C H A P T E R
60
Treatment of Psychiatric Disorders in
Chronic Kidney Disease Patients
John H. Fantona, Michael J. Germaina and Lewis M. Cohenb
a
Tufts University School of Medicine, Child Behavioral Health, Springfield, MA, USA,
b
Tufts University School of Medicine, Baystate Renal Palliative Care Initiative,
Baystate Medical Center, Springfield, MA, USA
SCOPE OF THE PROBLEM
Practical aspects of treatment of patients with CKD
and psychiatric disorders, which include making use of
community resources to attend to psychosocial problems,
and pharmacologic considerations for nephrologists, are
necessary to ensure the best patient care. Well-designed
studies on the treatment of psychiatric disorders in
patients with CKD are almost non-existent. The few
investigations that exist are primarily limited to ESRD,
rather than encompassing patients with the full range
of CKD. There are numerous obstacles encountered by
nephrologists in designing and conducting large-scale,
randomized, controlled, clinical trials. These problems
are magnified in studying CKD patients with co-morbid
neuropsychiatric disorders.1,2 It is hardly surprising that
patients with schizophrenia, bipolar disorder, active drug
abuse, or dementia are routinely excluded by nephrol-
ogy researchers. Pharmaceutical companies have little
incentive to perform anything other than the most cur-
sory investigations of psychotropic medication pharma-
cokinetics and dynamics in CKD patients, and these are
limited to the initial administration period and not to
long-term maintenance. Research is focused chiefly on the
psychiatric disorder of depression, and most studies are
hampered by inconsistent and often problematic diagnos-
tic criteria.3 Accordingly, the observations, conclusions,
and recommendations in this chapter are largely based
on theoretical grounds and the clinical experience of the
authors with all the consequential inherent limitations
and weaknesses.
P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease.
DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00060-3
DIAGNOSIS
Psychiatric treatment and comprehensive manage-
ment must begin by first determining the psychoso-
cial issue or underlying psychiatric disorder. There is a
widespread belief among nephrologists that the renal
patient population is more psychiatrically disturbed
than either the general population or those of other spe-
cialties. However, we suspect that this is based on the
wish for a simple explanation as to why clinical man-
agement is so frequently fraught with difficulty, espe-
cially for dialysis patients.
Major depression especially illustrates the difficulties
in reaching an accurate psychiatric diagnosis in the con-
text of co-morbid medical disorders and severe illness.46
A recent meta-analysis points out the need to distinguish
depressive symptoms from the disorder of depression.7
It is also crucial to not conflate major depressive disorder
with dysphoria or distress from the psychosocial stress-
ors that CKD patients encounter as part of their disease
experience.810 We have delineated a simple approach
to diagnosing depression in the physically ill.11 This
entails describing to patients the American Psychiatric
Associations Diagnostic Statistical Manual criteria for major
depression, eliciting their opinion as to whether they
believe they are depressed, and documenting the exis-
tence of associated factors, such as depressive episodes
prior to the onset of renal failure, a family history of
depression, and past suicide attempts.
There are a few neuropsychiatric conditions that are
over-represented in CKD patients, including substance
725 2015 Elsevier Inc. All rights reserved.
2012
726 60. Treatment of Psychiatric Disorders in Chronic Kidney Disease Patients
abuse, eating disorders, cognitive disorders, and bipo-
lar affective disorder (because of lithium toxicity).
Successful management requires that CKD patients with
psychiatric disorders usually be treated collaboratively
by nephrologists as well as various behavioral health
specialists.
Substance Abuse
Intravenous drug abuse can cause renal disease from
hepatitis B and C virus and human immunodeficiency
virus infected patients. Both heroin and cocaine abuse
have been associated with acute kidney injury (AKI)
and progressive renal disease. Alcoholism is widespread
among the general population.12 A high index of suspi-
cion for co-morbid alcoholism and CKD is warranted
because of associated difficulties with fluid restriction,
poor nutrition, vitamin deficiencies, accidental falls,
treatment adherence, and withdrawal seizures. Active
substance abusers frequently lead chaotic lives that
stymie attempts at managing coexistent CKD. It may
be impossible to treat such individuals unless they are
encouraged to make use of community substance abuse
rehabilitation resources.
Eating Disorders
Anorexia nervosa affects the kidney in many ways,
and chronic hypokalemia and volume depletion may
contribute to CKD.13 Eating disordered patients have
increased rates of AKI, electrolyte abnormalities such
as hypomagnesaemia, and nephrolithiasis. The man-
agement of such CKD patients needs to be coordinated
with local psychiatric services.
Cognitive Disorders
There may be a graded association between cogni-
tive disorders and severity of CKD. This is an area of
active research.14 The high prevalence of delirium and
dementia in ESRD is likely associated with clinical char-
acteristics such as older age, cardiovascular risk factors,
and cerebrovascular disease.15,16 Evaluation of dementia
in CKD is generally similar to that in patients who have
normal renal function, although there are some note-
worthy differences (Table 60.1).
Dementia due to structural and metabolic/electrolyte
disorders may be reversible following identification and
initiation of the appropriate therapy. Delirium is most
commonly a side-effect of drugs, and discontinuation
of medications or lowering their dosage especially in
patients newly started on drugs is a reasonable first
step in treatment. Management of patients with cog-
nitive impairment still chiefly involves the treatment
of associated behavioral disturbances, environmental
VIII. THERAPEUTIC CONSIDERATIONS
TABLE 60.1 CKD and Cognitive Disorders
Cognitive impairment can be produced by uremia, hyponatremia,
hypocalcemia, hypoglycemia, and hypercalcemia.
The central nervous symptoms of uremic encephalopathy range from
restlessness and irritability to seizures, coma, and death. A trial of
renal replacement therapy is often the only way to ascertain the
extent that uremia affects cognition.
Medications and their metabolites can accumulate because of
CKD, and they can then influence cognition and produce other
symptoms. Some of this is predictable and some can only be
ascertained by clinical intervention.
Since CKD largely involves a geriatric population that is often frail
and prone to falls, subdural hematoma and other structural central
nervous system lesions need to be considered.
Source: Reference70.
alterations to support function, and counseling regard-
ing safety issues. Increasing low hemoglobin levels to
target levels with erythropoietin stimulating agent ther-
apy may also improve cognitive function, quality of life,
and attention span in CKD patients.17
Bipolar Affective Disorder
The first-line treatment of bipolar affective disor-
der continues to be lithium, although the anticonvul-
sant valproate is increasingly being used. Lithium is
the most nephrotoxic psychotropic medication.18 After
years or decades of lithium use, a few patients develop
progressive CKD from tubular interstitial disease and
eventually require renal replacement therapy.19
TREATMENT
Non-Pharmacologic Interventions
Nephrology has always recognized the usefulness
of an interdisciplinary treatment team and the value of
using community resources. These are both especially
important when attending to the varied psychosocial
needs associated with CKD. While studies have under-
scored the importance of nephrology nurses and dialysis
social workers, these staff members function best when
they are able to coordinate care with local mental health
facilities, psychotherapists, and counselors, in order to
provide non-pharmacological treatment modalities.3
Similarly, for end-of-life issues involving severely ill
patients with poor prognoses, the involvement of com-
munity hospice and palliative care services is invalu-
able. Geriatric services may be invaluable in the care of
elderly patients.2 Some nephrology programs now have
care managers to follow patients and coordinate care,20
while others have developed comprehensive conserva-
tive management programs for those who do not wish
to initiate renal replacement therapies.2123
 Treatment
Transcultural issues, spirituality, religion and social
support are each matters requiring attention by the inter-
disciplinary CKD staff. Patient-centered approaches, such
as narrative medicine, mindbody medicine, or whole
person care, as well as stress management training (such
as mindfulness meditation) may play potential roles in
supporting people with CKD and be offered either by
renal staff or local behavioral health programs. Either
individual or group cognitive behavioral therapy (CBT)
appears to be a promising psychotherapeutic modality
for CKD patients.24,25 There are also some data suggest-
ing benefits from alternative treatments, including exer-
cise training regimens and music therapy.2628 Finally, it
is important to emphasize that the patient does not exist
in isolation marital and family discord are well docu-
mented in CKD patients and deserve close attention by
staff in order to provide the necessary support.29,30
There are several distinct situations where referrals
should be promptly made to mental health profession-
als. These include patients with psychosis, active bipo-
lar disorder, suicidal ideation, active drug abuse, and
treatment-resistant psychiatric disorders.31 Each of these
conditions requires the involvement of a specialist if the
patient is going to be able to responsibly work with the
renal team.
Pharmacologic Management
It is essential that nephrology practitioners under-
stand pharmacokinetics in order to make informed
treatment decisions. There is a discouraging lack of data
and paucity of large randomized placebo-controlled tri-
als involving CKD subjects receiving psychiatric treat-
ment.32,33 Most such research is based on investigations
of a handful of subjects, and there are very few in vivo
studies of psychiatric drug pharmacokinetics in patients
with CKD. However, in spite of the absence of empiri-
cal data, clinical experience suggests the majority of
psychotropic medications can be safely used in CKD
populations. Medication use in CKD requires some
degree of trial and error, and the clinician is well advised
to follow the adage start low and go slow.34
Special attention should be given to drugdrug
interactions, as well as to the increased risk of suicidal
ideation and death in vulnerable populations after ini-
tiation of antidepressant, antipsychotic and anticon-
vulsant medications. Several of these medications have
Black Box warnings.35,36 It is also necessary to explain
to patients and families that a treatment response rarely
occurs before several weeks of regularly taking the
medication. In addition, the usual physiological effects
that one notices about 20 minutes after taking medi-
cines, such as anxiolytics, are noticeably absent for other
drugs used for therapy of psychiatric disorders. Instead,
the selective serotonin reuptake inhibitors (SSRIs) work
VIII. THERAPEUTIC CONSIDERATIONS
727
in more subtle ways that probably involve a cascade of
neurotransmitter changes occurring over several weeks.
In selecting psychotropic medications, the nephrol-
ogy clinician needs to be aware of the degree of
impaired GFR and its effects on medication absorption
(i.e. bioavailability), volume of distribution, metabo-
lism, and excretion of the parent drug and its metabo-
lites in the CKD patient.
Since many CKD patients have co-morbid diabetes,
it is also important to appreciate that SSRI antidepres-
sant medications may worsen glucose control, especially
with the use of high dosages. However, the literature is
confusing. Some studies have linked these medications
with improved control, and others suggest that anti-
depressant use may be an independent risk factor for
type 2 diabetes.37 The same caveat has been also raised
with antipsychotic medications.38 Nephrologists need
to maintain heightened alertness and attend to changes
in glucose control and weight changes when initiating
these commonly used drugs.
Most psychotropic medications are fat-soluble and
metabolized by the liver. Very few (such as lithium)
are primarily excreted by the kidneys. Although the
Physician Desk Reference39 routinely recommends use
of partial dosages of psychotropic medications for renal
patients, data supporting these recommendations are
limited. Regular adult dosages may be necessary before
one sees a therapeutic effect in CKD patients. There is
even less empirical information available about psycho-
tropic medication use in pediatric CKD populations.40
Clinicians will find it necessary to engage in medication
trials that are influenced by individual patient tolerabil-
ity, response, and changes in clinical status.
Although medication metabolism mainly takes
place in the liver, hepatic changes associated with age
may increase serum drug levels and prolong half-life.
Complicating matters further, a drug like morphine
is primarily metabolized in the liver but it has renally
excreted active metabolites that may accumulate to toxic
levels.41
ESRD medication-related problems are frequent and
were identified in 98% of a sample of HD patients.42 In
this study, patients had a mean of 6 2.3 co-morbid ill-
nesses, 11 4.2 different drugs were prescribed per
patient, and a total of 475 medication-related problems
were detected in 133 patient records. Although there are
no available data for patients with earlier stages of CKD,
it is likely that similar (albeit less frequent) problems are
seen in this population as well.
Pharmacokinetics
The term pharmacokinetics (Table 60.2) refers to
the physiological handling of pharmacological agents
and includes absorption (i.e. bioavailability), volume
728 60. Treatment of Psychiatric Disorders in Chronic Kidney Disease Patients
TABLE 60.2Pharmacokinetics in CKD
Absorption decreased due to:
Gastric alkalinity due to uremia
Chelation due to concurrent use of medication (e.g. antacids)
Changes in gastrin metabolism
Nausea and vomiting
Delayed gastric emptying
Altered drug partitioning due to bowel edema and vitamin D
deficiency
Bioavailability
Decreased due to decreased absorption.
Increased due to decreased intestinal elimination as a result of:
Decreased intestinal CYP450 activity
Decreased in drug extrusion by Pgp and MDR2
Distribution
Volume of distribution may be:
Increased in patients with edema
Decreased in patients with muscle wasting, cachexia and
dehydration
Decreased protein binding may be due to:
Hypoalbuminemia
Altered albumin conformation
Competitive inhibition of plasma proteins by retained
endogenous binding inhibitors
Elimination:
Metabolism
Decreased kidney metabolic activity
Altered hepatic metabolic activity (increased, decreased or
unchanged)
Excretion
Most psychotropic drugs are excreted through the bile and
are not dialyzable
of distribution, metabolism, and excretion of the par-
ent drug and its metabolites.43 Patients with CKD may
evince alterations in any of these parameters, which is
why medication-related problems are difficult to predict.
Bioavailability is the extent to which a dose of drug
enters the systemic circulation. An oral dose is first
absorbed from the gastrointestinal tract, and subse-
quently passes through the liver where metabolism
and biliary excretion occur. For some agents a decrease
in bioavailability occurs at the level of drug absorption
from the gastrointestinal tract. Alterations in gastric
alkalinity (caused in part by excessive urea generation
by the internal ureaammonia cycle) result in alterations
in gastric pH that may affect the absorption of psycho-
tropic medications. Other factors that affect absorption
in patients with CKD include nausea and vomiting, as
well as increased gastric emptying time (often due to
diabetic or uremic gastroparesis).
Volume of distribution can effect the dilution or con-
centration of medications in the blood stream. The two
overarching factors influencing distribution in CKD
patients are the volume of distribution and protein
binding compared to younger patients. Elderly patients
with CKD are frequently cachectic. They often have
less fluid and less body mass and a decreased volume
VIII. THERAPEUTIC CONSIDERATIONS
of distribution than younger patients. Consequently,
a given dose of medication may be associated with a
greater circulating concentration than in a non-cachectic
patient with CKD.
Protein binding is a significant issue in CKD patients.
Albumin is the principal plasma protein responsible for
binding to acidic drugs. For alkaline drugs, the princi-
pal plasma protein responsible for binding is -1-acid
glycoprotein.44,45 Proteinuria and hypoalbuminemia are
common in CKD patients, and there is an accumulation
of endogenous binding inhibitors such as organic acids
or uremic toxins. Binding inhibitors may compete with
drugs for the carrier protein-binding site, and albumin
undergoes conformational changes with hypothesized
alterations in binding properties. The results in CKD
patients are often diminished protein binding and an
increase in the bioactive free fraction of acidic drugs in
plasma. All other factors remaining constant, the greater
the protein binding of a medication, the lower the dose
of the drug required in CKD, since there is increased risk
for toxicity when increased amounts of the free, unbound
forms of acidic drugs are present in the plasma.
Another factor to consider is that the circulating con-
centration of -1-acid glycoprotein may increase in renal
transplant patients or those treated with hemodialysis.
The effect may potentially be a decrease in the unbound
circulating fraction and diminished biological activity of
the drug.45
Metabolism or degradation of a medication is prob-
ably the least familiar area of pharmacokinetics, because
the intermediate products of metabolism are difficult to
isolate and identify. The rate of renal metabolism by the
renal tubular brush border is predicted to decrease as
the GFR declines. In addition, metabolism by the liver is
variably altered in CKD. Both the expression and func-
tion of CYP2C9 and CYP3A4 are decreased in ESRD.45
While the literature is contradictory, it appears that in
CKD there is a general slowing of chemical reduction
and hydrolysis but continued normal rates of glucuroni-
dation, microsomal oxidation, and sulfate conjugation.
Excretion of drugs and their metabolites takes place
through the gastrointestinal tract and the kidney. Renal
excretion varies in ESRD in proportion to the GFR,
which can range from 0 to as much as 1015mL/min.
Glomerular filtration, active tubular secretion, and pas-
sive tubular reabsorption are the three distinct mecha-
nisms of drug handling by the kidney. Hemodialysis
results in intermittent drug removal rather than the
continual process which occurs in normal kidneys. PD
is usually performed continuously but results in incom-
plete drug removal. Drugs are only occasionally metab-
olized to pharmacologically active compounds that are
then normally excreted in urine. Most psychotropic
medications are metabolized by the liver, eliminated in
bile, and excreted in feces.
 Prescribing Medications to Adults
PRESCRIBING MEDICATIONS TO
THE ELDERLY
Since at least half of the CKD population is elderly,
it is incumbent upon the clinician to be aware of the
effects of psychotropic medications on older people.
Psychopharmacological considerations when treating the
elderly with CKD include their co-morbid conditions, the
effects of the large quantity of other prescribed medica-
tions patient may take, their altered pharmacokinetics,
and the increased risk of mortality.46
Many of the landmark drug efficacy trials have
intentionally excluded patients greater than 65 years of
age let alone those with compromised renal function.
One needs to appreciate the delicate balance between
seeking therapeutic benefits and the increased poten-
tial for adverse events in the elderly. For instance, stud-
ies targeting blood pressure reduction among geriatric
patients have shown that reduction in systolic blood
pressure leads to a decreased risk for stroke and major
cardiac events. The target systolic blood pressure how-
ever must be adjusted for these patients because of the
risk of orthostasis and falls when the blood pressure is
too low.47 The addition of anticholinergic medications
is also well known to cause altered mental status in the
elderly that can be mistaken for progressive dementia.
Such events are often 3-fold to 10-fold higher in older
patients with CKD.48,49
PRESCRIBING MEDICATIONS
TO ADULTS
Most psychotropic medications are fat-soluble and
have large volumes of distribution. The drugs easily
pass the bloodbrain barrier, and they are not dialyz-
able. Attention needs to be paid to medications with
active metabolites those that are highly plasma pro-
tein bound and those with altered pharmacokinetics or
pharmacodynamics.
Like others, Hedayati etal.5 concluded that based on
available data, SSRIs are a prudent choice for the treat-
ment of depression in patients with CKD and ESRD.
Once a medication trial is initiated, then treatment
response, need for dose adjustment, and the onset of
side-effects should be closely monitored. Medication
dosages should not be escalated sooner than at intervals
of at least 1 to 2 weeks.
One important ongoing investigation is the Chronic
Kidney Disease Antidepressant Sertraline Trial (CAST
study),50 a double-blinded placebo-controlled trial that
examines the use of sertraline versus placebo in the
management of a major depressive episode. The study
explores whether the medication improves depression
severity, overall function, and quality of life in patients
VIII. THERAPEUTIC CONSIDERATIONS
729
with stage 35 predialysis CKD. Secondary outcomes
include the safety and tolerability of the medication.
Lithium, an alkali metal, is the gold standard for
pharmacological treatment of bipolar affective dis-
order. However, polyuria, polydipsia, and nephro-
genic diabetes insipidus are commonly observed.51
Lithium is the only known psychotropic medication in
which long-term use is associated with nephrotoxic-
ity, renal insufficiency, and even ESRD.45 The American
Psychiatric Association Treatment Guideline for Bipolar
Disorder recommends that psychiatrists periodically
assess kidney function every 23 months during the
first 6 months of treatment and subsequently every
6 months to 1 year in stable patients.52 This usually
consists of obtaining BUN, S[Cr], and perhaps a urine
analysis. Although renal function will often improve if
the drug is stopped, some patients ultimately require
maintenance dialysis or transplantation. The Swedish
Registry of Active Treatment of Uremia reported a 5.3%
prevalence of RRT in the lithium-treated population
and lithium-induced ESRD comprised 8.1% of the RRT
population.53 Attempts should be made to transition
CKD patients to alternatives, like the classic anticonvul-
sant medications, divalproex and carbamazepine. For
some people these prove to be inadequate mood stabi-
lizers or produce intolerable side-effects. For example,
in one case trials of carbamazepine resulted in a drug-
induced fever, olanzapine decreased mental acuity,
valproate worsened pre-existing tremors, and oxcar-
bazepine and lamotrigine provided minimal thera-
peutic effects, leading to the conclusion that continued
treatment with lithium was a necessity.54
Nephrologists can be quite helpful to patients with
lithium-induced polyuria, polydipsia, and diabetes
insipidus by recommending a once-daily dose of the
drug to be taken at bedtime, switching from lithium
to an alternative, and cautious use of a diuretic. Use
of thiazide diuretics require concomitant lowering of
the lithium dose in patients with CKD, and frequent
monitoring of lithium levels. Amiloride may not affect
the lithium level and CKD patients taking this drug
and lithium may also not require potassium supple-
mentation. Considerable care must be taken with CKD
patients who have lithium prescribed with NSAIDs
which alter prostaglandins and affect regulation of
urine flow.55,56 When nephrologists consult on cases
where there is evidence of a decrease in GFR then a
discussion needs to take place with the patient, family,
and psychiatrist in order to weigh whether the risk of
ESRD outweighs the benefit of continuing lithium. If
the eGFR is less than 60mL/min/1.73m2, the nephrolo-
gist should see the patient for a yearly visit. For patients
with eGFR between 40 and 60mL/min/1.73m2, the
nephrologist should see the patient every 6 months. For
patients with eGFR between 20 and 40mL/min/1.73m2,
730 60. Treatment of Psychiatric Disorders in Chronic Kidney Disease Patients
the patient should be seen every 3 months. Patients
with eGFR less than 20mL/min/1.73m2 should be seen
on a monthly basis.22 Renal function, fluid/electrolyte
status and lithium levels should be evaluated at such
visits. If CKD patients treated with lithium develop
hypernatremia, the clinician should employ trials of
amiloride and recommend high fluid intake, as toler-
ated. Nephrologists should follow lithium levels and
decrease the dose if the lithium concentration is increas-
ing or is found to be supratherapeutic. They should
maintain an awareness that lithium toxicity can follow
an intentional or unintentional overdose, but there are
also medications, such as ACEIs, thiazide diuretics, and
NSAIDs that cause increased lithium concentrations.57
Sodium restriction can also result in increased reabsorp-
tion of lithium and lead to intoxication. This in turn
may produce or worsen renal insufficiency.
There are a few bipolar patients who develop irre-
versible renal damage and will continue to require lith-
ium to maintain a reasonable quality of life.
Serum levels and clinical response are used to ascer-
tain whether patients receive therapeutic amounts of
lithium. Patients should be cautioned to hold inges-
tion of lithium if they are having diarrhea, vomiting,
or other problems that may lead to acute dehydration,
which can be associated with a sudden toxic increase in
the lithium level.
Benzodiazepine treatment is the most common cur-
rent strategy for the management of anxiety disorders,
especially acute situational anxiety. It is important to
consider that most of the CKD population is elderly.
Benzodiazepines have a particularly poor riskbenefit
ratio and may increase the risk of falls and fractures,
disability, and cognitive decline in the elderly.5861
Accordingly, a trial of an SSRI or bupropion, or use of
non-pharmacologic treatments, such as psychother-
apy or counseling, may be preferable in elderly CKD
patients with anxiety. However, treatment of elderly
CKD patients with benzodiazepines may ultimately be
necessary and beneficial.
A recent study of generalized anxiety disorder in
older adults suggests a combination strategy that is
consistent with the prevailing philosophy in psychiatry
that the majority of patient conditions will most likely
benefit by attention to both pharmacologic and psycho-
logical dimensions of care.62,63 Generalized anxiety dis-
order is considered by some authorities to be the most
common psychiatric illness in late life. Generalized
anxiety disorder is characterized by difficult-to-control
worry, and is accompanied by somatic and psychologi-
cal symptoms, such as restlessness, sleep disturbance,
and muscle tension.64 Generalized anxiety disorder is
a chronic condition that often responds poorly to anti-
depressant medication trials. In this study, not involv-
ing CKD patients, antidepressant medication was
VIII. THERAPEUTIC CONSIDERATIONS
augmented with CBT which led to short-term worry
reduction. Continued use of the medication pre-
vented relapse, but for some individuals, CBT resulted
in sustained remission without requiring long-term
pharmacotherapy.
PRESCRIBING MEDICATIONS TO
CHILDREN WITH CKD
Pediatric practitioners have no substantive data to
guide treatment decision-making for children with
emotionalbehavioral disorders in the context of severe
impairment of renal function. By and large, pediatric
pharmacology dosing is determined on the basis of
body surface area instead of body weight, but mini-
mal information is available concerning its relevance
to the use of psychotropic medications in contrast to
the definitive guidelines for antibiotic use in children.
Pediatric CKD differs in many ways (epidemiology,
risk for impact on growth, need for transplantation)
from the adult disorder, where diabetes and hyper-
tension are more frequent co-morbid and etiologic
disorders.
Of the few reviews available, none are contempo-
rary, two do not list any psychotropic medications in
their tables with the exception of anticonvulsants,65,66
and the other two predate the dramatic increase in use
of psychoactive medications for children suffering from
a variety of internalizing and externalizing behavioral
conditions.67,68
Many of the psychotropic medications listed in
Table 60.3 with the exception of the typical neurolep-
tics and somnolent tranquilizers are used in pediat-
ric psychiatry. In this population, some are relied upon
more often than others (e.g. fluoxetine is preferred over
paroxetine because of its longer half-life and research
data supporting its indication and use). Conservative
initial dosing for pediatric indications would frequently
suggest a 50% to 75% lesser dose strength than the typi-
cal adult dose with allowances to increase dosing dur-
ing subsequent care based on tolerability, response, and
changes in clinical status. This is especially advisable
for stimulant compounds such as amphetamine and
methylphenidate, which have a higher proportion of
elimination through the kidneys than most other medi-
cations listed in Table 60.3.
Because there are no available data, even the pack-
age inserts available for the stimulant medications do
not specify any specific dosing adjustments to be made
with children, but it appears that methylphenidate or
the clearance of its inactive hepatic metabolite, ritalinic
acid, is not as sensitive to the alkalinization of urine
as amphetamine products.69 Lower dosing and slower
increases during the clinical use of mixed amphetamine
TABLE 60.3 Psychotropic Medications and Renal Failure

Typical
Adult
Reference Removed by
Drugs Active Metabolites Dose Half-Life Adult Dose in ESRD Half-Life in ESRD Dialysis Comments

ANTIDEPRESSANTS

SSRIs

Escitalopram (S+) Desmethyl-citalopram 1020mg/d 2232hrs 1020mg/d 59hrs (metabolites) H: no ESRD likely has minimal impact on
(Lexapro) (SDMC) clearance, similar to normal renal
(S+)Didesmethyl citalopram function and similar to citalopram
Citalopram Desmethyl-citalopram 2040mg/d 3337hrs 1040mg/d 4349hrs H: no ESRD has minimal impact on
(Celexa) Didesmethyl-citalopram citalopram kinetics, but citalopram
affects magnesium and potassium and
can potentiate arrhythmias
Fluoxetine Norfluoxetine (NF) 20mg/d 14 days 20mg/d 715 days H: no No significant differences in fluoxetine
(Prozac, (metabolites) and NF levels in CKD or ESRD
Sarafem)
Fluvoxamine No active metabolites 50300mg/d 1522hrs 50300mg/d Similar to normal H: no No significant differences in
(Luvox) (levels decreased by renal impairment. Manufacturer
22%) recommends lower initial doses
Paroxetine No active metabolites 2060mg/d 17.325.1hrs 1030mg/d 10.954.8hrs H: unknown Increased AUC for paroxetine in ESRD
(Paxil) (possibly related to metabolite that is
inhibitor of CYP2D6). Reduced dosage
recommended. 10mg/day effective in
ESRD
Sertraline Desmethyl-sertraline 50200mg/d 24hrs 50200mg/d 4296hrs H: minimal Minimal changes in kinetics in ESRD
(Zoloft)

Tricyclics

Amitriptyline Nortriptyline 25mg q8hrs 3240hrs 1025mg q812hrs (or Likely prolonged. H: no Use of TDM with level of
(Elavil) Hydroxy-amitriptyline qhs only for insomnia Elevated conjugated CAPD: no 75175mcg/L may guide therapy for
Hydroxy-nortriptyline or neuropathic pain) metabolites in renal depression
failure
Clomipramine Desmethyl-clopramine 25250mg/d 1937hrs No data No data Little data in CKD
(Anafranil) (DMC) DMC 5477hrs
Desipramine 2-Hydroxy-desipramine 100200mg/d 1254hrs 75125mg/d Active metabolites H: no Effective in small trial for depression.
(Norpramin) (2-OHD) 2-OHD: 22hrs likely prolonged CAPD: no Use of TDM with level of 100
160mcg/L may guide therapy for
depression; unconjugated amine
and OH metabolites not removed by
dialysis
Doxepin Desmethyl-doxepine: DMD 25mg q8hr 825hrs 25mg q8hrs 1030hrs H: no Little data in CKD
(Sinequan) DMD: 3080hrs CAPD: no
(Continued)
TABLE 60.3(Continued)
Psychotropic Medications and Renal Failure

Typical
Adult
Reference Removed by
Drugs Active Metabolites Dose Half-Life Adult Dose in ESRD Half-Life in ESRD Dialysis Comments

Imipramine Desipramine 25mg q8hr 620hrs 25mg q8hr See desipramine See desipramine See desipramine
(Tofranil)
Nortryptiline 10-Hydroxy-nortriptyline 25mg q68hr 1893hrs 25mg q68hr 1566hrs H: no Use of TDM with level of
(Aventil, E 10-hydroxy-nortriptyline Active metabolites CAPD: no 50150mcg/L may guide therapy for
Pamelor) Z 10-hydroxy-nortriptyline likely prolonged. depression

OTHER

Bupropion Hydroxy-buproprion (HB) 100mg q8hr 1021hrs Limited data: ? reduce H: minimal Risk for seizures with elevated level of
(Wellbutrin, Threobupropion (TB) to 1/3 dose bupropion or metabolites.
Zyban) Use of TDM of bupropion (level 1050
g/L), HB (< 1200 g/L) and TB
< 400 g/L) may guide therapy to
avoid toxicity
Duloxetine 4-Hydroxy D glucouronide 2060mg/d 12h Not recommended AUC: Pharmacologic activity of metabolites
(Cymbalta) (4OHD) Duloxetine:100% may be minimal.
5-Hydroxy D sulfate 4OHD:700900%
(5OHD) 5OHD:700900%
6-Hydroxy D sulfate 6OHD:700900%
(6OHD) (see comments)
Maprotiline Desmethyl-maprotiline 75150mg/d 4851hrs 37.5100mg/d Minimal data Minimal data May have more cardiovascular risk in
(Ludiomil) CKD
Mirtazepine Desmethyl-mirtazepine 1545mg/d 2040hrs 7.522.5mg/d Clearance reduced Minimal data No clear role for TDM
(Remeron) (DMM) DMM: 25hrs by 50% in ESRD
Selegiline patch N-Desmethylselegiline or 612mg/d 1825hrs 612mg/d Unchanged No renal metabolism with transdermal
(EMSAM) R(-)-Methamphetamine patch.
Venlafaxine O-Desmethyl-venlafaxine 37.5225 XR 4hrs 37.5112.5 XR mg/d 611hrs H: no No clear role for TDM
(Effexor) (ODV) mg/d ODV 4hrs ODV 9hrs

ANTIMANIC AGENTS

Lithium None 900 1428hrs 200600mg/d 40hrs H: considerable Single dose after dialysis
(Eskalith, 1200md/d CAPD: variable Titrate level to dose/response
Lithobid, reports
Lithonate)

ANTIPSYCHOTICS

Atypical*

Aripiprazole Dehydroaripiprazole (DHA) 1015mg/d 75146hrs 1015mg/d Unknown H: unknown Little data
(Abilify) DHA: 94hrs

TABLE 60.3 Psychotropic Medications and Renal Failure

 Typical
Adult
Reference Removed by
Drugs Active Metabolites Dose Half-Life Adult Dose in ESRD Half-Life in ESRD Dialysis Comments

Clozapine N-Desmethyl-clozapine: 12.5 812hrs Titrate to response and Large variation H: probably Titrate using individual monitoring
(Clozaril) (NDC) 450mg/d NDC: 13.2hrs utilize TDM minimal and TDM. Avoid levels >400 g/L
slowly
titrated
Iloperidone P88 and P95 1224mg/d 1833hrs 1224mg/d H: no Inhibitors of CYP3A4 or CYP2D6
(Fanapt) increase levels. Poor metabolizers of
2D6 should take half dose
Lurasidone ID-14283 and ID-14326 40160mg/d 18hrs 2080mg/d H: no Taken with food, similar to
(Latuda) ziprasidone, to increase absorption.
Predominant hepatic metabolism
Paliperidone 312mg/d 23hrs 36mg/d 51hrs H: no This is the major active metabolite of
(Invega) risperidone. Decreased clearance with
increasing renal impairment
Olanzapine N-Desmethyl-olanzapine 520mg/d 3238hrs 520mg/d 3238hrs H: no Dose adjustment not necessary in
(Zyprexa) Olanzapine-10-N- CAPD: no renal insufficiency or failure per
glucuronide (activity may manufacturer
be minimal)

Quetiapine 7-Hydroxy-quetiapine 50800mg/d 6hrs 50800mg/d in divided Dose adjustment not necessary in
(Seroquel) N-Dealkylated quetiapine in divided dose renal insufficiency or failure per
dose manufacturer
Risperidone 9-Hydroxy-risperidone 13mg bid 330hrs 0.51.5mg bid 9ROH: 25hrs H: no Wide variation in clearance noted
(Risperdal) (9ROH) 9ROH 19hrs CAPD: no between poor and extensive
metabolizers. Clearance of sum of
risperidone and 9ROH is reduced by
60% in CKD
Ziprasidone Inactive metabolites 2080mg bid 7h 1080mg bid Dose adjustment not necessary for
(Geodon) CrCl 1060mL/min per manufacturer.
Some clinicians recommend avoiding
in ESRD due to prolonged QT
interval and risk for life threatening
arrhythmias that may be higher with
electrolyte shift

Typical

Chlorpromazine Chlorpromazine-N-oxide 50400mg/d 1142hrs Little data Unknown H: no Scant data, limited to case report
(Thorazine) Nor-1-CPZ
Nor-2-CPZ Nor-2-CPZ sulf
3-OH-CPZ
Haloperidol Hydroxyhaloperidol 12mg 1426hrs 12mg q68hrs Similar H: No < 1% excreted in urine
(Haldol) Plus other metabolites q68hr
(activity not clear)

(Continued)
TABLE 60.3(Continued)
Psychotropic Medications and Renal Failure

Typical
Adult
Reference Removed by
Drugs Active Metabolites Dose Half-Life Adult Dose in ESRD Half-Life in ESRD Dialysis Comments

ANXIOLYTICS AND HYPNOTICS

Alprazolam Alphahydroxy-alprazolam 0.253mg tid 919hrs 0.253mg tid 919hrs H: minimal Increased free fraction in ESRD.
4 Hydroxy-alprazolam Minimal kinetic differences in
dialysis-dependent patients, increased
potential for psychomotor and
memory impairment
Buspirone 1-Pyrimidinyl-piperazine 5mg tid 0.52.5hr 2.55mg tid 15hrs H: no Considerable inter- and intra-
(Buspar) (1-PP) 1-PP 6.3hr 1-PP 9hrs individual variability in kinetics in
ESRD. Patients with CKD may benefit
from 2550% dose reduction
Lorazepam No active metabolites 12mg bid 916h 0.52mg bid 3270h H: Reports vary
(Ativan) or tid CVVH: no
Midazolam Alphahydroxy-midazolam 1.25 IV titrate 1.212.3hrs 1.25mg IV titrate to 1.212.3hrs H: Accumulation ?increased effect due to altered protein
(Versed) conjugate (AHM-C) to response AHM-C 1hr response AHMC 50.476.8hrs of AHM-C binding
CVVH: no
Oxazepam No active metabolites 30120mg/d 625hrs 30125mg/d in divided 2590hrs H: no
(Serax) in divided dose
dose
Temazepam No active metabolites 7.530mg hs 410hrs 1530mg hs prn H: no
(Restoril) prn CAPD: no
Eszopiclone N Desmethyl-zopiclone 23mg hs 56hrs 2mg hs prn
(Lunesta) (NDZ) prn
Ramelteon M-II 8mg hs prn 12.5hrs 8mg hs prn No dose adjustment required per
(Rozerem) M-II 25hrs manufacturer
Zaleplon No active metabolites 520mg hs 1hr ?510mg hs prn No dose adjustment needed per
(Sonata) prn manufacturer for mild to moderate
renal impairment. Not studied in
ESRD
Zolpidem No active metabolites 10mg hs prn 23hrs May reduce by 50% 46hrs
(Ambien)

ANTICONVULSANTS

Carbamazepine Carbamazepine 100mg bid to 1217hrs 100mg bid to 400mg Similar to normal H: moderate
(Tegretol) 1011-epoxide 400qid (chronic qid renal function
9-Hydroxymethyl-10- dosing)
carbamoylacridan

TABLE 60.3 Psychotropic Medications and Renal Failure

 Typical
Adult
Reference Removed by
Drugs Active Metabolites Dose Half-Life Adult Dose in ESRD Half-Life in ESRD Dialysis Comments

Gabapentin 300600mg 57hrs 300mg every other day 132h H: yes Significant accumulation has occurred
(Neurontin) tid or 200300mg after CAPD: partial with typical dosing or interruption
each 4-h hemodialysis in hemodialysis. May be helpful
for uremic pruritus and restless leg
syndrome. ?increase myoclonus,
hypoglycemia
Lamotrigine Inactive Varies 1330hrs Conflicting reports 4358hrs H: moderate Reduced dose recommended by
(Lamictil) whether on manufacturer; altered dosing regimen
valproate or when on or off valproate
not
Oxcarbazepine 10-Monohydroxy metabolite 300 Parent: 2hrs 100600mg/d MHD: 19hrs 95% excreted in urine following
(Trileptal) (MHD) 2400mg/d MHD: 9hrs hepatic metabolism. Monitor Na+
levels, particularly when concomitant
medications affect Na+ metabolism
Phenobarbital No active metabolites 60250mg/d 1.54.9days Unknown Unknown H: yes Partial renal clearance
(Luminal) CAPD:
conflicting
reports
Phenytoin (Questionable activity) 200400mg/d 24hrs (at low 200300mg/d 24hrs (at low to H: no Increased free levels secondary to
(Dilantin) Conjugated and to moderate moderate levels) CAPD: no uremia. Monitor free phenytoin levels
unconjugated levels) 4-OH-DPH if high CVVH: moderate
5-4hydroxyphenyl- 12mg/L ultrafiltration
5-phenylhydantoin (?significance) rate with
(4-OH-DPH) fosphenytoin use
Pregabalin N-methyl-pregabalin 50100mg tid 56.5hrs 2575mg/d Increased and Supplemental dose after hemodialysis
(Lyrica) (probably not clinically correlated with of 100150% of daily renal dose
significant) CrCl
Topirimate Inactive 200400mg/d 21hrs 100200mg/d Approaching H: considerable Over 70% eliminated unchanged in
(Topomax) 40+ hrs CAPD: robust, urine, with well described altered
consider clearance in ESRD populations,
supplemental depending if on dialysis or not will
dose determine whether use higher dose
(CAPD) or lower (not on dialysis)
Valproic acid Unknown 1560mg/ 617hrs 1560mg/kg/d Possible increased risk of pancreatitis
(valproate or kg/d with ESRD. Increased free levels in
divalproex) ESRD. Monitoring free levels more
(Depakene, pragmatic than total concentration
Depakote)

Reproduced with permission from Psychiatric Times 2011 UBM Medica.

ESRD: end-stage renal disease, SSRIs: selective serotonin reuptake inhibitors, H: hemodialysis, AUC: area under curve, CAPD: continuous ambulatory peritoneal dialysis, CVVH: continuous veno-venous hemofiltration, TDM:
therapeutic drug monitoring, CrCl: creatinine clearance.
*
All atypical antipsychotics have risks for dyslipidemia, weight gain, insulin resistance, diabetes mellitus and metabolic syndrome, and are contraindicated for dementia-related psychosis.
736 60. Treatment of Psychiatric Disorders in Chronic Kidney Disease Patients
salts and dextroamphetamine is prudent. The level of
acidification of the urine associated with renal disease
reduces the clearance of amphetamine and its metabo-
lites to as low as 1%. Acidification increases clearance
and can thus reduce levels. Consulting psychiatrists
can be of assistance with assessing the indications and
judicious use of psychiatric medications in coordina-
tion with the primary care team and nephrologists for
any child with CKD and psychiatric co-moribidities.
Families need to be fully informed as to the literature
shortcomings.
SUMMARY
An interdisciplinary team approach is often a
requirement for the assessment and management of the
complicated psychiatric co-morbidities and psychoso-
cial circumstances associated with CKD. This entails the
involvement of nephrology clinicians, psychiatrists and
community resources. Prescribing psychotropic medica-
tions to patients with CKD requires an appreciation of
pharmacokinetics, including absorption, volume of dis-
tribution, metabolism, and excretion of the parent drug
and metabolites.
Most psychotropic medications are not metabolized
or excreted by the kidneys, and one must rely on infor-
mation from clinical trials. In the absence of systematic
data, caution is always necessary, but most of these
medications are well tolerated and produce their accus-
tomed beneficial affects at ordinary dosages. Renal dys-
function should not theoretically be associated with any
unusual drug interactions.
Serum levels of medications such as the anticonvul-
sants/mood stabilizers should be carefully monitored,
especially if patients receive renal transplantation and
immunosuppressants. Lithium is the only psychotropic
medication that over long-term use has been associated
with nephrotoxicity.
Caution is required in the pharmacologic treatment
of elderly and pediatric CKD patients. Nephrologists
and psychiatrists need to coordinate care of these
patients, and they should also jointly urge key opin-
ion leaders, the pharmaceutical industry, and research
organizations to expand efforts to understand these
challenges and to conduct coordinated, multi-center
empirical investigations.
Acknowledgments
Roger McIntyre, MD, FRCP for his work on an earlier draft of the
manuscript. Tables 60.2 and 60.3 are reproduced and updated from
an original published with permission from Psychiatric Times 2011
UBM Medica.
VIII. THERAPEUTIC CONSIDERATIONS
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