Adjunctive Nutriceuticals

Patients may be actively involved in their own treatment whether or not it is evident
during scheduled appointments. Patients frequently investigate a wide range of treatment
options, some well studied and others only anecdotal. Acupuncture, homeopathy, or dietary
supplements (nutriceuticals) with no known contraindications may be allowed, to encourage
patient empowerment in his or her treatment. However, it remains important to remind
patients that such interventions may have significant interactions and adverse effects, such as
treatment-emergent affective switch or drug-drug interactions (e.g., with St. John's wort)
Similar to other treatments, complementary and alternative medicine interventions should be
recorded in the clinical chart along with associated clinical changes.
This section focuses on the use of various adjunctive dietary supplements, which have
been assessed in uncontrolled and controlled studies in patients with mood disorders. Across
interventions and across studies, efficacy has been variable. Although tolerability has
generally been good, there have been sporadic reports of treatment-emergent affective switch.
The

omega-3

polyunsaturated

fatty

acids

eicosapentaenoic

acid

(EPA)

and

docosahexaenoic acid (DHA) are naturally occurring substances that like lithium and
valproate have effects on intracellular signaling that include inhibiting protein kinase C and
hence may have utility in bipolar disorders. Controlled studies of adjunctive EPA and DHA in
bipolar depression and unipolar depression have had variable results.
In randomized controlled trials in treatment-resistant bipolar depression and rapid
cycling, adjunctive omega-3 fatty acid therapy yielded benefit in two studies (Frangou et al.
2006; Stoll et al. 1999) but was no better than placebo in one study (Keck et al. 2006b)
Omega-3 fatty acid dosages varied across studies: EPA 6.2 g/day plus DHA 3.4 g/day (Stoll et
al. 1999), EPA 6 g/day (Keck et al. 2006b), and EPA 1 or 2 g/day (Frangou et al. 2006) Also,
a 10-patient pilot monotherapy preventive study of DHA 2 g/day in pregnant women with
bipolar disorder was negative (Marangell et al. 2006) Omega-3 fatty acids were generally
well tolerated.
Inositol is a naturally occurring substance that is important in intracellular signaling, and
inositol depletion has been proposed as a mechanism of action of lithium, so that it could
have utility in bipolar disorders. Controlled studies of adjunctive inositol in bipolar
depression and unipolar depression have also had variable results.
In randomized, controlled studies in treatment-resistant bipolar depression, adjunctive
inositol was no better than placebo in two trials (Chengappa et at. 2000; Eden Evins et at.
2006) and no better or worse than adjunctive lamotrigine or adjunctive risperidone in one

study (Nierenberg et al. 2006b) In these studies, inositol was started at 2.5-6 g/day, increased
every 27 days by 46 g/day to as high as 625 g/day, with mean final dosages ranging
between approximately 9.5 and 14 g/day administered in three divided doses. Also, metaanalysis of four controlled trials involving a total of 144 patients with bipolar or unipolar
depression failed to reveal benefit with inositol (Taylor et al. 2004b) Inositol was generally
well tolerated, but there have been case reports of treatmentemergent affective switch (Levine
et al. 1996)
The vitamin folate is a methyl donor for multiple reactions that influence, among other
things, amino acid metabolism and methylation of homocysteine to form S-adenosyl-Lmethionine (SAMe, discussed later in this chapter) Moreover, low plasma and red blood
folate concentrations have been observed in unipolar major depressive disorder; therefore,
folate administration might have antidepressant effects. Controlled studies of folate in bipolar
depression are lacking and in unipolar depression have had variable results.
Thus, meta-analysis of three 8-week, controlled trials involving a total of 247 patients
with unipolar depression suggested possible benefit with folate as an adjunct but not as an
alternative to antidepressants (Taylor et al. 2004a) These studies used folate 500 g/day, and
5-methyltetrahydrofolate at dosages of 15 mg/day and 50 mg/day. Folate was generally well
tolerated.
St. John's wort (extracts of Hypericum perforatum) is a naturally occurring substance with
affinity for several neuroreceptors; therefore, its effects upon serotonin reuptake and
monoamine oxidase inhibition could yield antidepressant effects. Controlled studies of St.
John's wort in bipolar depression are lacking and in unipolar depression have had variable
results.
Meta-analysis of 36 randomized, double-blind, placebo-controlled trials involving 3,320
patients indicated that St. John's wort efficacy compared with placebo was similar in patients
with syndromal unipolar depression but superior in heterogeneous samples of patients with
syndromal and subsyndromal unipolar depression (Linde et al. 2005) Also, meta-analysis of
14 randomized, double-blind, controlled trials involving 2,283 patients indicated that St.
John's wort compared with antidepressants had similar efficacy in patients with unipolar
depression (syndromal in 13/14 studies, subsyndromal in 1/14 studies) (Linde et al. 2005).
Thus, St. John's wort may offer benefit in patients with mild to moderate unipolar depression.
Dosages in these studies ranged between 350 and 1,500 mg/day, with 900 mg/day being the
most common dosage. St. John's wort was generally well tolerated, but drug interactions,
presumably related to induction of cytochrome P450 3A4 and possibly 2C19 (Markowitz et

al. 2003; Wang et al. 2004), and treatment-emergent affective switch have been reported
(Moses and Mallinger 2000; Nierenberg et al. 1999; O 'Breasail and Argouarch 1998; Schneck
1998).
SAMe is a naturally occurring methyl donor involved in cerebral transmethylation
reactions that affect, among other things, monoamine neurotransmission and thus could have
activity in mood disorders. SAMe has been prescribed for depression in Europe for over 30
years and has been available as an over-the-counter dietary supplement in the United States
since the late 1990s. Dosages for depression commonly range from 400 to 1,600 mg/day.
In meta-analyses of controlled depression studies, SAMe efficacy was superior to placebo
and similar to TCAs (Bressa 1994). Although SAMe is generally well tolerated, treatmentemergent affective switch has been reported with SAMe in patients with bipolar depression.
Thus, SAMe yielded switches in 9/11 bipolar and 0/11 unipolar patients in one report (Carney
et al. 1989) and 2/6 bipolar and 0/3 unipolar patients in another (Lipinski et al. 1984). Hence,
it appears prudent to avoid SAMe in patients with bipolar disorders, particularly in the
absence of an antimanic agent.
Adjunctive Vagus Nerve Stimulation
VNS involves surgical implantation of an electronic device similar to a pacemaker with
an electrode connecting it to the left vagus nerve and delivering lowfrequency, chronic
intermittent-pulsed electrical signals to the left vagus nerve, yielding deep brain and limbic
cortical stimulation. VNS was approved for the adjunctive treatment of medically refractory
partial-onset seizures in adults and adolescents over 12 years of age in 1997 and in 2005 was
approved by the FDA for the adjunctive long-term treatment of chronic or recurrent
depression resistant to four or more antidepressants in adults but not for rapid-cycling bipolar
disorder.
In a multicenter, randomized, controlled, masked trial, adjunctive VNS appeared to have
modest efficacy (NNTs for response of 20 and 11 on the primary and a secondary outcome
measure, respectively) in patients with treatmentresistant unipolar or bipolar depression
(Rush et al. 2005a). A 12-month, multicenter, nonrandomized, controlled, naturalistic
treatment as usual comparator study was more encouraging (NNT=8) (George et al. 2005). In
these studies, patients with bipolar disorders accounted for approximately 10% of participants, but patients with a history of psychosis or rapid-cycling bipolar disorder were
excluded. Adjunctive VNS was generally well tolerated, but treatmentemergent affective
switch occurred sporadically.

In a 10-week, multicenter, randomized, controlled, masked trial in chronically ill,

treatment-resistant, nonpsychotic, unipolar (n=210) and bipolar (n=25) depression, adjunctive
VNS compared with adjunctive sham VNS yielded a nonsignificantly higher Ham-D
response (>50% decrease, primary outcome) rate (15.2% vs. 10.0%, NNT=20) but a
significantly higher Inventory of Depressive Symptomatology-Self-Report response (50%
decrease, secondary outcome) rate (17.0% vs. 7.3%, NNT=11) (Rush et al. 2005a). VNS was
generally well tolerated, with voice alteration, increased cough, neck pain, dyspnea, and
dysphagia being the most common adverse effects, and only 1.3% (3/235) leaving the study
because of adverse events. Two of 235 patients (0.9%) had treatment-emergent affective
switch (YMRS? 15), which occurred at or within 8 weeks of VNS initiation and resolved
spontaneously after 1-2 weeks without altering of VNS treatment. One of these patients had a
prior diagnosis of bipolar I disorder.
In a 12-month, multicenter, open, uncontrolled, extension study in unipolar (n=185) and
bipolar (n=20) patients, VNS plus treatment as usual yielded a final Ham-D response (50%
decrease) rate of 27% (Rush et al. 2005b). Voice alteration, dyspnea, and neck pain were the
most frequent adverse events. Six of 205 patients (2.9%, including the three patients
mentioned in the preceding paragraph) had treatment-emergent affective switch (YMRS
15), and in one of these patients VNS was turned off during a manic episode. Three of these
patients had a prior diagnosis of bipolar disorder.
In a 12-month, multicenter, nonrandomized, controlled, naturalistic study in treatmentresistant, nonpsychotic, unipolar (n=178) and bipolar (n=22) depression, VNS plus treatment
as usual compared with treatment as usual only was associated with a significantly higher
final Ham-D response (50% decrease) rate (27% vs. 13%, NNT=8) (George et al. 2005).
Bipolar and unipolar disorder patients had similar response rates.
Encouraging uncontrolled open-label case (Bajbouj et al. 2006) and case series
(Marangell et al. 2008) data suggest that controlled trials of adjunctive VNS in treatmentresistant rapid-cycling bipolar disorder are warranted.
The cost and invasiveness of VNS and the relatively modest efficacy raise costbenefit
concerns. Indeed, often patients find their insurance companies deny reimbursement for VNS.
Adjunctive Transcranial Magnetic Stimulation
TMS strives to relieve depression by administration of nonconvulsive stimulation (with
high frequency) or inhibition (with low frequency) of cerebral activity. In late 2008, the
NeuroStar TMS system was approved for the treatment of (unipolar) major depressive

disorder in patients who fail to achieve satisfactory improvement from one prior
antidepressant at or above the minimal effective dose and duration in the current episode.
The NeuroStar TMS registration trial was a multicenter, randomized, shamcontrolled
study in patients with unipolar major depressive disorder resistant to one to four
antidepressant medications during the current or most recent episode (O'Reardon et al. 2007)
The study excluded patients with histories of psychosis, bipolar disorder, obsessivecompulsive disorder, posttraumatic stress disorder, eating disorder, resistance to ECT, prior
TMS or VNS treatment, pregnancy, seizure disorders or medical or medication risk factors
for seizure disorders, or ferromagnetic material in or in close proximity to the head. After a 1week lead-in phase without psychotropic treatment (other than limited anxiolytics/hypnotics),
patients received active TMS or sham treatment 5 days per week for 6 weeks, followed by 3
weeks of tapering active TMS or sham treatment and starting antidepressant medication.
The left dorsolateral prefrontal cortex was the treatment location, 5 cm anterior to the
motor threshold location. TMS was administered at 120% magnetic field intensity relative to
the patient's observed motor threshold, at a repetition rate of 10 magnetic pulses per second,
with a stimulus train duration (on time) of 4 seconds and an intertrain interval (off time) of 26
seconds, yielding a total of 80 magnetic pulses per minute of treatment. Treatment sessions
lasted 37.5 minutes and thus involved 3,000 (37.5 x 80) magnetic pulses.
For the primary outcome measure (baseline to week 4 MADRS decrease), 155 patients
receiving active TMS compared with 146 receiving sham TMS tended to show benefit
(P=0.057) When four active and two sham TMS patients with baseline MADRS scores < 20
were excluded, the trend became statistically significant (P=0.038) At the week 6 secondary
efficacy time point, active TMS also tended to be superior to sham TMS for the entire sample
(P= 0.057) and for the subset of patients with baseline MADRS > 20 (P= 0.052) In contrast,
MADRS response ( 50% decrease from baseline) rates were significantly higher for active
TMS compared with sham TMS, not only at week 4 (18.1% compared with 11.0%, P=0.045,
NNT =15), but also at week 6 (23.9% compared with 12.3%, P=0.007, NNT=9) Application
site pain was more common with active TMS than with sham TMS (35.8% compared with
3.8%), and although this had the potential to compromise blinding, it was not related to the
primary outcome measure. No seizure was reported in this study as well as in additional
experience, involving a total of 10,000 outpatient TMS sessions (Janicak et al. 2008)
There are at least seven parameters involved in TMS: 1) number of trains per session, 2)
duration of trains, 3) stimulation frequency, 4) stimulation intensity, 5) stimulation location,
6) number of sessions per week, and 7) total number of sessions. Results in prior smaller

controlled studies were variable, perhaps understandably, given the number of parameters
involved. For example, in randomized, controlled studies in patients with treatment-resistant
bipolar depression, antidepressant effects with TMS as compared with sham TMS were
superior in one trial (Dolberg et al. 2002) and similar in another trial (Nahas et al. 2003)
In an open uncontrolled case series, high-frequency right prefrontal TMS yielded
decreases in Bech-Rafaelsen Mania Scale scores (Michael and Erfurth 2004) TMS is
generally well tolerated, but adverse effects may include seizures (Tharayil et al. 2005) and
treatment-emergent affective switch (Garcia-Toro 1999), although the risk of the latter may
be no greater than with sham TMS (Xia et al. 2008)
TMS is contraindicated in patients with 1) conductive, ferromagnetic, or other magneticsensitive metals in the head or within 30 cm of the treatment coil; or 2) any (even more than
30 cm away from the treatment coil) implanted devices activated or controlled by
physiological signals, such as pacemakers, implantable (and even wearable) cardioverter
defibrillators, and vagus nerve stimilators. The United States NeuroStar TMS System user
manual also includes warnings regarding the risks of seizures and worsening of depression or
suicidality (an antidepressant class warning) Patients must wear earplugs or similar hearing
protection devices with a rating of 30 db of noise reduction, and similar protection is also
advised for the clinical operator. In controlled trials, the most common adverse events were
headache and temporary mild discomfort at the site of stimulation during and/or shortly after
treatment.
In summary, TMS is a generally well-tolerated, recently approved treatment for unipolar
major depressive disorder, with a high single-digit NNT for response compared with sham
TMS. Large randomized controlled trails are needed to assess the efficacy and safety of TMS
in acute bipolar depression.

Special Subpopulations With Bipolar Depression

Optimal practice of evidence-based medicine involves applying findings of medical
research in a fashion that yields the most favorable benefit-risk ratio for individual patients.
This section describes several subpopulations with distinctive therapeutic implications for
clinical decision making in the management of acute bipolar depression.
Patients With a Prior History of Antidepressant-Induced Affective Switch or Rapid
Cycling

Patients with a prior history of antidepressant-induced treatment-emergent affective

switch or rapid cycling are at particularly high risk for mood destabilization if treated with
antidepressants (Truman et al. 2007; Wehr et al. 1979) In such patients, it appears prudent to
emphasize mood stabilizers, second-generation antipsychotics, and no antidepressant
interventions (including psychotherapy and ECT) rather than antidepressants in efforts to
attenuate the risk of switching. If antidepressants are used, it is prudent to avoid
antidepressant(s) that have destabilized mood in the past and, if feasible, even classes of
antidepressants that have destabilized mood in the past. It is crucial to have sufficient
antimanic coverage. The optimal duration of antidepressant administration after achieving
response or remission may range from as brief as a few days (i.e., not waiting for recovery
from the acute episode) to as long as 2 months, depending on the degree of historical mood
instability.
Patients With Depression-Mania-interval Sequence
Patients with the sequence of first depression, then mania, then interval of euthymia (DMI
sequence) may be at particularly high risk of treatment-emergent affective switch with
antidepressants because mood elevation naturally follows depression (Kessing 1999) Also,
patients with the DMI sequence appear to have poorer responses to lithium maintenance
compared with the classic sequence of first mania, then depression, then interval of
euthymia (MDI sequence) (Faedda et al. 1991; Grof et al. 1987; Haag et al. 1987; Kukopulos
et al. 1980; Maj et al. 1989) However, the utility of these observations appears to be limited
by the existence of a substantial number of patients who have irregular episode sequences.
Nevertheless, in patients with a clear DMI sequence, it appears prudent to emphasize mood
stabilizers, second-generation antipsychotics, and nonantidepressant interventions in efforts
to attenuate the risk of switching and to limit the duration of adjunctive antidepressant
exposure, in some instances to as little as a few days after achieving response or remission.
Patients With a Prior History of Psychotic Mania
Because of the severity of mania in patients with a history of psychotic mania
(particularly with antidepressants), the consequences of a treatment-emergent affective switch
maybe sufficient to warrant minimizing administration of antidepressant medications. Thus,
in such patients, it appears prudent to emphasize mood stabilizers, second-generation
antipsychotics, and nonantidepressant interventions in efforts to attenuate the risk of
switching. If antidepressants are necessary, combinations of mood stabilizers and second-

generation antipsychotics may be necessary to provide sufficient protection against the risk of
treatment-emergent affective switch.
Patients With Bipolar II Disorder
Bipolar II disorder is a condition with substantial interpatient variability. Thus, some
patients with bipolar II disorder may have an illness more like major depressive disorder,
with relatively infrequent recurrent pure (with minimal mixed features) depressive episodes,
and rare hypomanias, and, with antidepressants, may experience relief of depression without
treatment-emergent affective switch into hypomania or accelerating episodes. Antidepressants
may be considered foundational treatments for such patients and may prove to be effective
not only acutely but also in longer-term treatment. In academic centers with specialty clinics,
such patients may more often be referred to major depressive disorder clinics, where
clinicians may view antidepressants as treatments of choice for this type of patient with
bipolar II disorder.
However, other patients with bipolar II disorder may have an illness more akin to bipolar
I disorder, with relatively frequent recurrent depressive episodes that include mixed features
(in some instances concurrently experiencing syndromal depression and hypomania [i.e.,
dysphoric hypomania]), common hypomanias, in some instances rapid cycling, and with
antidepressants experience inadequate relief of depression and/or treatment-emergent
affective switch or cycle acceleration. For such patients, mood stabilizers or atypical
antipsychotics, instead of antidepressants, may be considered foundational treatments. In
academic centers such patients may more often be referred to bipolar disorder clinics, where
clinicians may view antidepressants as potentially problematic for this type of patient with
bipolar II disorder.
Clinicians in the community, compared with providers in subspecialty major depressive
disorder or bipolar disorder clinics, arguably face greater challenges related to encountering a
full spectrum of clinical heterogeneity in patients with bipolar II disorder and need to
administer carefully individually tailored treatments, balancing the relative risks and benefits
of intervening with antidepressants.

Conclusion
The depressive phase of bipolar disorder is particularly challenging because of the
chronicity of syndromal and subsyndromal symptoms, the significant morbidity and

mortality, the common phenomenon of treatment resistance, and the limited evidence base to
inform clinical practice. Thus, clinical need is profoundly underaddressed by the two FDAapproved medications for the treatment of acute bipolar depression (olanzapine plus
fluoxetine combination and quetiapine monotherapy) when compared with the nine approved
for treatment of acute mania and the five approved for bipolar prophylaxis.
The hierarchy of prioritized treatment options in Table 7-1 provides a schema for
clinicians seeking to apply the limited but dynamic medical evidence base to the management
of acute bipolar depression. The treatments in Tier I (OFC and quetiapine monotherapy) merit
high priority because they have the most compelling evidence of efficacy in acute bipolar
depression.
However, tolerability limitations of the Tier I treatments commonly result in clinicians
preferring to use unapproved treatments such as the Tier II treatments (lithium and
lamotrigine), which also receive high priority. Lithium and lamotrigine have less compelling
evidence of efficacy compared with the approved treatments but have mitigating qualities
such as tolerability and maintenance indications that may lead to their use instead of the
approved treatments.
Adjunctive antidepressants (Tier III options) are also commonly used in spite of having
even more limited evidence of efficacy compared with lithium or lamotrigine and concerns
regarding the risk of treatment-emergent affective switch. Determining the appropriate
priority for adjunctive antidepressants in bipolar disorder in general and for individual
patients in particular constitutes one of the most controversial challenges faced by researchers
and clinicians. Adjunctive antidepressants are still deemed to be high-priority options by
some researchers, particularly in Europe, and many clinicians, even in North America.
Additional research is needed to provide an adequate evidence base to address this important
issue.
The other treatments in Tier III (other mood stabilizers, other secondgeneration
antipsychotics, ECT, and adjunctive psychotherapy) merit intermediate priority because they
also have limited evidence of efficacy in acute bipolar depression. However, Tier III options
may be attractive for selected patients and in certain circumstances considered early on (e.g.,
psychotherapy or ECT in pregnant women with acute bipolar depression) For some of these
treatments (e.g., aripiprazole monotherapy and ziprasidone monotherapy and ECT), the
efficacy and/or tolerability limitations leading to their placement in Tier III are already clear.
For other Tier III treatments (e.g., adjunctive psychotherapy), advances in research,
familiarity, and/or availability ultimately may be sufficient to merit their consideration for

placement in higher tiers.

The Tier IV treatment options (thyroid hormones, pramipexole, modafinil, topiramate,
stimulants, sleep deprivation, light therapy, nutriceuticals, vagus nerve stimulation, and
transcranial magnetic stimulation) have even more limited evidence of efficacy than Tier I, II,
or III options and are considered lowpriority interventions, and are most often reserved for
patients who are treatment resistant or intolerant to Tier 1-411 treatments. However, for some
of these treatments (e.g., pramipexole and modafinil) advances in research may ultimately
provide sufficient evidence to merit their consideration for placement in higher tiers.
Data to support the evidence-based management of acute bipolar depression are
beginning to emerge. Table 7-3 provides selected clinical decisions and evidence-based
recommendations. Clearly, additional research is needed to better inform practice and enable
clinicians and patients to address the substantial clinical challenges encountered in the
management of bipolar depression.
Case Study: Management of Acute Bipolar Depression
Ms. Black is a 31-year-old, married, Caucasian attorney with a history of mood swings
since her midteens. In her teenage years, she developed depressive episodes manifested by
pervasive sadness, anhedonia, social isolation, hypersomnia (sleeping 11-12 hours per night),
lethargy, guilty ruminations, increased appetite with weight gain, and passive thoughts of
death. These episodes lasted about 2-4 weeks, followed by 2-4 weeks of her mood returning
to a baseline level of poor self-esteem and sleeping 9-10 hours per night but with good occupational and social function. Her mood would continuously alternate between these two
states of functionally disabling depression and intervals with adequate function but poor selfesteem.
At age 21, while in college, Ms. Black first sought psychiatric care and was diagnosed with
double depression (major depressive disorder plus dysthymic disorder) Fluoxetine up to 20
mg/day for 2 months was ineffective, with dosage limited by intolerable nausea. Sertraline up
to 100 mg/day for 2 months was also ineffective, with dosage this time limited by intolerable
diarrhea. Venlafaxine extended-release formulation was started at 37.5 mg/day and yielded
relief of depression within 1 week, and the patient reported feeling as if her whole life had
been abnormally depressed until therapy with venlafaxine. She began to recognize multiple
new opportunities in her life and experienced gradually increasing self-confidence,
graduating with honors and deciding to apply to graduate school. One month after Ms. Black
moved across the country to attend law school, she had a return of the depressive symptoms.
The patient lost confidence in treatment and did not see a psychiatrist for another 2 years.

However, as her depressive symptoms worsened to the point of interfering with her academic
function, she returned to psychiatric care and started taking bupropion sustained-release
formulation 100 mg/day, which was discontinued after 1 week because of intolerable
irritability, agitation, and insomnia. As a result of the inefficacy of prior antidepressant
medication trials, a psychopharmacology consultation was sought.
TABLE 7-3 Selected clinical decisions and evidence-based recommendations
Clinical decisions
Evidence based recommendations/references
Initial treatment of acute bipolar
depression
High-priority options

Olanzapine plus fluoxetine (Brown et al. 2006; Tohen et

al. 2003)
Quetiapine (Calabrese et al. 2005; Thase et al. 2006)
Lithium (Zornberg et al. 1993)
Lamotrigine (Brown et al. 2006; Calabrese et al. 2008)
Mood stabilizer plus antidepressant (Gijsman et al.

Controversial option
Bipolar

depression

2004; Nemeroff et al. 2001; Sachs et al. 2007)

breaking Optimize mood stabilizer dosage (Nemeroff et al.

trough mood stabilizer

Bipolar
depression

2001)
despite Optimize mood stabilizer dosage (Nemeroff et al. 2001)

optimized mood stabilizer

Avoid venlafaxine and tricyclic
antidepressants because of
higher switch risk

Add antidepressant? (Gijsman et al. 2004; Nemeroff et

al. 2001; Young et al. 2000)
Higher switch rate with venlafaxine (Post et al. 2006; Vieta
et al. 2002)
Higher switch rate with tricyclic antidepressants (Cohn et
al. 1989; Gijsman et al. 2004; I Iimmelhoch et al. 1991;
Nemeroff et al. 2001; Sachs et al. 1994; Silverstone 2001)

Upon careful questioning of both the patient and her fiance, it was determined that over
the last 2 years she had experienced frequent 2-week periods with improved function, during
which she could catch up on her lost productivity and felt that she was more talented and
energetic than the rest of her class because she could rapidly more than make up for times
with decreased productivity. During these productive periods, she would be more gregarious
but also on occasion irritable, particularly if others (including her fiance) interfered with her
work. She slept 7 hours, in contrast to requiring the usual 910 hours, and felt energetic
rather than drowsy during the day. Her thoughts would come quickly, and her physical

activity was increased to a level that at least some peers found excessive. She had increased
libido, which both she and her fiance agreed helped enhance intimacy in their relationship.
Ms. Black had no significant medical problems. She used marijuana in her late teens but
had not used any other illicit drugs or abused alcohol. She denied any history of psychosis or
psychiatric hospitalization. She reported a family history of depression in a brother and her
maternal grandmother, and her mother was taking divalproex and paroxetine for bipolar
depression.
Ms. Black was informed that her history indicated a diagnosis of bipolar II disorder. After
a discussion of the potential benefits and risks of various treatments for bipolar depression,
Ms. Black agreed to a trial of lamotrigine. Following the recommended gradual titration, a
dosage of 200 mg/day of lamotrigine was reached after 6 weeks, at which point she began to
report improvement in her mood and over the next month experienced remission of
depressive symptoms. She reported tolerating lamotrigine well. She continued with euthymic
mood for 4 years, until a month after the birth of her first child. Immediately prior to and
during pregnancy she had tried to taper and discontinue lamotrigine but eventually plateaued
the dosage at 100 mg/day in order to control symptoms of irritability and depression. One
week after delivery, after deciding to forgo breastfeeding, she increased lamotrigine back to
200 mg/day. Three weeks later she developed a major depressive episode. Mood stabilized
after lamotrigine was increased to 250 mg and remained stable for another 15 months until
the birth of her second child. She suffered another major depressive episode, again within 1
month of delivery, this time despite uninterrupted treatment with lamotrigine 250 mg/day, but
has since been stable for 3 years, after lamotrigine was increased to 300 mg/day.
In summary, this woman who struggled with depression had inadequate efficacy and/or
tolerability to fluoxetine, sertraline, and bupropion, and a switch out of depression with
venlafaxine. Careful assessment including information from a significant other revealed a
diagnosis of bipolar II disorder. Based on generally very good tolerability, and the potential
for preventing depression, and in spite of the limited efficacy in acute depression, the patient
received a trial of lamotrigine. She was fortunate enough to have an acute antidepressant response with lamotrigine monotherapy-although she experienced postpartum breakthroughs
that ultimately required increasing the dosage of lamotrigine to 300 mg/day, which was well
tolerated-and has maintained stable mood for 3 years. One concern is that should she have
another child, she may be at risk for yet another postpartum breakthrough depression.

Longer-Term Management of Bipolar Disorders

Terence A. Ketter, M.D.
Po W. Wang, M.D.
The recurrent episodic nature of bipolar disorders and the dysfunction, morbidity, illness
progression, and mortality associated with acute episodes make the prevention of new
episodes one of the most important goals in the management of these conditions.
Lithium was approved by the U.S. Food and Drug Administration (FDA) for bipolar
maintenance therapy in 1974 and for almost three decades was the only approved longer-term
treatment for bipolar disorders. During this time, the robust efficacy of lithium in bipolar
disorders, compared with its much less impressive benefits in other psychiatric conditions,
led to the view that lithium had specific efficacy for bipolar disorders (Soares and Gershon
2000)
Lithium was perceived as being unique because it was effective in acute mania and
maintenance treatment as well as (perhaps to a lesser extent) in acute bipolar depression. In
contrast, first-generation antipsychotics could relieve mania but might exacerbate depression,
and antidepressants could relieve depression but might trigger mania. Thus, first-generation
antipsychotics and antidepressants were considered adjunctive unimodal agents that could
provide acute symptomatic relief for one pole of bipolar disorders. Lithium was considered
the only bimodal agent that could address not only acute episodes of either polarity but also
the disorder as a whole over time. Eventually, the term mood stabilizer (synonymous with
antibipolar medication) was applied to lithium, distinguishing it from other classes of agents
and emphasizing its role as the comprehensive treatment for bipolar disorders.
After two decades, the notion that lithium was the rather than a mood stabilizer was
challenged, when in the middle 1990s divalproex was approved for the treatment of acute
mania. Divalproex was not an antipsychotic, had efficacy for acute mania, and did not appear
to exacerbate the depressive component of the illness. Perhaps by a process of elimination, in
an effort to maintain mutually exclusive psychotropic drug categories, divalproex became
referred to as a mood stabilizer. There is no consensus definition of the term mood stabilizer,
and the FDA does not use the term. However, over time common usage of the term evolved

so that agents with bipolar indications that are not antipsychotics have been referred to as
mood stabilizers. As discussed later in this chapter, because of methodological limitations, the
pivotal divalproex monotherapy maintenance study failed; neither divalproex nor lithium
separated from placebo on the primary outcome measure and thus divalproex monotherapy
has not been approved by the FDA for the longer-term treatment of bipolar disorders.
Similarly, carbamazepine is another agent approved for acute mania that is not an
antipsychotic and does not appear to exacerbate the depressive component of the illness, but
lacks randomized, double-blind, placebo-controlled evidence of maintenance efficacy, and
hence lacks a longer-term indication for the management of bipolar disorders. The term mood
stabilizer is also applied to carbamazepine.
Thus, it was not until 2003, when lamotrigine was approved, that clinicians had a
sanctioned alternative to lithium for the longer-term treatment of bipolar disorders.
Lamotrigine was distinctive in two important ways. First, lamotrigine appeared to stabilize
mood from below; in that it was more effective against depressive than the mood elevation
aspects of the illness (Ketter and Calabrese 2002) Second, lamotrigine was the first, and
remains the only, medication to receive a maintenance indication while lacking an acute
indication. The latter was particularly challenging because one of the fundamental approaches
to selecting treatments for the maintenance treatment phase is to utilize agents that prove
themselves effective in the acute treatment phase. Nevertheless, lamotrigine became the third
anticonvulsant that was not an antipsychotic that was approved to address a component (in
this case maintenance treatment) of bipolar disorders without exacerbating other aspects of
the illness. Thus, over time the term mood stabilizer was also applied to lamotrigine.
In 2004 and 2005, two agents already approved for acute mania, the secondgeneration
antipsychotics olanzapine and aripiprazole, respectively, received FDA approval for the
longer-term treatment of bipolar disorders. In addition, in 2008 quetiapine immediate-release
formulation and, later, extended-release formulation (quetiapine XR) received the first
adjunctive (added to lithium or divalproex) longer-term bipolar treatment indications. These
developments further challenged assumptions regarding longer-term management because
previously, first-generation antipsychotics were considered mere short-term adjuncts for acute
mania, which needed to be discontinued as quickly as possible in order to minimize the risks
of tardive dyskinesia and exacerbation of depressive symptoms in patients with bipolar
disorders. Arguably, the ambivalence of the FDA in granting longer-term approvals for
second-generation antipsychotics (particularly as monotherapy) is evident in the prescribing
information for secondgeneration antipsychotics in monotherapy longer-term bipolar

treatment, which emphasizes utility in the continuation treatment phase more than in the
maintenance treatment phase. Moreover, at least some second-generation antipsychotics have
substantial tolerability limitations that limit their utility in longerterm treatment. Thus, despite
evidence of efficacy, ongoing controversy is expected regarding the roles of olanzapine,
aripiprazole, and adjunctive quetiapine in the longer-term management of bipolar disorders.
Another controversial issue is the role of adjunctive antidepressants in the longer-term
management of bipolar disorders. In the past, these agents were considered mere short-term
adjuncts for acute bipolar depression that needed to be discontinued as quickly as possible in
order to minimize the risk of exacerbation of mood elevation symptoms in patients with
bipolar disorders. However, limited data suggest that the subset (perhaps 15%) of patients
with excellent responses during the acute treatment phase and the continuation treatment
phase may receive benefit from longer-term treatment with these agents (Altshuler et al.
2003)
Thus, four monotherapies (lithium, lamotrigine, olanzapine, and aripiprazole) and one
adjunctive (added to lithium or divalproex) therapy (quetiapine/ quetiapine XR) have been
approved for the longer-term treatment of bipolar disorders. Two of these agents that are not
antipsychotics (lithium and lamotrigine), along with divalproex and carbamazepine, are
referred to as mood stabilizers. In contrast, the antipsychotics with evidence of longer-term
efficacy (olanzapine, aripiprazole, quetiapine/quetiapine XR) are still called secondgeneration
(or atypical) antipsychotics rather than mood stabilizers, despite each not only having
evidence of efficacy for longer-term treatment but also having acute treatment phase
indications. In addition to these advances in pharmacological longer-term treatment,
emerging data suggest the adjunctive psychosocial interventions could contribute importantly
to prevention of relapse and recurrence in patients with bipolar disorders.
Preceding chapters in this volume have described the management of acute manic and
mixed episodes, and major depressive episodes in patients with bipolar disorders. In this
chapter we focus on longer-term management of bipolar disorders, initially in the temporal
order encountered clinically: first the continuation treatment phase and then the maintenance
treatment phase, as described in Chapter 4 of this volume, Multiphase Treatment Strategy for
Bipolar Disorders. This is followed by a discussion of clinical implications of bipolar
disorder longer-term treatment trial designs and a description of the individual approved and
unapproved longer-term treatment options for bipolar disorders.
Continuation Treatment Phase

The continuation treatment phase provides a crucial bridge between the acute treatment
phase and the maintenance treatment phase and shares some characteristics with each. This
phase starts with either response or (ideally) remission, so that subsyndromal symptoms may
be present or absent, respectively. Thus, overt or covert (partially or fully suppressed) mood
symptoms are considered to be present. The continuation treatment phase ends ideally with
recovery, leading to the maintenance treatment phase. The duration of this phase is the time
needed to exceed the natural episode duration (Prien and Kupfer 1986), which is commonly
considered to be 2-6 months in patients with bipolar disorders.
The distinction between the continuation treatment phase and the maintenance treatment
phase is commonly blurred in clinical research and clinical practice (Quitkin et al. 1976) For
example, contemporary longer-term registration studies in patients with bipolar disorders tend
to be continuation/maintenance studies, with two stages: 1) a briefer open stabilization stage
corresponding to the acute treatment phase and the early/middle part of the continuation
treatment phase, and 2) a longer randomized, double-blind, placebo-controlled stage
corresponding to the middle/late continuation treatment phase and the maintenance treatment
phase (Figure 8-1) For example, in the olanzapine longerterm treatment registration study,
patients were only euthymic for 2 weeks prior to randomization, perhaps explaining why the
longer-term indication in the prescribing information for this agent appears to resemble more
a description of the continuation treatment phase than the maintenance treatment phase.

FIGURE 8-1. Contemporary randomized controlled continuation/ maintenance

study paradigm.
Depending on the duration of mood stability required in the open stabilization stage, the randomized controlled stage may or may not include an early continuation treatment phase component (top, gray portion to left of dotted line) in addition to the later maintenance treatment
phase component.

The therapeutic goals of the continuation treatment phase include attaining sufficient and
persistent enough relief of mood symptoms to yield recovery, and preventing relapse.
Medication strategies focus on balancing the dual and at times conflicting needs for efficacy
and tolerability. This primarily involves striving to continue full doses of mood stabilizer(s)
and adjuncts that yielded remission as tolerated. However, it may be necessary to decrease
doses to relieve adverse effects or increase doses to relieve subsyndromal symptoms.
Suboptimal timing and rate of medication reduction and discontinuation can entail
substantial risks. Medication reduction and/or discontinuation that is too early risks loss of
remission and relapse and can undermine symptomatic recovery. Similarly, medication
reduction and/or discontinuation that is too rapid risks relapse or recurrence. In contrast,
attempts to decrease medication burden that are too late or slow risk nonadherence and
erosion of the therapeutic alliance and can undermine functional recovery.
In longer-term treatment clinical trials that have only a brief period of stability prior to
randomization, patients have not yet attained recovery, so those assigned to placebo are at
high risk for relapse back into the index episode. In the survival curve, this can result in a
precipitous (exponential) decrease in the percentage of patients taking placebo remaining in
remission (Figure 8-2, black line) In trials with a longer period of stability prior to
randomization, patients have attained recovery, so those assigned to placebo are at a risk for
recurrence of a new episode, which in many instances evolves over a much longer time frame
than relapse. In the survival curve, this may result in a gradual (linear) decrease in the
percentage of patients taking placebo remaining in remission (Figure 8-2, gray line) Thus, as
described in more detail later in this chapter, the duration of stability prior to randomization
influences the interpretation of longer-term treatment trials. Very brief periods of initial
stability indicate that the randomized stage may have a substantial continuation treatment
phase component, whereas longer periods of initial stability suggest that the randomized
stage may primarily represent the maintenance treatment phase.