent depressive recurrence. Although numerous treatment options exist for
bipolar disorder, few have data supporting both short-term and long-term efficacy
for bipolar depression. When choosing among treatments, clinicians must consider
the existing evidence for the long-term effectiveness of various pharmacologic and
psychosocial interventions for controlling all types of mood events.

Vieta, E., et al. (2011). "Effectiveness of psychotropic medications in the

maintenance phase of bipolar disorder: a meta-analysis of randomized controlled
trials." Int J Neuropsychopharmacol 14(8): 1029-1049.
The purpose of this meta-analysis was to examine the efficacy of maintenance
treatments for bipolar disorder. Placebo-controlled or active comparator bipolar
maintenance clinical trials of >/=6 months' duration with at least 15
patients/treatment group were identified using Medline, EMBASE, clinicaltrials.gov,
and Cochrane databases (1993 to July 2010). The main outcome measure was relative
risk for relapse for patients in remission. Twenty trials (5,364 patients) were
identified. Overall, lithium and quetiapine were the most studied agents (eight and
five trials, respectively). The majority of studies included patients who had
previously responded to treatment for an acute episode. All interventions, with the
exception of perphenazine+mood stabilizer, showed a relative risk for manic/mixed
or depressive relapse below 1.0, although there was variation in the statistical
significance of the findings vs. placebo. No monotherapy was associated with a
significantly reduced risk for both manic/mixed and depressed relapse. Of the
combination treatments, only quetiapine+lithium/divalproex, was associated with a
significantly reduced risk vs. comparator (placebo+lithium/valproate) for relapse
at both the manic/mixed and depressed poles of bipolar illness. Limitations for the
analysis include differences in study durations and definitions of relapse. In
conclusion, available maintenance therapies show considerable variation in
efficacy. The efficacy of lithium and divalproex has been confirmed, but newer
therapies, such as a number of atypical antipsychotics were also shown to be
effective in bipolar disorder. Efficacy of all maintenance interventions needs to
be balanced against the safety and tolerability profiles of individual agents.

Vieta, E., et al. (2010). "A randomized, placebo- and active-controlled study of
paliperidone extended release for the treatment of acute manic and mixed episodes
of bipolar I disorder." Bipolar Disord 12(3): 230-243.
OBJECTIVES: To evaluate the antimanic efficacy and safety of paliperidone
extended-release (ER) tablets in patients with bipolar I disorder. METHODS: This
study included a 3-week, double-blind, acute treatment phase (paliperidone ER
versus placebo, with quetiapine as control), and a 9-week, double-blind,
maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young
Mania Rating Scale (YMRS) score >or= 20] were randomized (2:2:1) to flexibly dosed
paliperidone ER (3-12 mg/day), quetiapine (400-800 mg/day), or placebo for the
acute treatment phase. During the maintenance phase, patients assigned to placebo
were switched to paliperidone ER but not included in analysis of efficacy. RESULTS:
Paliperidone ER was superior to placebo at the 3-week endpoint {primary outcome;
least-squares mean difference in change from baseline in YMRS scores [95%
confidence interval (CI)]: -5.5 (-7.57; -3.35); p < 0.001} and noninferior to
quetiapine at the 12-week endpoint [least-squares mean difference (95% CI): 1.7 (-
0.47; 3.96)]. The median mode dose during the 12-week treatment period was 9 mg for
paliperidone ER and 600 mg for quetiapine. The most common (>or= 10%) treatment-
emergent adverse events during the 12-week period were: headache (16%), somnolence
(10%), and akathisia (10%) for paliperidone ER; somnolence (21%), sedation and dry
mouth (17% each), headache (14%), and dizziness (13%) for quetiapine. Body weight
increase >or= 7% from baseline to 12-week endpoint was 8% with paliperidone ER and
17% with quetiapine. A higher percentage of paliperidone ER (13.9%) versus
quetiapine patients (7.5%) 'switched to depression' at the12-week endpoint.
CONCLUSIONS: Paliperidone ER (3-12 mg/day) was efficacious and tolerable in the
treatment of acute mania.

Vieta, E., et al. (2010). "Ziprasidone in the treatment of acute mania: a 12-week,
placebo-controlled, haloperidol-referenced study." J Psychopharmacol 24(4): 547-
558.
This 12-week, double-blind, two-part study in 438 adults with bipolar-
associated acute mania began with a 3-week period comparing ziprasidone (80-160
mg/day) and placebo with haloperidol (8-30 mg/day) as active reference. Changes
from baseline Mania Rating Scale (MRS) scores for ziprasidone and haloperidol were
superior to placebo from day 2 (P = 0.001) to week 3 (P < 0.001); change from
baseline at week 3 was greater for haloperidol than ziprasidone (P <or= 0.001). At
week 3, the response rate (>or=50% decrease from baseline MRS score) was 36.9, 54.7
and 20.5% for ziprasidone, haloperidol and placebo, respectively (P <or= 0.05,
active treatments versus placebo and ziprasidone versus haloperidol). In the 9-week
extension phase, ziprasidone replaced placebo to examine tolerability. Maintenance
of improvement was evaluated for ziprasidone (40-160 mg/day) or haloperidol (4-30
mg/day). Responses were maintained through the last visit for 88.1% receiving
ziprasidone and 96.3% receiving haloperidol. More patients receiving haloperidol
than ziprasidone discontinued treatment during weeks 4-12 (21.1% versus 9.6%) and
had significantly higher rates of movement disorders. Mean doses of ziprasidone and
haloperidol for the first 3-week and 9-week extension were 116.2 mg/day and 121.4
mg/day and 16.0 mg/day and 16.1 mg/day, respectively. Ziprasidone was shown to be
effective monotherapy for acute treatment of bipolar mania. Although haloperidol
showed greater efficacy, ziprasidone showed a superior tolerability profile.

Vieta, E. and M. Valenti (2013). "Pharmacological management of bipolar depression:

acute treatment, maintenance, and prophylaxis." CNS Drugs 27(7): 515-529.
Although the most distinctive clinical feature of bipolar disorder is the
pathologically elevated mood, it does not usually constitute the prevalent mood
state of bipolar illness. The majority of patients with bipolar disorder spend much
more time in depressive episodes, including subsyndromal depressive symptoms, and
bipolar depression accounts for the largest part of the morbidity and mortality of
the illness. The pharmacological treatment of bipolar depression mostly consists of
combinations of at least two drugs, including mood stabilizers (lithium and
anticonvulsants), atypical antipsychotics, and antidepressants. Antidepressants are
the most frequently prescribed drugs, but recommendations from evidence-based
guidelines are not conclusive and do not overtly support their use. Among
antidepressants, best evidence exists for fluoxetine, but in combination with
olanzapine. Although some guidelines recommend the use of selective serotonin
reuptake inhibitors or bupropion in combination with antimanic agents as first-
choice treatment, others do not, based on the available evidence. Among
anticonvulsants, the use of lamotrigine is overall recommended as a first-line
choice, but acute monotherapy studies have failed. Valproate is generally mentioned
as a second-line treatment. Lithium monotherapy is also suggested by most
guidelines as a first-line treatment, but its efficacy in acute use is not totally
clear. Amongst atypical antipsychotics, quetiapine, in monotherapy or as adjunctive
treatment, is recommended by most guidelines as a first-line choice. Olanzapine
monotherapy is also suggested by some guidelines and is approved in Japan.
Armodafinil, pramipexole, ketamine, and lurasidone are recent proposals. Long-term
treatment in bipolar disorder is strongly recommended, but guidelines do not
recommend the use of antidepressants as a maintenance treatment. Lithium,
lamotrigine, valproate, olanzapine, quetiapine, and aripiprazole are the
recommended first-line maintenance options.

Vila-Rodriguez, F., et al. (2011). "ApoE and cholesterol in schizophrenia and

bipolar disorder: comparison of grey and white matter and relation with APOE
genotype." J Psychiatry Neurosci 36(1): 47-55.
BACKGROUND: Apolipoprotein E (apoE) and cholesterol play a critical role in
synapse and myelin maintenance and integrity and are thus appealing candidates in
the pathogenesis of schizophrenia and bipolar disorder. To explore the role of
these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and
white matter in patients with schizophrenia, bipolar disorder and healthy controls.
Furthermore, we investigated the relations between apoE and cholesterol levels and
the APOE genotype. METHODS: We obtained dorsolateral prefrontal grey and white
matter from the Stanley Medical Research Institute Brain Collection (schizophrenia
n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were
quantified using high-pressure liquid chromatography, whereas apoE was measured by
enzyme-linked immunosorbent assay. RESULTS: We found no significant differences in
cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter
than in white matter in all groups; conversely, levels of cholesterol were higher
in white matter than in grey matter. We observed a significant inverse correlation
between apoE and cholesterol levels in both grey and white matter. Furthermore, in
grey matter, apoE levels were significantly higher in APOE epsilon2 carriers
compared with APOE epsilon3 or APOE epsilon4 carriers, with cholesterol levels
following the opposite trend. LIMITATIONS: LIMITATIONS of our study include our
inability to control for potential confounding variables and the small numbers of
APOE epsilon2 and epsilon4 carriers in each group. CONCLUSION: Although large
amounts of cholesterol are present in white matter, apoE expression is limited. The
APOE genotype may play a role in the regulation of both cholesterol and apoE levels
in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people
with psychiatric disorders warrants further investigation.

Villagonzalo, K. A., et al. (2010). "The utility of the Mood Disorders

Questionnaire as a screening tool in a methadone maintenance treatment program."
Int J Psychiatry Clin Pract 14(2): 150-153.
Abstract Objective. Comorbid mental illness amongst methadone maintenance
therapy clients may be common and screening may be warranted. The Mood Disorders
Questionnaire (MDQ) is a screening tool for bipolar disorder that has been
validated in other treatment settings. Its utility for patients with substance use
disorders is assessed in this study. Methods. Clients of a methadone maintenance
program were invited to complete the MDQ when they attended a public Drug and
Alcohol Service for their regular scheduled appointments. Information about their
history of substance use was also collected. Results. Eighty clients (43 females,
37 males) aged 35 +/- 8.0 years (mean +/- SD) participated in the study. Seventy-
four clients completed the MDQ of which 36 (48.6%) obtained a positive screen. A
check of client files suggested that only three of the 74 participants had a
current working diagnosis of bipolar disorder. These three participants had
screened positive on the MDQ. Conclusions. There was a high prevalence of manic
symptoms reported by participants, suggesting that screening for bipolar disorder
in this population may be warranted. However, there is a risk of false positives
with the MDQ, as it does not clearly differentiate between symptoms of mania and
drug intoxication.

Visinet, A., et al. (2016). "[Psychometric approach of metacognition: Pilot study

in clinical population]." Encephale.
BACKGROUND: Metacognition describes the process of thinking about one's own
thought processes. This concept was introduced by Flavell in 1979 and has since
been widely developed in the cognitive approach to mood and anxiety disorders. As
it happens, many recent studies have underlined the links between metacognition and
anxio-depressive symptoms, pointing out the interest of assessing its various
dimensions. The short form of the Metacognitions Questionnaire is a brief
multidimensional measure of a range of metacognitive processes and metacognitive
beliefs about worry and cognition relevant to the vulnerability to and the
maintenance of emotional disorders. The aim of this study was twofold: firstly to
adapt and validate a French version of the short form of the Metacognitions
Questionnaire (MCQ-30) and to assess its psychometric properties in a clinical
sample, and secondly to investigate metacognitive predictors of anxiety and
depression in this sample. METHOD: The sample included 55 clinical participants (24
men, 31 women, mean age=51.33+/-14.62) with DSM-IV-TR psychiatric disorders (major
depression, bipolar disorder and obsessive-compulsive disorder). Instrument
reliability (internal consistency), construct validity (confirmatory factor
analysis), and convergent validity were measured. The total score and the five
subscale scores were also compared with previous results in non-clinical samples.
RESULTS: Reliability analyses indicated that the French version of the MCQ-30
possessed satisfactory internal consistency (Cronbach alpha=0.84), and confirmatory
factor analysis supported the MCQ's original five-factor structure. Correlation
with measurements of depression, anxiety and pathological worry demonstrated
convergent validity (r=0.62, P<0.01 for anxiety; r=0.47, P<0.01 for rumination;
r=0.33, P<0.05 for depression). Moreover, our clinical sample scored higher on the
global scale when compared to previous non-clinical samples (mean score=71.85+/-
13.57 while previous studies global scores ranged from 48.41+/-13.31 to 65.89+/-
17.17). Consistent with others studies, negative beliefs about worry concerning
uncontrollability and danger, as well as beliefs about the need to control thoughts
were the strongest predictors of pathological worry (respectively r=0.68, P<0.01
and r=0.48, P<0.01) and depression (respectively r=0.45, P<0.01 and r=0.39,
P<0.01), providing further support for the validity of the measure. CONCLUSION:
These findings provide general support for the internal consistency of the French
version of the MCQ-30, as well as its five-factor structure and its good concurrent
validity in a clinical sample. They also confirm that this version is a valuable
tool for the assessment of various dimensions of metacognition, in relation to the
anxio-depressive symptomatology and the subsequent management of patients.

Volkert, J., et al. (2014). "Predominant polarity in bipolar disorder and

validation of the polarity index in a German sample." BMC Psychiatry 14: 322.
BACKGROUND: A large number of patients with bipolar disorder (BD) can be
characterized by predominant polarity (PP), which has important implications for
relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339-346,
2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance
treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in
treatment of BD. In the present retrospective study, we aimed to validate this
Index in a large and well characterized German bipolar sample. METHODS: We
investigated 336 bipolar patients (BP) according to their PP and calculated the PI
for each patient in order to prove if maintenance treatment differs according to
their PP. Furthermore, we analysed whether PP is associated with demographic and
clinical characteristics of BP. RESULTS: In our sample, 63.9% of patients fulfilled
criteria of PP: 169 patients were classified as depressive predominant polarity
(DPP), 46 patients as manic predominant polarity (MPP). The two groups differed
significantly in their drug regime: Patients with DPP were more often medicated
with lamotrigine and antidepressants, patients with MPP were more often treated
with lithium, valproate, carbamazepine and first generation antipsychotics.
However, patients with DPP and MPP did not differ significantly with respect to the
PI, although they received evidence-based and guideline-driven treatment.
CONCLUSION: The reason for this negative finding might well be that for several
drugs, which were used frequently, no PI value is available. Nevertheless we
suggest PP as an important concept in the planning of BD maintenance treatment.

Vugler, A. A. (2010). "Progress toward the maintenance and repair of degenerating

retinal circuitry." Retina 30(7): 983-1001.
BACKGROUND: Retinal diseases such as age-related macular degeneration and
retinitis pigmentosa remain major causes of severe vision loss in humans. Clinical
trials for treatment of retinal degenerations are underway and advancements in our
understanding of retinal biology in health/disease have implications for novel
therapies. METHODS: A review of retinal biology is used to inform a discussion of
current strategies to maintain/repair neural circuitry in age-related macular
degeneration, retinitis pigmentosa, and Type 2 Leber congenital amaurosis. RESULTS:
In age-related macular degeneration/retinitis pigmentosa, a progressive loss of
rods/cones results in corruption of bipolar cell circuitry, although retinal output
neurons/photoreceptive melanopsin cells survive. Visual function can be
stabilized/enhanced after treatment in age-related macular degeneration, but in
advanced degenerations, reorganization of retinal circuitry may preclude attempts
to restore cone function. In Type 2 Leber congenital amaurosis, useful vision can
be restored by gene therapy where central cones survive. Remarkable progress has
been made in restoring vision to rodents using light-responsive ion channels
inserted into bipolar cells/retinal ganglion cells. CONCLUSION: Advances in
genetic, cellular, and prosthetic therapies show varying degrees of promise for
treating retinal degenerations. While functional benefits can be obtained after
early therapeutic interventions, efforts should be made to minimize circuitry
changes as soon as possible after rod/cone loss. Advances in retinal
anatomy/physiology and genetic technologies should allow refinement of future
reparative strategies.

Wachtel, L. E., et al. (2011). "Electroconvulsive therapy for psychotropic-

refractory bipolar affective disorder and severe self-injury and aggression in an
11-year-old autistic boy." Eur Child Adolesc Psychiatry 20(3): 147-152.
We report the successful use of electroconvulsive therapy in a 11-year-old
boy with autism and a 4-year history of psychotropic-resistant bipolar affective
disorder associated with dangerous episodes of self-injurious and aggressive
behaviors placing his caregivers and himself at significant safety risk. Extensive
behavioral and medication interventions in both inpatient and outpatient settings
had been ineffective, and the boy was at risk for acute physical injury and
restrictive out-of-home placement. An acute course of eight bilateral
electroconvulsive therapies resulted in significant mood stabilization and
significant improvement of self-injury and aggression. Maintenance
electroconvulsive therapy and psychotropic interventions were then pursued.

Wada, K., et al. (2013). "One-year outcomes of unipolar depression patients with
manic or hypomanic switch during acute antidepressant treatment." Int J Psychiatry
Clin Pract 17(3): 219-222.
OBJECTIVE: The aim of the study was to investigate one-year outcomes of
unipolar depression patients with manic or hypomanic switch during acute
antidepressant treatment. METHODS: A review of medical records revealed 37
consecutive patients admitted from 1997 to 2002 who underwent an antidepressant-
induced manic or hypomanic switch fulfilling DSM-IV criteria. Their clinical
courses were retrospectively investigated after discharge. RESULTS: Of the 37
patients, 33 (89.2%) were followed up for 1 year after discharge. None developed a
manic episode, while seven developed a hypomanic episode, including 1 patient who
was lost after emerging from a hypomanic episode within 6 months after discharge.
Only one of those seven patients developed hypomania during acute antidepressant
treatment for a recurrent depressive episode under maintenance mood stabilizer
treatment. Furthermore, bipolar conversion occurred in four patients within the
first 6 months and in another two patients, including 1 with rapid cycling, over
the subsequent 6 months after discharge. Of these 33 patients, 28 received
continuous maintenance treatment with mood stabilizers for the one-year period
after discharge. CONCLUSIONS: The subjects were considered to have a bipolar nature
according to the prevalence rate of bipolar conversion over a one-year period.
Longer follow-up studies appear warranted determine the diagnostic issues of
antidepressant-induced switch in unipolar depression.

Walker, A. J., et al. (2014). "Stress, Inflammation, and Cellular Vulnerability

during Early Stages of Affective Disorders: Biomarker Strategies and Opportunities
for Prevention and Intervention." Front Psychiatry 5: 34.
The mood disorder prodrome is conceptualized as a symptomatic, but not yet
clinically diagnosable stage of an affective disorder. Although a growing area,
more focused research is needed in the pediatric population to better characterize
psychopathological symptoms and biological markers that can reliably identify this
very early stage in the evolution of mood disorder pathology. Such information will
facilitate early prevention and intervention, which has the potential to affect a
person's disease course. This review focuses on the prodromal characteristics, risk
factors, and neurobiological mechanisms of mood disorders. In particular, we
consider the influence of early-life stress, inflammation, and allostatic load in
mediating neural mechanisms of neuroprogression. These inherently modifiable
factors have known neuroadaptive and neurodegenerative implications, and
consequently may provide useful biomarker targets. Identification of these factors
early in the course of the disease will accordingly allow for the introduction of
early interventions which augment an individual's capacity for psychological
resilience through maintenance of synaptic integrity and cellular resilience. A
targeted and complementary approach to boosting both psychological and
physiological resilience simultaneously during the prodromal stage of mood disorder
pathology has the greatest promise for optimizing the neurodevelopmental potential
of those individuals at risk of disabling mood disorders.

Wang, L., et al. (2014). "[Comparison of therapeutic effects of olfactory

ensheathing cells derived from olfactory mucosa or olfactory bulb on spinal cord
injury mouse models]." Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 30(4): 379-383.
OBJECTIVE: To isolate and culture olfactory ensheathing cells from different
origins, compare their different biological characteristics, and evaluate their
therapeutic effect on spinal cord injury mouse models. METHODS: The olfactory
ensheathing cells from olfactory mucosa or olfactory bulb were isolated and
cultured by differential adhesion method. The expressions of S100 and P75 proteins
were examined by immunofluorescence staining; their growth curves were drawn by MTT
colorimetric assay; the secretion of neurotrophic factors, brain-derived
neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3)
was measured by ELISA; the gene expressions of BDNF, NGF, NT-3, neurotrophin-4 (NT-
4), growth-associated protein 43 (GAP-43), and microtubule-associated protein (MAP-
2) were quantified by real-time PCR; the therapeutic effect on spinal cord injury
mouse models was evaluated by Basso, Beattie and Bresnahan (BBB) locomotor rating
scale, which had been carried out daily for 8 weeks after the olfactory ensheathing
cells of the two different origins were respectively grafted to the mouse models.
RESULTS: The two types of olfactory ensheathing cells showed bipolar or tripolar
shape; both of them were S100 and P75 protein positive; both of them expressing the
gene of BDNF, NGF, NT-3, and NT-4; the olfactory bulb-derived cells did not express
MAP-2, but it highly expressed GAP-43 gene; the olfactory mucosa-derived cells
displayed a low expression of MAP-2 and GAP-43; the growth speed of olfactory bulb-
derived cells was faster than that of the olfactory mucosa-derived cells. Both of
them could secrete BDNF, NGF, and NT-3, but the neurotrophic factor levels secreted
in the olfactory mucosa-derived cells were higher. The daily neurological BBB
scoring showed that the therapeutic effect of olfactory mucosa-derived cells on
spinal cord injury mouse models was better than that of the olfactory bulb-derived
cells. CONCLUSION: There exist biological differences between the olfactory mucosa-
derived cells and the olfactory bulb-derived cells. The olfactory mucosa-derived
cells showed the better therapeutic effect on spinal cord injury mouse models.

Wang, S. M., et al. (2012). "Paliperidone: a review of clinical trial data and
clinical implications." Clin Drug Investig 32(8): 497-512.
Paliperidone, 9-hydroxy-risperidone, is the major metabolite of the atypical
antipsychotic risperidone and is available in an oral extended-release (ER)
formulation. Paliperidone ER was approved for treating schizophrenia in 2006, and
in 2009 it became the first atypical antipsychotic licensed for treating
schizoaffective disorder. The short-term efficacy, safety and tolerability of
paliperidone ER for patients with schizophrenia were demonstrated in three pivotal
6-week, randomized, double-blind, placebo-controlled studies. Data from the long-
term trial showed that paliperidone ER is also effective in preventing relapse of
schizophrenia. Two randomized, placebo-controlled, short-term studies have
documented the efficacy and tolerability of paliperidone ER in the treatment of
schizoaffective disorder, but no long-term or maintenance study has been conducted
in patients with schizoaffective disorder. Two 3-week, randomized, double-blind,
placebo-controlled studies showed that paliperidone ER is significantly superior to
placebo for treating patients with bipolar disorder, but the results were driven by
certain subpopulations. Limited evidence suggests that paliperidone ER can
potentially be superior to quetiapine and risperidone. However, few direct head-to-
head comparisons between paliperidone ER and other antipsychotics have been
conducted to confirm these results. The distinctive pharmacological characteristics
of paliperidone ER, including smooth fluctuations in plasma drug concentrations,
predominantly renal excretion, low risk of causing hepatic impairment and low drug-
drug interaction, might provide important clinical advantages compared with
risperidone. However, certain side effects require clinical attention. The rate of
extrapyramidal side effects was considerably higher than that of a placebo at doses
>/=9 mg/day. The risks for orthostatic hypotension, prolongation of the corrected
QT interval and hyperprolactinaemia are also concerns. This review summarizes the
currently published data on paliperidone ER for treating patients with
schizophrenia, schizoaffective disorder and bipolar disorder, and suggests its
appropriate use in clinical practice.

Wang, Z., et al. (2015). "Guidelines concordance of maintenance treatment in

euthymic patients with bipolar disorder: Data from the national bipolar mania
pathway survey (BIPAS) in mainland China." J Affect Disord 182: 101-105.
BACKGROUND: Although the treatment guidelines of bipolar disorders (BPD) have
spread more than a decade, the concordance with evidence-based guidelines was
typically low in routine clinical practice. This study is to present the data on
the maintenance treatment of BPD in mainland China. METHODS: One thousand and
twenty-three patients who had experienced a euthymia were eligible for entry into
this survey on the maintenance treatment of BPD. Guidelines disconcordance was
determined by comparing the medication(s) that patients were prescribed with the
recommendations in the guidelines of the Canadian Network for Mood and Anxiety
Treatments. RESULTS: Three hundred and sixty-four patients (35.6%) had not been
prescribed with the maintenance treatment as guidelines recommendations, and 208
patients (20.3%) were prescribed with the antidepressants. A longer duration of
BPD, a depressive episode at first onset, and a recent depressive or mixed episode
significantly increased the risk for guidelines disconcordance and prescribing
antidepressant. In contrast, a hospitalization history due to manic episode was
associated with a significant decrease in the risk for guidelines disconcordance
and prescribing antidepressant. LIMITATION: This study was a cross-sectional and
retrospective investigation based on medical records. CONCLUSIONS: Considering the
potentially hazardous effects of inappropriate treatment, individualized
psychoeducational strategies for subjects with BPD are necessary to enhance
treatment adherence and close the gap between guidelines and clinical practice in
mainland China.

Warren, C. G. and S. L. Dubovsky (2013). "New approaches for the management of

bipolar disorder: role of sublingual asenapine in the treatment of mania."
Neuropsychiatr Dis Treat 9: 753-758.
Bipolar disorder is a prevalent disorder that tends to become progressive
without treatment and with inadequate treatment. Second generation (atypical)
antipsychotic drugs have increasingly been used as adjunctive treatment or
monotherapy for mania, but they have the potential for significant adverse effects
and their role in maintenance treatment remains unclear. Asenapine is a new
atypical antipsychotic medication formulated in a sublingual preparation that has
been studied for mania but not maintenance therapy. Evidence indicating efficacy,
adverse effects, and potential benefits and drawbacks of using asenapine in the
treatment of bipolar disorder based on currently available published data are
summarized.

Weck, F., et al. (2013). "Relapses in recurrent depression 1 year after maintenance
cognitive-behavioral therapy: the role of therapist adherence, competence, and the
therapeutic alliance." Psychiatry Res 210(1): 140-145.
The prevention of relapse in recurrent depression is considered a central aim
in cognitive-behavioral therapy, given the high risk of relapse. In this study,
patients with recurrent major depressive disorder (currently remitted) received 16
sessions of Maintenance Cognitive-Behavioral Therapy (M-CBT) over a period of 8
months, in order to prevent relapse. Therapist adherence and competence, as well as
the therapeutic alliance, were investigated as predictors for reducing the risk of
recurrence in depression. Videotapes of 80 participants were analyzed in order to
evaluate therapist adherence and competence. Additionally, the therapeutic alliance
was assessed by questionnaire. No associations were found between therapist
adherence or competence, and the risk of relapse 1 year after treatment. By
contrast, the therapeutic alliance was a significant predictor of the time to
relapse. Moreover, we found that the number of previous depressive episodes (>/= 5
vs. </= 4) was a significant moderator variable. This indicates that the alliance-
outcome relationship was particularly important when patients with five or more
previous depressive episodes were taken into account, in comparison to patients
with four or fewer episodes. For the psychotherapeutic treatment of recurrent
depression and the prevention of relapse, sufficient attention should be paid to
the therapeutic alliance.

Weinstock, L. M. and I. W. Miller (2010). "Psychosocial predictors of mood symptoms

1 year after acute phase treatment of bipolar I disorder." Compr Psychiatry 51(5):
497-503.
OBJECTIVE: The aim of the current study was to evaluate family functioning,
social support, and functional impairment as predictors of mood symptoms 1 year
after acute phase treatment of bipolar I disorder. This study builds upon the
extant literature by evaluating these putative psychosocial risk factors
simultaneously to determine whether they account for unique variance in clinical
outcomes. METHOD: Patients (N = 92) were recruited from hospital settings during an
acute mood episode to participate in pharmacologic or combined family and
pharmacologic interventions. The Modified Hamilton Rating Scale for Depression,
Bech-Rafaelson Mania Scale, Family Assessment Device, Interpersonal Support
Evaluation List, and UCLA Social Attainment Survey were administered at acute phase
treatment completion and again at 1-year follow-up. Controlling for mood symptom
severity at acute phase treatment completion, multiple regression analyses were
used to examine longitudinal associations between the psychosocial variables and
subsequent depressive and manic symptoms. RESULTS: None of the aforementioned
psychosocial variables predicted manic symptomatology, and social support alone
emerged as a unique predictor of depression at the 1-year follow-up. Effects of
social support were moderated by recovery status, such that the strength of
association between social support and subsequent depression was stronger for those
who had not fully recovered during the acute phase of treatment than for those who
had. CONCLUSIONS: Low levels of social support at acute phase treatment completion,
especially in concert with residual symptomatology, may place individuals with
bipolar I disorder at risk for subsequent depressive symptoms. These data suggest
that maintenance therapies focused on improving level of social support might be
especially important to consider in the management of bipolar depression, and add
to a growing literature focused on unique vs shared effects of psychosocial risk
factors for poor illness course in bipolar disorder.

Weisler, R. H., et al. (2011). "Continuation of quetiapine versus switching to

placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a
randomized controlled study)." J Clin Psychiatry 72(11): 1452-1464.
OBJECTIVE: Quetiapine, combined with lithium or divalproex, demonstrates
efficacy in the maintenance treatment of bipolar I disorder. This study
investigated the efficacy and safety of quetiapine monotherapy as maintenance
treatment in bipolar I disorder compared with switching to placebo or lithium.
METHOD: Patients aged >/= 18 years with DSM-IV-diagnosed bipolar I disorder and a
current or recent manic, depressive, or mixed episode received open-label
quetiapine (300-800 mg/d) for 4-24 weeks. Patients achieving stabilization were
randomized to continue quetiapine or to switch to placebo or lithium (0.6-1.2
mEq/L) for up to 104 weeks in a double-blind trial. Outcome measures included times
to recurrence of any mood event (primary outcome measure), manic event, or
depressive event. Safety assessments included adverse events and laboratory values.
The study was terminated early after planned interim analysis provided positive
results. The study was conducted between March 2005 and July 2007. RESULTS: Of
2,438 patients starting open-label quetiapine, 1,226 (50.3%) were randomized to
double-blind treatment, including 1,172 (95.6%) in the intent-to-treat population.
Time to recurrence of any mood event was significantly longer for quetiapine versus
placebo (hazard ratio [HR] = 0.29; 95% CI, 0.23-0.38; P < .0001) and for lithium
versus placebo (HR = 0.46; 95% CI, 0.36-0.59; P < .0001). Quetiapine and lithium
significantly increased time to recurrence of both manic events (quetiapine: HR =
0.29; 95% CI, 0.21-0.40; P < .0001; lithium: HR = 0.37; 95% CI, 0.27-0.53; P < .
0001) and depressive events (quetiapine: HR = 0.30; 95% CI, 0.20-0.44; P < .0001;
lithium: HR = 0.59; 95% CI, 0.42-0.84; P < .004) compared with placebo. Overall
rates of adverse events were generally similar between treatment groups, and safety
findings for quetiapine were consistent with its known profile. CONCLUSIONS: In
patients stabilized during acute quetiapine treatment, continuation of quetiapine
significantly increased time to recurrence of any mood, manic, or depressive event
compared with switching to placebo. Switching to lithium was also more effective
than placebo for the prevention of manic and depressive events. TRIAL REGISTRATION:
clinicaltrials.gov Identifier: NCT00314184.

Welge, J. A. and M. P. DelBello (2013). "Treatment of youth with bipolar disorder:

long-term versus maintenance." Bipolar Disord 15(2): 150-152.

Werneke, U., et al. (2012). "A decision analysis of long-term lithium treatment and
the risk of renal failure." Acta Psychiatr Scand 126(3): 186-197.
OBJECTIVE: To establish whether lithium or anticonvulsant should be used for
maintenance treatment for bipolar affective disorder (BPAD) if the risks of suicide
and relapse were traded off against the risk of end-stage renal disease (ESRD).
METHOD: Decision analysis based on a systematic literature review with two main
decisions: (1) use of lithium or at treatment initiation and (2) the potential
discontinuation of lithium in patients with chronic kidney disease (CKD) after 20
years of lithium treatment. The final endpoint was 30 years of treatment with five
outcomes to consider: death from suicide, alive with stable or unstable BPAD, alive
with or without ESRD. RESULTS: At the start of treatment, the model identified
lithium as the treatment of choice. The risks of developing CKD or ESRD were not
relevant at the starting point. Twenty years into treatment, lithium still remained
treatment of choice. If CKD had occurred at this point, stopping lithium would only
be an option if the likelihood of progression to ESRD exceeded 41.3% or if
anticonvulsants always outperformed lithium regarding relapse prevention.
CONCLUSION: At the current state of knowledge, lithium initiation and continuation
even in the presence of long-term adverse renal effects should be recommended in
most cases.

Woo, Y. S., et al. (2011). "Aripiprazole plus divalproex for recently manic or
mixed patients with bipolar I disorder: a 6-month, randomized, placebo-controlled,
double-blind maintenance trial." Hum Psychopharmacol 26(8): 543-553.
OBJECTIVES: The goal of this study was to investigate the safety and efficacy
in preventing relapse of a mood episode in recently manic or mixed episode patients
with bipolar I disorder stabilized with aripiprazole and divalproex combination.
METHODS: This randomized, 24-week, double-blind, placebo-controlled multicenter
study enrolled patients from 23 centers in Korea. Patients with bipolar I disorder
who had manic or mixed episode entered a 6-week open-label stabilization phase.
After meeting stabilization criteria, 83 patients were randomly assigned to placebo
+ divalproex or aripiprazole + divalproex treatment group for the 24-week, double-
blind maintenance phase. RESULTS: During the 6-month double-blind treatment, the
time to relapse of any mood episode in the aripiprazole group was longer than the
placebo group, but the difference did not reach statistical significance (p =
0.098). After controlling for mean divalproex level, the time to depressive episode
relapse in the aripiprazole group was longer than those in the placebo group (p =
0.029). Weight gain (>/= 7% increase) occurred in 22.5% aripiprazole group and
18.6% placebo group (p = 0.787). CONCLUSIONS: In this study, relapse of mood
episode occurred fewer and later for aripiprazole with divalproex treatment than
divalproex monotherapy, but the differences were not statistically significant.

Woo, Y. S., et al. (2015). "Korean Medication Algorithm Project for Bipolar
Disorder: third revision." Neuropsychiatr Dis Treat 11: 493-506.
OBJECTIVE: To constitute the third revision of the guidelines for the
treatment of bipolar disorder issued by the Korean Medication Algorithm Project for
Bipolar Disorder (KMAP-BP 2014). METHODS: A 56-item questionnaire was used to
obtain the consensus of experts regarding pharmacological treatment strategies for
the various phases of bipolar disorder and for special populations. The review
committee included 110 Korean psychiatrists and 38 experts for child and adolescent
psychiatry. Of the committee members, 64 general psychiatrists and 23 child and
adolescent psychiatrists responded to the survey. RESULTS: The treatment of choice
(TOC) for euphoric, mixed, and psychotic mania was the combination of a mood
stabilizer (MS) and an atypical antipsychotic (AAP); the TOC for acute mild
depression was monotherapy with MS or AAP; and the TOC for moderate or severe
depression was MS plus AAP/antidepressant. The first-line maintenance treatment
following mania or depression was MS monotherapy or MS plus AAP; the first-line
treatment after mania was AAP monotherapy; and the first-line treatment after
depression was lamotrigine (LTG) monotherapy, LTG plus MS/AAP, or MS plus AAP plus
LTG. The first-line treatment strategy for mania in children and adolescents was MS
plus AAP or AAP monotherapy. For geriatric bipolar patients, the TOC for mania was
AAP/MS monotherapy, and the TOC for depression was AAP plus MS or AAP monotherapy.
CONCLUSION: The expert consensus in the KMAP-BP 2014 differed from that in previous
publications; most notably, the preference for AAP was increased in the treatment
of acute mania, depression, and maintenance treatment. There was increased expert
preference for the use of AAP and LTG. The major limitation of the present study is
that it was based on the consensus of Korean experts rather than on experimental
evidence.

Woodward, T. C., et al. (2010). "Cost effectiveness of adjunctive quetiapine

fumarate extended-release tablets with mood stabilizers in the maintenance
treatment of bipolar I disorder." Pharmacoeconomics 28(9): 751-764.
BACKGROUND: Bipolar I disorder (BPD I) is a recurrent illness that affects 1%
of the US population and constitutes a large economic burden. However, few studies
have investigated the cost effectiveness of maintenance treatment options for BPD
I. OBJECTIVE: To determine the cost effectiveness of maintenance treatment with
quetiapine fumarate extended-release (XR) tablets in combination with mood
stabilizers (lithium or divalproex) in comparison with the following treatments:
placebo in combination with lithium or divalproex; no maintenance treatment;
lithium monotherapy; lamotrigine monotherapy; olanzapine monotherapy; and
aripiprazole monotherapy. METHODS: The analysis was conducted from the societal and
payer perspectives in the US, using a Markov model. The model simulated a cohort of
1000 stabilized BPD I patients and estimated the quarterly risk in three health
states: euthymia, mania and depression. Efficacy data were derived from two
randomized, double-blind trials comparing quetiapine + lithium/divalproex with
placebo + lithium/divalproex for up to 2 years, as well as other published
literature. Resource data were extracted from published literature. Drug costs,
hospitalizations and physician visits were among the direct costs. Indirect costs
included absenteeism, and mortality rates included suicide. Benefits and costs were
discounted at 3% and the price reference year was 2009. Endpoints included number
of acute mood episodes, hospitalizations due to an acute mood event and costs per
QALY. Probabilistic sensitivity analysis (PSA) was conducted to evaluate
uncertainty in the model inputs. RESULTS: Treatment with quetiapine XR +
lithium/divalproex was associated with reductions in acute mania (46%), acute
depression (41%) and related hospitalizations (44%) compared with placebo +
lithium/divalproex, and similar reductions in events were observed relative to
lithium monotherapy. In the base-case analysis from the payer perspective, the
discounted incremental cost per QALY for quetiapine XR + lithium/divalproex
compared with placebo + lithium/divalproex was $US22 959, and compared with lithium
monotherapy was $US100 235, while all other comparators were dominated. PSA showed
these results to be robust to select assumptions. CONCLUSIONS: Quetiapine XR +
lithium/divalproex may be a cost-effective maintenance treatment option for
patients with BPD I.

Yatham, L. N. (2011). "A clinical review of aripiprazole in bipolar depression and

maintenance therapy of bipolar disorder." J Affect Disord 128 Suppl 1: S21-28.
BACKGROUND: Bipolar disorder is a chronic, recurrent disorder with a
significant negative impact on quality of life. Effective treatments are available
for acute mania. In contrast, there is a lack of consensus on the treatment of
acute bipolar depression and long treatment options for bipolar disorder require
more study. Aripiprazole is FDA approved for the treatment of acute mania. This
paper reviews current data on the efficacy of aripiprazole in the treatment of
acute bipolar depression and in maintenance therapy of bipolar disorder. METHODS:
PubMed and abstracts of recent conferences were searched for randomized, double-
blind studies that investigated the efficacy of aripiprazole in acute bipolar
depression or maintenance therapy of bipolar disorder. RESULTS: Two studies
assessed the efficacy of aripiprazole monotherapy in the treatment of acute bipolar
depression. These showed that although aripiprazole significantly reduced
depressive symptoms early in treatment, the results were not significantly
different from placebo at the primary end point of week 8. As to long-term
treatment, aripiprazole was superior to placebo in delaying time to relapse for
manic episodes, but not for depressive episodes after 26 and 100 weeks of
maintenance therapy. Aripiprazole was as effective as lithium, and adjunctive
aripiprazole with lithium or valproate was more effective than placebo plus lithium
or valproate, in preventing a manic relapse. Reductions in manic and mixed relapse
rates compared to placebo were achieved in a study combining aripiprazole with
lamotrigine; however, the results were not statistically significant. Similar to
other maintenance studies, depressive relapse rates were not significantly reduced
compared to placebo. LIMITATIONS: Negative findings for aripiprazole in the
treatment of acute bipolar depression have been attributed to high study doses,
rapid titration, and high placebo rates. A recent post-hoc analysis demonstrated
that aripiprazole was more effective in patients with severe depressive symptoms,
particularly for patients on a lower dose. Further research is needed to confirm
this finding. The inability of aripiprazole to reduce the time to depressive
relapse during maintenance therapy may be due to the recruitment of patients with
an index manic episode and a consequent lower incidence of depressive relapses.
Therefore, studies using a depression index episode are needed to appropriately
evaluate relapse prevention. CONCLUSIONS: Although aripiprazole has proven efficacy
for acute mania and the prevention of mania, the evidence available thus far does
not support the efficacy of aripiprazole for the treatment of acute bipolar
depression and prevention of depressive relapse. Further studies with appropriate
doses and a depressive index episode are needed to clarify the role of aripiprazole
in bipolar disorder.

Yatham, L. N., et al. (2013). "Efficacy of aripiprazole versus placebo as adjuncts

to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar
I patients stratified by index manic or mixed episode." J Affect Disord 147(1-3):
365-372.
BACKGROUND: Differences in response to treatment have been observed for
bipolar disorder (BPD) patients with manic or mixed episodes. This post-hoc
analysis examined the maintenance effect of aripiprazole in combination with
lithium or valproate in subpopulations of patients entering a relapse prevention
study with either manic or mixed bipolar episodes. METHODS: A long-term relapse
prevention study of BPD patients with manic or mixed episodes included a single-
blind stabilization phase, in which patients were stabilized with single-blind
aripiprazole plus lithium or valproate (maintaining stability for 12 weeks), and a
double-blind relapse assessment phase, where patients were randomized to
aripiprazole or placebo plus lithium or valproate for up to 52 weeks. Lithium and
valproate groups were pooled. RESULTS: The time to relapse of any mood episode was
longer in the adjunctive aripiprazole group versus the lithium/valproate
monotherapy group for the manic (p<0.01) but not mixed population (p=0.59). The
LOCF analysis indicated a significantly greater reduction in YMRS total score from
baseline with continued aripiprazole versus placebo at 52 weeks in both manic
(treatment difference=-3.32, p<0.01) and mixed episode populations (treatment
difference=-2.56, p=0.02). Overall, adverse event profiles were similar between the
populations. LIMITATION: The lithium and valproate subgroups were combined.
CONCLUSIONS: The continuation of aripiprazole in stabilized BPD patients treated
with lithium or valproate increased the time to relapse of any mood episode for
manic but not mixed patients; both groups achieved greater stability in YMRS total
score with adjunctive aripiprazole. Thus, adjunctive aripiprazole may be more
appropriate for stabilized patients with manic episodes.

Yatham, L. N., et al. (2013). "Canadian Network for Mood and Anxiety Treatments
(CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative
update of CANMAT guidelines for the management of patients with bipolar disorder:
update 2013." Bipolar Disord 15(1): 1-44.
The Canadian Network for Mood and Anxiety Treatments published guidelines for
the management of bipolar disorder in 2005, with updates in 2007 and 2009. This
third update, in conjunction with the International Society for Bipolar Disorders,
reviews new evidence and is designed to be used in conjunction with the previous
publications.The recommendations for the management of acute mania remain largely
unchanged. Lithium, valproate, and several atypical antipsychotic agents continue
to be first-line treatments for acute mania. Monotherapy with asenapine,
paliperidone extended release (ER), and divalproex ER, as well as adjunctive
asenapine, have been added as first-line options.For the management of bipolar
depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine
plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus
SSRI/bupropion remain first-line options. Lurasidone monotherapy and the
combination of lurasidone or lamotrigine plus lithium or divalproex have been added
as a second-line options. Ziprasidone alone or as adjunctive therapy, and
adjunctive levetiracetam have been added as not-recommended options for the
treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine,
quetiapine, aripiprazole, risperidone long-acting injection, and adjunctive
ziprasidone continue to be first-line options for maintenance treatment of bipolar
disorder. Asenapine alone or as adjunctive therapy have been added as third-line
options.

Zaki, H., et al. (2013). "[The interest of maintenance electroconvulsive therapy in

mood disorders]." Encephale 39(5): 367-373.
Maintenance electroconvulsive therapy (M-ECT) is a treatment indicated for
the treatment and prevention of recurrent depression in patients who either do not
respond or do not tolerate psychotropic medication. We evaluated, retrospectively,
clinical response to a 6-month minimum course of M-ECT in 25 patients with a
diagnosis of bipolar disorder or schizoaffective disorder according to DSM IV-TR
criterion. Our study demonstrated a significant improvement of Global Assessment of
functioning (GAF) scores after a six month minimum course of M-ECT (34.8 +/- 12.6
vs 65.6 +/- 10.8; P<0.05) as well as Brief Psychiatric Rating Scale scores (BPRS):
79.3 +/- 12.4 vs 43.4 +/- 10.2; P<0.05). We observed a slight increase of Mini
Mental State Examination (MMSE) scores after M-ECT; nonetheless, it was not
statistically significant (24.2 +/- 2.4 vs 26.2 +/- 2.4; P=0.2). Regarding the mean
duration of hospitalizations, we showed a statistically significant decrease in the
median number of days of hospitalization (72 [59-93.50] days before M-ECT vs 43
[25-76] days since the first M-ECT; P=0.017). Maintenance ECT allowed a significant
improvement in psychiatric symptoms and global functioning of the patients included
in this study, as well as a decrease in the number of days of hospitalization.
However, our pattern is limited because of its small size; so, further prospective
studies in this field, including larger population is highly recommended.

Zandieh, S., et al. (2013). "The maintenance of wakefulness test in pediatric

narcolepsy." Pediatr Neurol 48(6): 443-446.
Objective tools are needed to assess the response to treatment in pediatric
narcolepsy. This article presents a single-center experience documenting the use of
the maintenance of wakefulness test (MWT) in a pediatric series. This study
reviewed the charts of children with narcolepsy who had an MWT performed between
January 2008 and June 2012. A cutoff was used for mean sleep latency: <8 minutes
for inadequate control of hypersomnia, and >20 minutes to indicate adequate control
on medications. Thirteen tests were performed on 10 children (median age 15.8
years, range 8.7-20.3 years) with narcolepsy, of which six had cataplexy and three
were boys. Comorbid conditions included Prader-Willi syndrome, bipolar affective
disorder, and epilepsy (n = 1 each). The median mean sleep latency for all studies
was 16 minutes (range 5.8-40 minutes). Sleep-onset rapid eye movement sleep events
were seen in three of 13 studies. In seven patients, findings from the MWT resulted
in changes in management. These data suggest that the MWT may be a useful and
feasible test for assessing response to treatment in children with narcolepsy.
Future research is needed to obtain normative MWT data on children with and without
narcolepsy.

Zhang, L., et al. (2013). "Retrospective analysis of factors associated with

quetiapine dosage in the acute and subsequent six-month maintenance treatment of
bipolar disorders." Neuropsychiatr Dis Treat 9: 575-580.
BACKGROUND: Although quetiapine has often been used as monotherapy or
adjunctive therapy in bipolar disorder, there is very limited clinical evidence
regarding prescribing practices for quetiapine as maintenance treatment for bipolar
disorder. METHODS: We reviewed the inpatient and outpatient records of 175 Chinese
patients who received treatment with quetiapine for bipolar disorder both during
and following hospitalization. We compared patients treated with high-dose (>300
mg/day) and low-dose (</=300 mg/day) quetiapine during the acute treatment phase
and in the subsequent 6 months of maintenance treatment, with assessments at months
1, 3, and 6. Multifactor logistic regression analysis was performed to identify
factors associated with quetiapine dosage. RESULTS: The proportion of patients
receiving combination therapy of quetiapine and a mood stabilizer as acute and
maintenance treatment was 99.4% and 84.6%, respectively. The mean dose of
quetiapine when used for acute treatment in the 175 patients was 395.7 mg/day. The
following factors were found to be independently associated with use of high-dose
quetiapine: male gender (odds ratio [OR] 2.712, 95% confidence interval [CI] 1.372-
5.362, P < 0.01), a manic or mixed episode (OR 2.786, 95% CI 1.362-5.699, P <
0.01), and psychotic features (OR 2.658, 95% CI 1.318-5.361, P < 0.01). In the
subsequent 6 months, the mean dose of quetiapine prescribed steadily decreased to
375.0 mg/day, 330.6 mg/day, and 293.7 mg/day at months 1, 3, and 6. The main
factors associated with high-dose quetiapine in maintenance treatment were male
gender (month 1, OR 2.761; month 3, OR 2.583; month 6, OR 2.686; P < 0.01) and a
manic or mixed episode (month 1, OR 2.626; month 3, OR 2.334; P < 0.01).
CONCLUSION: Higher doses of quetiapine (>300 mg/day) are more likely to be
prescribed to patients who are male, those who are experiencing a manic or mixed
episode, and those who have psychotic features during acute treatment of bipolar
disorder. For patients who remain clinically stable during the subsequent months,
the quetiapine dose should be adjusted according to patient gender and the most
recent type of episode experienced.
Zhang, Y., et al. (2013). "Antidepressants for bipolar disorder: A meta-analysis of
randomized, double-blind, controlled trials." Neural Regen Res 8(31): 2962-2974.
OBJECTIVE: To examine the efficacy and safety of short-term and long-term use
of antidepressants in the treatment of bipolar disorder. DATA SOURCES: A literature
search of randomized, double-blind, controlled trials published until December 2012
was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central
Register of Controlled Trials databases. The keywords "bipolar disorder, bipolar I
disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia,
mixed mania and depression, rapid cycling and bipolar disorder", AND
"antidepressant agent, antidepressive agents second- generation, antidepressive
agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake inhibitor,
serotonin uptake inhibitor, and tricyclic antidepressant agent" were used. The
studies that were listed in the reference list of the published papers but were not
retrieved in the above-mentioned databases were supplemented. STUDY SELECTION:
Studies selected were double-blind randomized controlled trials assessing the
efficacy and safety of antidepressants in patients with bipolar disorder. All
participants were aged 18 years or older, and were diagnosed as having primary
bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers
were used in experimental interventions. Placebos, mood stabilizers, antipsychotics
and other antide pressants were used in the control interventions. Studies that
were quasi-randomized studies, or used antidepressants in combination with
antipsychotics in the experimental group were excluded. All analyses were conducted
using Review Manager 5.1 provided by the Cochrane Collaboration. MAIN OUTCOME
MEASURES: The primary outcome was the response and switching to mania. The
secondary outcomes included remission, discontinuation rate, and suicidality.
RESULTS: Among 5 001 treatment studies published, 14 double-blind randomized
controlled trials involving 1 244 patients were included in the meta-analysis.
Eleven short-term studies and three maintenance studies were included. Studies
suggested that patients treated with antidepressants were not significantly more
likely to achieve higher response and remission rates in the short-term or long-
term treatment than patients treated with placebo and other medications.
Antidepressants were not associated with an increased risk of discontinuation,
relapse or suicidality. When one antidepressant was compared with another, no
significant difference in efficacy and tolerability was found. CONCLUSION: Existing
evidence of efficacy does not support the short-term or long-term application of
antidepressant therapy in patients with bipolar disorder, although the tolerability
and safety of antidepressants have been generally acknowledged. There is a need for
large-sample, double-blind, randomized controlled trials to elucidate the role of
antidepressants in patients with different subcategories of bipolar disorder.

Zupancic, M. and M. L. Gonzalez (2012). "Aripiprazole in the acute and maintenance

phase of bipolar I disorder." Ther Clin Risk Manag 8: 1-6.
Bipolar affective disorder is a disabling illness with substantial morbidity
and many management challenges. Traditional mood stabilizers such as lithium,
valproate, and carbamazepine are often inadequate in controlling symptoms both
during the acute and maintenance phase of treatment. Aripiprazole is a second-
generation antipsychotic with a unique mechanism of action. Evidence suggests that
it is effective in acute manic and mixed states. There are limited data to suggest
its efficacy as a maintenance agent. Future studies will be needed to better define
the role of aripiprazole relative to other traditional pharmacologic agents.

Zupancic, M. L. (2011). "Role of atypical antipsychotics in rapid cycling bipolar

disorder: a review of the literature." Ann Clin Psychiatry 23(2): 141-149.
BACKGROUND: The role of atypical antipsychotics in the management of bipolar
disorder continues to expand. This review summarizes the literature on use of
atypicals in rapid cycling bipolar disorder in clinical practice and highlights
areas for future study. METHODS: A PubMed search was done using keywords rapid
cycling, atypical antipsychotics, refractory bipolar, aripiprazole, clozapine,
olanzapine, risperidone, quetiapine, and ziprasidone. Reference lists from original
peer-reviewed articles, review articles, and book chapters were reviewed and
articles were extracted. RESULTS: Data on the use of atypical antipsychotics in
rapid cycling bipolar disorder are sparse. Atypical antipsychotics may be effective
as anti-manic agents during acute mania and may reduce depressive symptoms when
used for short and intermediate durations. Their efficacy as mood stabilizers in
maintenance therapy has not been demonstrated. CONCLUSIONS: The study of atypical
antipsychotics in rapid cycling bipolar disorder is in its infancy. Although
atypical antipsychotics are useful in acute mania, current data do not support
their use as maintenance agents. Future double-blind, randomized studies are needed
to establish their efficacy relative to traditional mood stabilizers and their
utility as adjuvant agents in this subset of patients.