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DOI: 10.1176/appi.books.9781585622825.239373
Manual of Clinical Psychopharmacology >
Chapter 12. Pharmacotherapy in Special Situations
INTRODUCTION
One of the difficulties that clinicians face is that a typical clinic patient often does not resemble the
sanitized patients selected for in research studies. Most published reports evaluating the efficacy of
psychoactive drugs in psychiatric patients carefully select physically healthy adult, but not
geriatric, pediatric, or pregnant, patients. Unfortunately, in clinical practice, physicians frequently
encounter patients with psychiatric disorders who are also pregnant, juvenile, elderly, brain
damaged, or medically ill but who are otherwise appropriate candidates for conventional
pharmacotherapy. Since the last edition of this book, much has been learned about treating special
populations with psychotropic agents. In this chapter, we address some of these special situations.
PREGNANCY
Pregnancy, current or planned, poses a complex problem for the psychiatrist, for the psychiatric
patient, and for her fetus. Folk wisdom has suggested that pregnancy is a relatively protected time
in which women may be less susceptible to psychiatric difficulties. This, unfortunately, is not the
case. Pregnancy does not protect patients against the occurrence, recurrence, or exacerbation of
psychiatric conditions. For example, most patients with recurrent depression who stop taking an
antidepressant in anticipation of conceiving are back taking an antidepressant before delivery. At
least 10% of patients meet criteria for a depressive disorder during pregnancy. Pregnancy appears
to increase the risk of obsessive-compulsive disorder (OCD) and other anxiety disorders. Mania and
schizophrenia may all occur or worsen during pregnancy.
The risks of drug administration during pregnancy include teratogenesis, particularly during the
first trimester, and possibly behavioral teratogenesis (Table 12–1). All psychotropic agents cross
the placenta to some degree. Gross physical malformations are easy to detect and document, and
the possibility that drugs given during pregnancy may affect brain function and behavior years later
exists, but there is no clear evidence that it actually occurs. Direct toxic effects on the fetus can
occur later in pregnancy. Drugs can affect labor and delivery, with residual effects on the infant’s
behavior after delivery. All psychotropic drugs are excreted in the mother’s milk during
breast-feeding, to different degrees. This puts both doctor and patient in a very unpleasant bind.
Ideally, every mother should be totally drug free throughout every pregnancy. However, there are
many instances in which the known risks of discontinuing psychiatric medications are greater than
the unknown risks of continuing to take them.
Table 12–1. Teratogenic risks of psychotropic medications
Class Drug Risk
categorya
Possible effects
Anxiolytics benzodiazepines D “Floppy baby,” withdrawal, increased risk of
cleft lip or palate
hypnotic benzodiazepines X Decreased intrauterine growth
buspirone C Unknown
Antidepressants TCAs
amitriptyline, imipramine,
nortriptyline
other TCAs
D
C
Fetal tachycardia, fetal withdrawal, fetal
anticholinergic effects, urinary retention,
bowel obstructionPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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Class Drug Risk
categorya
Possible effects
MAOIs C Rare fetal malformations; rarely used in
pregnancy due to hypertension
SSRIs
paroxetine
C
D
Increased perinatal complications
Cardiovascular malformations, increased
perinatal complications
Antipsychotics classic C Rare anomalies, fetal jaundice, fetal
anticholinergic effects at birth
atypicals: clozapine
aripiprazole, risperidone,
olanzapine, quetiapine,
ziprasidone
B
C
Unknown
Mood stabilizers lithium D Associated with increase in birth defects,
including cardiac anomalies, especially
Ebstein’s anomaly; behavioral effects
valproate D Neural tube defects
carbamazepine D Neural tube defects, minor anomalies
oxcarbazepine C Unknown
lamotrigine C Unknown
gabapentin/pregabalin C Unknown
Note. TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin
reuptake inhibitor.
aU.S. Food and Drug Administration use-in-pregnancy risk categories: A: Controlled studies show no risk to
humans. B: No evidence of risk in humans, but adequate human studies may not have been performed. C:
Risk cannot be ruled out. D: Positive evidence of risk to humans; risk may be outweighed by potential benefit.
X: Contraindicated in pregnancy.
Not treating mental illness during pregnancy has significant risks. Severely depressed pregnant
women do not take care of themselves optimally, and conflicting reports have suggested a higher
risk of low birthweight and preterm delivery in untreated depressed women. When the risk of
suicide is added to the equation, the risk can be overwhelming. Similarly, untreated schizophrenia
has been associated with an increase in perinatal deaths. Psychosis can jeopardize both mother and
fetus. There is at least a theoretical risk that elevated cortisol levels associated with severe stress
during pregnancy might impact fetal brain development.
This dilemma is illustrated by the case of a markedly manic drug-free patient believed to be in the
sixth week of pregnancy who was admitted a number of years ago to McLean Hospital. She was
kept drug free in seclusion, and often in restraint, for a week because the treating psychiatrist was
afraid to initiate neuroleptic treatment for fear of harming the fetus. One of us who consulted on
the case advised proceeding with haloperidol therapy, despite the presumed pregnancy, on the
grounds that severe hyperactivity and distress were a risk to both patient and fetus, whereas there
was no direct evidence that haloperidol or any other neuroleptic leads to any specific birth defect.
The physician in charge disagreed. Finally, an ultrasound examination revealed a false pregnancy,
and appropriate drug treatment was begun. This case illustrates one kind of clinical dilemma.
Thalidomide, with its gross fetal deformities, still haunts all of pharmacotherapy.
As far as we can determine, the only drugs commonly used in psychiatry with proven relationships
to specific birth defects are lithium, most anticonvulsants, and benzodiazepines. Lithium has been
associated with cardiac abnormalities, especially Ebstein’s anomaly, and anticonvulsants have beenPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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associated with a variety of birth defects, including facial deformity and spina bifida. However,
studies in the 1990s (Cohen et al. 1994) suggested that first-trimester lithium teratogenic effects
had been overestimated in the earlier studies and that the risks of stopping lithium in some
patients outweighed the risks of birth defects.
Beyond this, there is no clear evidence that any standard psychiatric drug does not (or does) cause
birth defects. Minor congenital abnormalities occur in up to 4% of infants born to drug-free
mothers. However, there is a general suspicion that any drug might be bad for the fetus, and no
doctor feels totally comfortable recommending drug therapy for a patient who is believed to have
recently become pregnant or who intends to become pregnant. Whenever possible, drug therapy
should be avoided in such instances.
Unfortunately, some women with severe, even disabling, psychiatric disorders either want to
become or actually become pregnant, and a choice must be made between treating the patient and
avoiding medicating the fetus. If the situation is not a crisis, as with the patient who is taking
maintenance medication but would like to become pregnant, outside consultation can be obtained
from a psychiatrist experienced in working collaboratively with obstetricians or from a
dysmorphologist (an expert in birth defects), a type of specialist found in major medical centers.
Telephone hotlines providing information about the effects of drugs on the fetus are also available.
One of these is the California Teratogen Information Service (CTIS, 1-800-532-3749) based at the
University of California, San Diego, and at Stanford. Staff members are willing to accept calls and
refer callers to other programs around the country when appropriate. Web sites addressing issues
of drugs and pregnancy—such as those of the CTIS (www.ctispregnancy.org), which is a member of
the Organization of Teratology Information Services (OTIS) (www.otispregnancy.org), and Illinois
Teratogen Information Specialists (www.fetal-exposure.org), are also available. Major reference
works in this area are listed in the bibliography of this chapter.
Information from a psychiatrist, a dysmorphologist, or a telephone hotline can indicate whether
there is any solid evidence that a particular drug is teratogenic, but it does not solve the clinician’s
whole problem. The final decision must be based on the seriousness of the patient’s distress and
the reasonableness of the desire to have a child. Documented informed consent from the patient
and her family (including her husband or her parents, when appropriate) for the treatment plan is
necessary, whether one decides to leave the patient drug free with the risks of that course or to
continue with a needed medication despite the pregnancy.
It is likely that stopping most psychotropic medication 2–3 weeks before the pregnancy is early
enough to avoid malformations.
If medication can be avoided for the first 3 months of pregnancy, the risk of fetal abnormality is
much reduced, but other risks can occur. Babies born to mothers who are physically dependent on
sedatives or opiates suffer withdrawal syndromes and need to be treated postnatally. Autonomic
withdrawal symptoms presumably can occur in the newborn if the mother has been taking tricyclic
antidepressants (TCAs) or short-acting antidepressants such as paroxetine and venlafaxine. One
can justify withdrawing medication carefully from pregnant women a few weeks before delivery in
some circumstances. However, the risk to the fetus/newborn may be small relative to the risks
posed by not treating a vulnerable woman as she begins the postpartum period.
Overall, antidepressants are probably the best-studied class of agents during pregnancy relative to
all other medicines. The most recent data on fluoxetine exposure (Goldstein et al. 1997a, 1997b;
Pomp and Gedde-Dahl 2001; Rahimi et al. 2006) suggest that exposure during pregnancy is not
associated with a higher rate of birth anomalies. More than 5,000 women in a national database
who were taking fluoxetine have been prospectively studied, and there is no clear evidence of
teratogenic effects for fluoxetine. However, there has been an association of selective serotonin
reuptake inhibitor (SSRI) exposure in pregnancy with higher rates of spontaneous abortions
(Rahimi et al. 2006), a self-limiting neonatal behavioral syndrome characterized by motor effects,
irritability, and gastrointestinal upset (Moses-Kolko El et al. 2005), and possibly even a small risk Print: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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of postnatal pulmonary hypertension (Chambers et al. 2006). In addition, women exposed to high
doses of fluoxetine in pregnancy might have a somewhat increased risk of delivering a
low-birthweight infant (Hendrick et al. 2003; Simon et al. 2002). The clinical significance of an
infant with somewhat lower birthweight is unclear. Preliminary evidence also suggests that
citalopram and sertraline do not appear to be teratogens. However, paroxetine does appear to be a
potential teratogen associated with an increase in cardiovascular malformations, including atrial
and septal defects (Cuzzell 2006). Thus, paroxetine generally should be avoided in pregnancy if
possible. Given the known risk of relapse or recurrence when antidepressants are stopped, we
have, along with our patients, concluded many times that patients are better off continuing their
SSRIs throughout pregnancy.
All the SSRIs except paroxetine are currently considered U.S. Food and Drug Administration (FDA)
category C agents, meaning that the risk of teratogenic effects cannot be ruled out because of
insufficient evidence. However, the FDA classification of drugs taken during pregnancy is
inadequate. Bupropion is a category B drug, suggesting that the known risk with bupropion is less
than that of the SSRIs. Although animal data on bupropion may suggest minimal risk of teratogenic
effects, there are virtually no clinical data. Thus, we would not suggest using bupropion over an
SSRI in pregnancy. Likewise, some TCAs such as nortriptyline are category D agents, suggesting
that there is positive evidence of risk. For patients who have clearly responded to nortriptyline, it
may be much safer for them to continue the drug than to switch to an SSRI.
There are convincing data that valproate is associated with a variety of neural tube defects in the
first trimester, including spina bifida and anencephaly (see Chapter 5: “Mood Stabilizers”).
Hydantoin and carbamazepine may be associated with similar defects. The fetal serum levels of the
anticonvulsants are around 50%–80% of the maternal dose. Most of the anticonvulsants are
category D agents as a result. We know very little about lamotrigine, topiramate, and gabapentin in
pregnancy, although these drugs are currently considered risk category C simply because data do
not exist to define a risk. Likewise, atypical antipsychotics (except clozapine) are currently class C
agents for the same reason. Thus far, experience with the atypical antipsychotics has not
suggested that these agents are teratogens (McKenna et al. 2005). We are more confident about
the typical antipsychotics, since so many women have been exposed to these agents since the
1950s. Many women have been treated with phenothiazine-like agents for nausea during the first
trimester, and there is no clear evidence of a teratogenic effect. Since psychosis can be such a
hazard during pregnancy, the benefits of the typical agents often outweigh the risks of untreated
psychosis. At this time, it probably preferable to employ high-potency typical agents during
pregnancy rather than either atypical agents, whose risks are unknown, or low-potency agents with
significant anticholinergic properties.
Benzodiazepines were traditionally to be contraindicated in pregnancy. Many benzodiazepines
carried an FDA X category risk in pregnancy, meaning that these agents should not be used. The
concern was that first-trimester exposure was associated with an increased risk of cleft lip and
palate. The association with cleft palate with benzodiazepine exposure has been questioned in
studies (Dolovich et al. 1998; Eros et al. 2002). The risk of oral clefts with benzodiazepine exposure
in pregnancy appears to be less than we once believed, but there does appear to be some increased
risk.
The issue of behavioral teratogenicity of drugs taken during pregnancy is more difficult to assess.
Cocaine and alcohol intake during pregnancy are sometimes associated with behavioral problems in
child development, even if there are no physical deficits. Although physical anomalies are easy to
quantify, behavioral effects may be more subtle. The best study to date could find no difference in
language, temperament, activity level, or intelligence in 135 children exposed to fluoxetine or TCAs
in utero compared with those who were not (Nulman et al. 1997, 2002). A study done by the
Stanford group suggests that there may be mild motoric differences in children exposed to
antidepressants in utero but no effects on mental development (Casper et al. 2003). Delayed motor
development has also been reported in a rat study of fluoxetine exposure in utero. However, in this
same study, prenatal exposure to fluoxetine had an unexpected beneficial effect on subsequentPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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cognitive ability in rat pups (Bairy et al. 2006). These studies, although important, are insufficient
to answer the question of whether in utero exposure to an antidepressant has negative behavioral
effects. Our clinical experience, however, has not indicated any clear behavioral effects of
antidepressant exposure during pregnancy, but further study is certainly warranted.
After the baby is born, nursing mothers taking medication excrete some drug in breast milk,
because all known psychoactive drugs are secreted in breast milk. While fetal serum levels of
antidepressant may approach 50% of the maternal serum levels, less than 1% of the maternal dose
is present in breast milk. In the absence of data on breast milk concentrations of a specific drug, it
is hard to estimate the seriousness of this problem; generally, however, breast milk concentrations
are much lower than drug levels in the blood, and the total dose ingested by the infant may be
quite small (Berle et al. 2004). Studies have suggested that antidepressant serum levels are often
undetectable in infants who breast-fed while their mothers were taking antidepressants (Birnbaum
et al. 1999). Stowe et al. (1995) followed seven nursing women with severe postpartum depression
who were taking sertraline and found that the maximum daily dose to which their infants were
exposed was 0.026–0.044 mg/kg. In related work (Winn et al. 1995), nursing infants exposed to
sertraline in breast milk were monitored by growth charts, number of illnesses, and developmental
milestones; no adverse effects were noted, compared with controls. As with many risk-benefit
situations in medicine, the suffering and hospitalization of the mother must be weighed against the
often unknown risk to the infant, as interpreted by the doctor, the patient, and the patient’s family.
PEDIATRIC PSYCHOPHARMACOLOGY
The decision to use a drug treatment for a psychiatrically ill child or young adolescent must be
based on a clear clinical need. There are few data on the long-term consequences of psychiatric
drug therapy in childhood for brain function, behavior, or physical health in adult life. The
psychiatric disorder should pose significant danger to the child’s development and well-being and
should be undertaken only after considered medical and psychiatric evaluation.
Prepubescent children have efficient livers. This generally allows them to metabolize drugs rapidly
and enables them to tolerate somewhat higher doses of psychiatric drugs per unit of weight than
adults tolerate. After puberty, drug metabolism resembles that seen in young adults. The lesson
here, of course, is not that 7-year-olds should be given huge doses of drugs, but that they should be
started on very small doses and, if there is no response, that the dose can be gradually increased to
adult dosages, adjusted for weight, without fear of unusual toxicity.
It should be noted that most standard psychiatric drugs have not received FDA approval for use in
children or even in adolescents, mainly because the necessary studies have not been carried out.
Recently, the FDA has begun to require that manufacturers of antidepressants do studies in
children and adolescents.
Stimulants
The best-studied and best-validated drug therapy for psychiatrically ill children is the use of
stimulants (D-amphetamine, methylphenidate, and magnesium pemoline; see Chapter 8:
“Stimulants”) in attention-deficit/hyperactivity disorder (ADHD). More than 170 trials of stimulants
in the treatment of ADHD involving 5,000 children attest to the benefits of these drugs. Since the
early 1990s, the number of children taking stimulants has risen dramatically. Between 1990 and
1993, the number of outpatient visits devoted to ADHD increased from 1.6 million to 4.2 million per
year, with 90% of children diagnosed with ADHD receiving a stimulant at some point in their
treatment (Swanson et al. 1995). In 1996 alone, more than 10 million prescriptions
for methylphenidate were written. It is unclear whether the marked increase in stimulant
prescriptions is the result of better ADHD recognition or overprescription, but both factors are likely
involved (Greenhill et al. 1999). However, the suggestion in some quarters that ADHD is simply an
excuse to medicate annoying behavior in children or to sell more drugs does not appear sound.
Research regarding the effects of stimulants on various kinds of behavior suggests that the drug
effects are complex. The dose that controls overactivity best may be too high for optimalPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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improvement in learning. The stimulants may cause a slight decrease in body growth, perhaps 1–3
cm in height over the entire developmental period, although a recent follow-up study showed no
effect of stimulant exposure on adult height (Kramer et al. 2000). Children taking stimulants may
show side effects such as anorexia, insomnia, dysphoria, and even tics.
Some children with ADHD are markedly benefited—generally more in behavior than in academic
performance—whereas others received only some benefit and a few are not benefited or even
become more agitated. Distractibility, overt aggression, and daily class performance are improved
with stimulant use and worsen when the drug is stopped or a placebo is substituted. Most of the
studies have been for 12 weeks or less. However, long-term trials with both stimulants and
atomoxetine have confirmed that the benefits of pharmacotherapy in children treated for ADHD are
sustained (Arnold et al. 1997; Barbaresi et al. 2006; Kratochvil et al. 2006).
A long-acting form of methylphenidate (Concerta) is now widely being used in the treatment of
ADHD. Concerta circumvents the problem of trying to fit in tid dosing during the school day and
appears to be as effective as the short-acting form of methylphenidate. Dosing of Concerta is about
20% higher than the total methylphenidate dose. Thus, the total Concerta dose is 18–54 mg taken
once a day.
Some children respond better, unpredictably, to one of the three stimulants than to the other two.
Methylphenidate is usually started at 5 mg bid, and the dosage may be increased over time up to 20
mg tid. Dextroamphetamine is less expensive than the other stimulants. It is initiated at 2.5 mg
bid, and the dosage is gradually increased to a maximum of 40 mg in two to four divided doses. The
common clinical practice with the shorter-acting stimulants is to prescribe dosing twice a day, with
the last dose around noontime to reduce the risk of insomnia. A report by Kent et al. (1995)
suggested that adding a third dose in the late afternoon rarely disrupted sleep. Lunchtime doses
are frequently a problem, however, for schoolchildren. Sustained-release preparations of
D-amphetamine, methylphenidate, and methamphetamine are available, but their usefulness in
children with ADHD is not well documented. These preparations can certainly be tried if once-a-day
dosing is desired or needed. In patients with a good stimulant response, drug holidays every few
months to discover whether the drug is still needed are worth trying. The practice of giving a child
with ADHD his or her medication only on school days may have the disadvantage of impairing the
child’s family and peer relationships as well as impairing learning outside school. Some children
continue to benefit from stimulants into adolescence or even adulthood. The dosage may need to be
adjusted, up or down, over time as the child grows and matures.
A number of other agents have proved useful in the treatment of ADHD. TCAs (e.g., desipramine) at
low dosages (10–25 mg qid) may be useful but may act more slowly: it may take several weeks for
them to work. In addition, their effects have been said to fade after a few months. Another
antidepressant that has shown promise in the treatment of ADHD is bupropion. Studies have
reported that bupropion may be effective in the behavioral and cognitive problems associated with
ADHD (Casat et al. 1989) and in the treatment of adult ADHD (Wilens et al. 2005). In children, the
bupropion dosage is 3–6 mg/kg/day in divided doses. One case report suggested that there may be
a role for the SSRIs in the treatment of ADHD (Frankenburg and Kando 1994). Guanfacine (Tenex)
has also been used over the years for the treatment of ADHD. The efficacy of guanfacine may be
less than that of an antidepressant in the treatment of ADHD.
Finally, clonidine is often used in combination with stimulants to reduce side effects and enhance
effects on hyperactivity and hyperkinesis. Clonidine at dosages of 0.1 mg tid has been reported to
reduce stimulant-induced insomnia as well as impulsivity. As a monotherapy of ADHD, however,
clonidine appears to be inferior to desipramine (Singer et al. 1995).
Various antidepressants, including venlafaxine, bupropion, and desipramine, have been found to be
effective in the treatment of ADHD and are discussed later in this section.
Two newer, “nonstimulant,” agents—atomoxetine and modafinil—have been studied in the
treatment of ADHD. Atomoxetine is a pure inhibitor of the presynaptic norepinephrine transporterPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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that was approved in 2003 for the treatment of ADHD in both children and adults. Atomoxetine has
been reported, at dosages of 1.2 mg/kg/day and 1.8 mg/kg/day, to be significantly more effective
than placebo in children and adolescents with ADHD (Buitelaar et al. 2004; Kelsey et al. 2004).
Most children are treated once a day, with the dosage in the range of 40–80 mg/day. In addition,
atomoxetine could be an adjunctive treatment in depression; however, our experience to date with
this drug has been disappointing.
Atomoxetine is well absorbed orally and has a half-life that averages about 4 hours. However, slow
metabolizers of cytochrome P450 (CYP) 2D6 metabolize the drug more slowly. We would anticipate
that the combination of atomoxetine with SSRIs might increase toxicity. Thus, lower doses of
atomoxetine may be needed when a patient is already taking fluoxetine or paroxetine.
Atomoxetine has the advantage over standard stimulants of not having a significant abuse
potential. Thus, atomoxetine does not require triplicate prescriptions as do standard stimulants. On
the other hand, atomoxetine shares with the stimulants a tendency to suppress weight and to
increase heart rate and blood pressure. Both the anorexic and cardiovascular effects of
atomoxetine appear to be dose related. Other reported side effects include rash, anxiety,
somnolence, and, most recently, liver function test abnormalities.
Several studies have evaluated the efficacy of atomoxetine compared with placebo or standard
stimulants. In a randomized comparison of atomoxetine and methylphenidate in 228 children with
ADHD, both drugs were equally effective (Kratochvil et al. 2002). In a placebo-controlled study of
297 children with ADHD, atomoxetine consistently beat placebo on measures of attention and
hyperactivity (Michelson et al. 2001). In addition, atomoxetine also improved social and family
functioning relative to placebo.
Modafinil, which is FDA approved for the treatment of narcolepsy, has also been studied for the
treatment of ADHD. Modafinil has the distinct advantage over stimulants of not requiring a
triplicate prescription, because its abuse potential appears to be very low. In addition, it is better
tolerated than amphetamines and simple to dose.
Like atomoxetine, modafinil does not act on the dopaminergic system and, as noted earlier, does
not have a significant abuse potential. Modafinil is therefore in Drug Enforcement Administration
(DEA) schedule IV and does not require a triplicate prescription. Modafinil appears to act on
excitatory histamine projections in very specific regions of the brain and lacks the generalized
effects of stimulants. It may also have effects on the hypocretin/orexin system. As such, it is less
likely to produce cardiovascular changes of weight gain than either amphetamine or atomoxetine.
The most common side effect of modafinil has been headache, but the drug can also produce some
mild gastrointestinal side effects. Central nervous system (CNS) side effects such as anxiety or
insomnia occur infrequently. Modafinil is an inducer of the CYP 3A3/4 enzyme, so it can speed up
the metabolism of oral contraceptives, steroids, and other 3A3/4-dependent compounds. Thus,
women taking birth control pills should be advised that there is a theoretical risk of contraceptive
failure when modafinil is taken concurrently.
Modafinil has been studied in many conditions associated with producing fatigue, including shift
work, sleep apnea, multiple sclerosis, fibromyalgia, Parkinson’s disease, and depression (see
Chapter 9: “Augmentation Strategies for Treatment-Resistant Disorders”). Preliminary results
suggest that modafinil may have a role in the treatment of fatigue in many disorders without a
significant downside.
The efficacy of modafinil in the treatment of ADHD has been evaluated in a number of trials.
Studies of modafinil in the treatment of ADHD in children have suggested a benefit over placebo
and effectiveness equal to that of dextroamphetamine (Rugino and Copley 2001; Taylor and Russo
2000). In a 4-week study of 248 children with ADHD, modafinil at a dosage of 300–400 mg/day
was more effective than placebo in treating the symptoms of ADHD and was well tolerated
(Biederman et al. 2006). Likewise, in a 9-week double-blind trial of 194 children and adolescents
with ADHD, 52% of patients randomly assigned to modafinil improved versus 18% of childrenPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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randomly assigned to placebo (Greenhill et al. 2006). These data appeared to be sufficient to
prompt an approvable letter in 2005 for the treatment of ADHD in children with modafinil.
However, there was a report of possible Stevens-Johnson syndrome in a child participating in one
of the trials. The etiology of this rash was unclear but might have been related to the study drug.
This report resulted in the FDA requesting additional safety information. The company decided to
withdraw its application for modafinil in the treatment of ADHD, apparently because of the
extensive safety studies that would be required for final approval.
Antipsychotics
Very few trials of antipsychotics have ever been done with children who have schizophrenia. There
has been a general impression that children benefit less from antipsychotics that do adults.
However, with the limited data on drug therapy in childhood schizophrenia, it is difficult to make
any generalizations. To date, relatively few controlled trials with antipsychotics have ever been
done with children. The first showed a modest benefit of haloperidol and loxapine compared with
placebo in 75 adolescents with schizophrenia (Pool et al. 1976). Another study showed that
haloperidol was superior to placebo in the treatment of childhood schizophrenia (Spencer et al.
1992).
Even fewer data exist on the efficacy and safety of atypical agents in the treatment of childhood
schizophrenia. In one controlled trial, clozapine was compared with haloperidol in 21 patients over
6 weeks (Kumra et al. 1996). The group that was randomized to clozapine showed superior
improvement in both positive and negative symptoms relative to the haloperidol-treated children.
However, the clozapine was poorly tolerated. Five of 10 clozapine-treated children had significant
drops in their neutrophils. In addition, 2 of the 10 children experienced seizures. The average
dosage of clozapine was 237 mg/day. Another small randomized controlled trial found that
olanzapine and risperidone were somewhat more effective than haloperidol in the treatment of
childhood schizophrenia (Sikich et al. 2004). However, weight gain was significantly more
problematic in the children treated with atypicals.
Despite the lack of published reports, atypical agents such as risperidone and olanzapine offer clear
advantages in a population that may need to be treated for many years. The risk of extrapyramidal
symptoms (EPS) with typical antipsychotics is substantial in children who need to be treated
through adulthood. While akathisia and dystonic reactions are seen in children treated with
atypicals, the risk of tardive dyskinesia is exceedingly small (Correll et al. 2004). On the other
hand, obesity may be a limiting factor for some atypical antipsychotics. Low-dose risperidone (at
dosages of 1–2 mg/day) appears to be effective for many without the weight gain associated with
other atypical agents. Clozapine is a last resort in children in whom trials of both typical and
atypical agents have failed.
Table 12–2 lists common pediatric therapeutic dosages of selected antipsychotics in children. In
children with developmental disorders such as autism, antipsychotics have a more clear utility. In
fact, risperidone became the first drug approved by the FDA for the treatment of some behavioral
aspects of autism in 2006. Developmental disorders in children younger than age 15 rarely show
marked improvement with antipsychotic treatment, although some decrease in overactive,
disorganized behavior can occur. In fact, the best studies of the atypicals for any condition in
childhood are studies of the use of risperidone in children with pervasive developmental disorders.
For example, in a multisite study of 101 autistic children, risperidone was significantly more
effective than placebo in controlling tantrums, aggression, and self-injurious behavior (McCracken
et al. 2002). Additionally, the effects were sustained for at least 6 months.
Table 12–2. Antipsychotic dosages in children
Drug Common pediatric therapeutic dosage
Chlorpromazine 0.25 mg/kg tid
Trifluoperazine 0.5–10 mg bidPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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Drug Common pediatric therapeutic dosage
Haloperidol 0.15–0.5 mg/kg/day (in divided doses [bid])
Olanzapine 2.5–5 mg qhs
Risperidone 1–2 mg/day
Psychosis associated with affective disorders in children is also helped by antipsychotics. There is
no evidence that children are any less tolerant of these drugs than are adults, except perhaps for
an even higher rate of dystonia early in treatment in adolescent males. However, the risk of tardive
dyskinesia and the lower likelihood of marked improvement make it necessary that clinicians use
these agents cautiously, documenting carefully the clinical effects observed and periodically
assessing the patient without the medication to make sure that the treatment is really useful as a
maintenance therapy. In older adolescents, acute psychotic syndromes begin to resemble those
seen in adults and may be treated in the same manner (see Chapter 4: “Antipsychotic Drugs”).
Sedative neuroleptics (e.g., thioridazine and chlorpromazine) may interfere with learning. Of the
nonsedative neuroleptics, haloperidol has been best studied in children with autism (pervasive
developmental disorder) and has limited efficacy. Recent reports have discussed the utility of
atypical antipsychotics such as risperidone and clozapine in treating psychotic children. Earlier case
reports attested to the utility of clozapine in child and adolescent schizophrenic patients (Mozes et
- 1994). Although we know of no controlled studies on risperidone that have been completed at
the time of this writing, preliminary experience with the drug in children has been positive
(Armenteros et al. 1995).
Antipsychotics used at low dosages (e.g., 0.5–3 mg/day of haloperidol or 2–10 mg/day of
pimozide) can also control the tics of Tourette’s disorder. Clonidine has also been reported to be
helpful in severe cases of this disorder. Clonidine can suppress tics fairly well, but it may be more
effective in Tourette’s disorder patients with explosive violent behaviors. Clonidine causes dry
mouth, sedation, constipation, and hypotension.
Antipsychotics have often been used to control the behavior of angry, impulsive children and
adolescents without psychosis. This use is not well validated, but most clinicians use low doses of
antipsychotics to control angry, violent behavior in child or adolescent inpatients. Some prefer
haloperidol in low doses (e.g., 2 mg every hour until the patient is calm), whereas others use more
sedative drugs like chlorpromazine in 10- to 50-mg doses three or four times a day. Risperidone
has been studied in the treatment of aggression associated with autism in adults and is clearly
more effective than placebo (McDougle et al. 1998). Open studies and reports of risperidone in the
treatment of aggression in children have also been positive at dosages of 1–2 mg/day (Horrigan
and Barnhill 1997; Schreier 1998).
A well-controlled study (Platt et al. 1984) comparing haloperidol (2–6 mg/day), lithium carbonate,
and placebo in hospitalized nonpsychotic aggressive children with conduct disorder showed the two
drug regimens to be more effective than placebo on various measures. The nursing staff judged the
lithium responders to have done best. Sedation and dystonia were problems in patients taking
haloperidol. The risks and benefits of this use are unclear. If antipsychotics are used to reduce
aggression in children with conduct disorder and actually are effective, the continued use of these
potentially harmful drugs to control deviant behavior must be strongly justified. For each particular
patient, the drug must make a major and clinically important difference.
Another growing use of antipsychotics in children is for the treatment of anorexia. There are no
known effective pharmacotherapies for anorexia nervosa. However, preliminary studies have
reported that atypical antipsychotics may help with the agitation, obsessiveness, and disturbing
cognitions associated with anorexia nervosa (Dennis et al. 2006; Mondraty et al. 2005). Olanzapine
and quetiapine have been most investigated and, as expected, also may be associated with steady
weight gain. Additional trials are clearly called for on the utility of antipsychotics in pediatric
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The side effects and risks of antipsychotics, including tardive dyskinesia with typical agents and
weight gain with atypical agents, are similar in children as in adults. However, the possibility of
cognitive blunting with these drugs may be relatively more of a problem in children. An inert child
who is not learning or functioning may be less trouble to others, but the child may develop more
normally if medication is reduced or stopped. In addition, it appears that adolescent males are at
much greater risk for dystonic reactions than are older adults (Rosenberg et al. 1994).
When neuroleptics are prescribed for children or adolescents, documented informed consent from
the responsible parent or parents is mandatory. Even if the child or adolescent patient is too young
to give informed consent, the risks and benefits of the drug should be explained to the patient, and
his or her assent to the treatment should be obtained when possible (see Chapter 1: “General
Principles of Psychopharmacological Treatment”).
Antidepressants
The 2004 decision of an FDA advisory panel to put a black box warning on antidepressants used in
children appeared to have resulted in fewer parents seeking or accepting pharmacotherapy for
their children in 2005, but antidepressant use in children rebounded somewhat in 2006 (see
Chapter 3: “Antidepressants”). While the FDA’s review of 25 studies involving 4,600 children
suggested an increased risk of suicidal thoughts or gestures by 3% in antidepressant-treated
patients versus 1.5% in patients receiving placebo, the review did not adequately weight the risks
of no treatment at all. Child psychiatrists are also more reluctant to prescribe antidepressants
because of the enhanced risk of liability associated with a black box warning. That is not to
discount the findings of the FDA. Some children appear to be at increased risk for more suicidal
thoughts while taking antidepressants. We suspect that children with bipolar spectrum disorders
and those with treatment-emergent akathisia may be at greatest risk. However, the slightly
increased risk associated with antidepressants must be weighed against the risk of suicidality in
depressed children who are inadequately treated or not treated at all.
The SSRIs have been considered the pharmacotherapy of choice for depression in childhood and
adolescence. Although it has been difficult to demonstrate that the TCAs or other antidepressants
are more effective than placebo in the treatment of childhood depression, there is some evidence of
at least fluoxetine’s superiority to placebo in children. In addition, the safety and side-effect
profiles of the SSRIs are superior to those of the TCAs. Emslie and colleagues (1997) randomized
76 children (ages 7–17) to either fluoxetine 20 mg/day or placebo. Whereas 56% of the
fluoxetine-treated patients responded in 8 weeks, only 33% of the placebo-treated patients
responded. Nonetheless, remission was rare for both groups. A more recent study by Emslie and
colleagues (2002) in 219 children also found fluoxetine well tolerated and effective in the
treatment of pediatric depression. In addition, fluoxetine maintenance treatment appears to be
effective in preventing relapse in children (Emslie et al. 2004).
Fluoxetine’s oral elixir is quite useful in children. Experience has shown that children are better off
starting at lower dosages of fluoxetine. We tend to start at 5 mg/day and increase the dosage
every 1–2 weeks to a maximum dosage of 60 mg/day.
Studies on the efficacy of other SSRIs in pediatric depression have been less convincing. Two
published trials of sertraline in the treatment of depression in childhood suggest a modest but
statistically significant benefit of sertraline after 10 weeks of treatment (Wagner et al. 2003). One
published study indicated a somewhat higher rate of remission in depressed children treated with
paroxetine but little difference in mean depression scores at the end of 8 weeks (Keller et al.
2001). In another study, paroxetine (20–40 mg/day) and imipramine (200–300 mg/day) at their
maximum did not separate from placebo in adolescent depression (Keller et al. 2001). In addition,
two unpublished studies of paroxetine did not find benefit in adolescents. One study indicated that
citalopram at an average dosage of about 23 mg/day was significantly more effective than placebo
in childhood/adolescent depression (Wagner et al. 2001). However, response rates to both drug
(36%) and placebo (24%) were relatively low. The drug was well tolerated.Print: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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The sum of published and unpublished studies suggests that the benefits of SSRIs in children
appear most solid with fluoxetine. Other SSRIs, including paroxetine, citalopram, escitalopram, and
sertraline, do appear to have some benefits, but these benefits are more modest and not
established in controlled studies. Some investigators have concluded that when unpublished
studies are considered and the risks of SSRIs are weighed against the benefits in children, the
benefits are not overwhelming (Whittington et al. 2004). Given that only a handful of studies on
the use of SSRIs in treating pediatric depression have been completed, we believe that it is too
early to draw any strong conclusions about the utility of SSRIs in children. However, the need for
clinicians to have access to previously unpublished studies is clear. Only with more complete
information can the risks and benefits for these treatments be adequately assessed.
It has been even more difficult to demonstrate clear efficacy of TCAs and other antidepressants in
controlled studies of childhood depression. For example, a meta-analysis of 12 randomized studies
of TCAs in pediatric depression failed to demonstrate a significant difference relative to placebo
(Hazell et al. 1995). However, some children who clearly meet criteria for major depressive
disorder do appear to respond to TCAs. FDA guidelines recommend an upper dose limit of 2.5
mg/kg for imipramine; however, some studies report doses up to 5.0 mg/kg as often being
necessary for clinical response (Table 12–3).
Table 12–3. Common antidepressant dosages in children
Drug Dosage range Serum level (ng/mL)
imipramine 1–5 mg/kg/day 150–250
desipramine 1–5 mg/kg/day 150–250
nortriptyline 0.5–2 mg/kg/day 75–150
phenelzine 0.25–1 mg/kg/day NA
fluoxetine 5–30 mg/day NA
bupropion 1–7 mg/kg/day NA
citalopram 10–20 mg/day NA
Note. NA = not applicable.
Monitoring of cardiac function is wise when TCAs are used in children: electrocardiograms (ECGs)
should be done prior to starting therapy, again when the dose exceeds 3 mg/kg, and then every
2 weeks if the dose is being increased. Doses greater than 5 mg/kg should not be given without
outside consultation. Significant slowing of cardiac conduction (PR interval over 0.20 msec, QRS
interval over 0.12 msec) may require lowering the dose. Between 1986 and 1992, at least four
cases of sudden death occurred in children taking desipramine. The cardiac long QT syndrome has
been proposed as a mechanism of action in these sudden deaths. A more recent review of the topic
(Biederman et al. 1995) failed to find a strong association between desipramine use and sudden
death in children 5–14 years old.
TCAs are effective in the treatment of enuresis at doses of 0.3–1.0 mg/kg of imipramine or an
equivalent drug, but behavioral treatments are generally preferred because they are also effective
and may have a lower relapse rate. ADHD tends to respond in the same dosage range. It is
interesting to note that TCAs improve enuresis within a few days, whereas response to ADHD or
depression takes 1–4 weeks. Monoamine oxidase inhibitors (MAOIs) are also said to be effective in
the treatment of both enuresis and ADHD, but their use has not been well studied. Clomipramine is
available for the treatment of OCD; it has been shown to be effective in children and adolescents
with this condition (see Chapter 6: “Antianxiety Agents” for additional discussion).
Side effects of antidepressants in children resemble those seen in adults. Blood level monitoring is
about as useful as it is in adults. That is, it is useful for the TCAs but not for other antidepressants,
except, perhaps, to test for compliance. Imipramine is the best-studied TCA, and positivePrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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correlations between blood level and improvement are often found in clinical trials. Our experience
at McLean Hospital and Stanford University Hospital suggests that depressive symptoms in
adolescents rarely include major appetite changes or early-morning awakening. Overly sound and
lengthy sleep and dysphoria on awakening are more common. Physical symptoms, fatigue,
irritability, anger, and retardation for the first few hours in the day may be present without
subjective recognition of depression or sadness. Sex drive is decreased. These adolescents often
have a family history of affective disorder. This pattern often responds to TCA therapy, although
formal controlled studies have not been done. Panic agoraphobia can occur in adolescents and can
be treated with antidepressants.
There is little published data on the use of serotonin2 (5-HT2) antagonists, selective
serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion in pediatric depression. One
small, controlled trial of venlafaxine in pediatric depression showed no benefit (Mandoki et al.
1997). In addition, two unpublished trials did not show benefits for venlafaxine in pediatric
depression. However, cautious trials with bupropion may be indicated if the patient has failed to
respond to trials of SSRIs or TCAs. Bupropion has been used for ADHD at dosages of 3–7
mg/kg/day in divided doses. In addition, we (Killen et al. 2004) recently reported on a trial of
bupropion SR in combination with a nicotine patch in adolescent smoking cessation. The drug was
well tolerated. In addition, open-label studies have suggested that there may be a role for
bupropion in treating adolescents with depression and comorbid ADHD (Daviss et al. 2001;
Solhkhah et al. 2005). Anorexia and the risk of seizures may be problems for some children, and,
particularly in those cases, the dose should be titrated upward slowly. The few small studies of
MAOIs in the treatment of children with depression and phobias have generally yielded positive
findings, but the results are inconclusive.
Mood Stabilizers
Adolescents can show a typical bipolar picture that often responds to lithium therapy or treatment
with an atypical antipsychotic. Preadolescent children rarely show mania, but they can show cyclic
mood and behavior shifts with periods of impulsivity, social intrusiveness, tantrums, mood lability,
and nonpsychotic euphoria, with parallel shifts in vegetative symptoms, which sometimes respond
to lithium. However, there are no controlled studies with adequate sample size that have
demonstrated the efficacy of lithium in childhood bipolar illness (Kafantaris 1995). One of the
better studies was a study in adolescents treated with lithium who had bipolar disorder with
comorbid substance abuse (B. Geller et al. 1998). Lithium appeared to help both the bipolar
disorder and the substance abuse. A randomized comparison of lithium and divalproex in the
maintenance treatment of pediatric bipolar patients (average age = 10.8 years) found that
valproate was about as effective as lithium in the time it took to require an additional intervention
(Findling et al. 2006). Smaller open-label studies have suggested that lithium is effective and often
well tolerated in treating bipolar depression (Patel et al. 2006) and in restabilizing bipolar disorder
when combined with valproate in children (Findling et al. 2006).
Explosive, violent behavior in pediatric patients with conduct disorder, mental retardation, and
hyperactivity has also responded to lithium treatment in a number of studies (Campbell et al. 1984;
Vetro et al. 1985).
No one knows the long-term consequences of long-term maintenance lithium treatment begun in
childhood or adolescence. Children have increased renal clearance relative to adults and may
tolerate larger doses of lithium. For children older than 12, the lithium may often be dosed as it is
for adults (Table 12–4). However, younger children under 25 kg are best started at 150–300
mg/day. The dosage may then be increased in 150- to 300-mg increments every 3–7 days in a tid
regimen as tolerated. It is not unusual for children to require more than 2,100 mg/day in divided
doses to maintain adequate serum levels. The serum levels should be monitored carefully and
checked every 3–5 days after each increase in dosage. The side effects of lithium in children are the
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Table 12–4. Common mood stabilizer dosages in children
Drug Dosage range Serum level
lithium 300–2,400 mg/day 0.5–1.2 mEq/L
valproate 15–60 mg/kg/day 50–100 g/mL
carbamazepine 10–50 mg/kg/day 8–12 g/mL
oxcarbazepine 5–30 mg/kg/day (150–1,200 mg/day) NA
lamotrigine 0.15–5.0 mg/kg/day (25–200 mg/day) NA
Carbamazepine, oxcarbazepine, lamotrigine, and valproate appear to also have a role in pediatric
psychiatric disorders. Controlled data demonstrate carbamazepine’s efficacy in conduct disorder
and intermittent explosive disorder in children and adolescents. There are also data suggesting that
anticonvulsants may have utility in the treatment of bipolar disorder and other pediatric conditions.
Oxcarbazepine may be somewhat easier to use in children, but the only double-blind study in a
pediatric bipolar population failed to show a benefit of oxcarbazepine in this population (Wagner et
- 2006). In Canadian studies, there is a suggestion that adolescents with bipolar disorder prefer
valproate to lithium. Valproate has also been reported to help aggressive behavior in adolescents
who do and who do not have mood disorders (Saxena et al. 2006; Steiner et al. 2003). While there
have been no controlled studies of lamotrigine in pediatric bipolar disorder, open-label studies have
reported benefit in the treatment of bipolar depression (Chang et al. 2006). Side effects of
anticonvulsants in children parallel those in adults. However, very young children (younger than 2
years) appear at greatest risk for hepatic toxicity with valproate. As with lithium, children often
require higher doses of carbamazepine or valproate on a mg/kg basis than adults because of their
more efficient hepatic and renal metabolism, as already mentioned. Children may be more at risk
for rash while taking lamotrigine than are adults, and slow titration of the drug to therapeutic
levels is prudent. The dosage range of carbamazepine in children is 10–50 mg/kg/day in divided
doses; the dosage range of valproate is 15–60 mg/kg/day.
Antianxiety Drugs
Benzodiazepines are sometimes of use for short periods in treating pavor nocturnus or
sleepwalking. If used for daytime anxiety, they can increase activity and produce or aggravate
behavior disorders, particularly in children with ADHD. Severe school phobia may be better treated
with an antidepressant, although a single dose of a benzodiazepine may be used occasionally to
allay anticipatory anxiety and help a child return to a feared situation for the first time. Alprazolam
has been used successfully to treat panic disorder, generalized anxiety disorder, and avoidant
personality disorder in children. Buspirone also appears to have some utility in childhood anxiety
disorders (Simeon 1993). Sedative antihistamines are believed to have some antianxiety or
hypnotic utility in children for short periods. Prolonged use may lead to anticholinergic side effects
and cognitive impairment. Venlafaxine and paroxetine are also being studied in adolescents with
social phobia. It is worth remembering that newer drugs are rarely studied in children or
adolescents before marketing, and even the older drugs are often only partially studied in children
and adolescents. Newer anticonvulsants, such as pregabalin, have not been studied in pediatric
anxiety but could prove a useful alternative to benzodiazepines.
The place of drug therapy for children and adolescents is still controversial. Drugs should be
reserved for clearly distressed or dysfunctional conditions for which psychosocial treatments either
have failed or are likely to be only of short-term benefit. Drug therapy needs to be carefully
monitored and requires close collaboration among the physician, the parents, and often school
personnel or other caregivers. Prolonged maintenance drug therapy is sometimes justifiable, but
there should be strong clinical evidence of benefit, and trials of withdrawal from medication are
often indicated to make sure the drug is still making a useful difference.
GERIATRIC PSYCHOPHARMACOLOGY
Elderly psychiatric patients present a variety of potential problems for the psychiatrist consideringPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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prescribing psychoactive drugs. Elderly persons may have decreased ability to metabolize some
drugs, although it has been documented only infrequently. These patients may have low serum
protein levels, which could lead them to have relatively higher levels of free drug (not bound to
protein) at any given blood level. Free drug is usually presumed to be more active and more likely
to cross the blood-brain barrier. Elderly patients may be more sensitive to peripheral side effects
(e.g., hypotension, constipation) than younger patients at the same dose or blood level. They may
also be more prone to CNS side effects (e.g., delirium, tremor, tardive dyskinesia). None of these
presumptions is well documented except for delirium and tardive dyskinesia, chiefly because no
adequate studies have been done.
Elderly persons appear to have a reduced reserve of both brain function and cardiovascular
competence, which leaves them more vulnerable to drug side effects. Decreased hepatic function
and renal function also contribute to side effects in geriatric patients. In addition, the
consequences of side effects—such as falls due to orthostatic hypotension, falls due to confusion, or
ataxia or decubitus ulcers due to prolonged oversedation—are more likely to be serious in elderly
persons. The situation is made worse by the higher likelihood of coexisting medical illness and the
use of other drugs for these illnesses in elderly patients. In addition, there is a lack of clear criteria
for predicting which elderly patients need very low, cautious dosage regimens of psychoactive
drugs and which patients require (and tolerate) rather large dosages to attain adequate treatment
response.
Moreover, the definition of geriatrics has changed over the years. The average 60-year-old of today
is far more fit than his or her counterpart of 20 years ago and probably does not demonstrate any
significant decrease in drug metabolism or tolerability. For the standard psychiatric conditions,
such as depression, mania, chronic schizophrenia, and generalized anxiety disorder, the only safe
and reasonable approach is to begin with a very low drug dosage and to increase the dosage
cautiously after other organic etiologies are ruled out. As an example, 25 mg of imipramine or
trimipramine at bedtime is a reasonable starting dose for healthy patients older than 65, and a
10-mg dose is reasonable for patients older than 70 or for patients older than 60 with concurrent
medical problems or with evidence of dementia. In such patients, dosage increments should be
scheduled for every 3–7 days, not every day, so that the clinician has a chance to assess side
effects before increasing the dose.
Antidepressants
Most antidepressants and electroconvulsive therapy (ECT) have been used effectively in elderly
patients with major depression. In the past 10 years, SSRIs, particularly sertraline, citalopram, and
escitalopram, have grown more popular in the first-line treatment of geriatric depression. In
addition, controlled trials of mirtazapine suggest that the sedating and weight-gain effects of the
drug are useful in many elderly depressed patients. Furthermore, mirtazapine may be better
tolerated in geriatric patients than some SSRIs with which it has been compared, such as
paroxetine. The SSRI side-effect profile is superior to that of the TCAs in most geriatric patients. All
TCAs, including the secondary amines, have the disadvantage of producing at least some
anticholinergic side effects and orthostasis. However, for more serious depressive episodes in
geriatric patients, many clinicians prefer venlafaxine or nortriptyline to SSRIs. Some controversial
data suggest that nortriptyline may be superior to fluoxetine in geriatric melancholic depression
(see Chapter 3: “Antidepressants”). Our experience, confirmed by discussions with other geriatric
psychiatrists and family practitioners, suggests that fluoxetine and other SSRIs are sometimes less
useful than TCAs in hospitalized elderly depressed patients.
Five geriatric depression studies are worthy of comment. In one, venlafaxine, fluoxetine, and
placebo were all of similar efficacy in depressed patients over 65 years of age. The high response
rate with placebo limits the inferences that can be drawn from this study. Both active drugs were
well tolerated. ECG and blood pressure effects were minimal with both drugs (Schatzberg and
Roose 2006). In contrast, a study involving frail nursing home patients reported higher rates, and
perhaps less safety, with venlafaxine than with sertraline (Oslin et al. 2003). In another study,Print: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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citalopram was not more effective than placebo in so-called old old patients (Roose et al. 2004).
Again, a high placebo response was observed. In another presentation, duloxetine was significantly
more effective than placebo in depressed geriatric patients (Raskin et al. 2004). A composite
cognition score was used as the primary outcome measure. In the last study, mirtazapine was
significantly more effective than paroxetine in the first 6 weeks of an 8-week trial. Mirtazapine was
associated with significantly fewer dropouts due to adverse events than was paroxetine. The
average dosage in this study was approximately 30 mg/day for both (Schatzberg et al. 2002).
Trazodone has been a somewhat effective antidepressant in elderly depressed patients and is an
excellent hypnotic. It should not cause orthostatic hypotension except for a couple of hours after a
bedtime dose. However, some patients in their 70s and 80s have daytime hypotension when
treated with trazodone.
Nefazodone was generally well tolerated in the elderly but was associated with orthostasis and
dysphoric activation in some geriatric patients. The risk of hepatotoxicity has limited the use of
nefazodone in the elderly, and it is now rarely used. Lower doses of both trazodone and nefazodone
are often necessary in older patients, particularly when treatment is being started.
Bupropion appears to be well tolerated in the treatment of geriatric depression but is experienced
as too activating by some patients. Dosages in the range of 200–300 mg/day appear to be
adequate in many cases of geriatric depression.
ECT remains the major treatment for depressed elderly patients when drug therapy fails. ECT is
often very effective. However, some patients with recurring depressions stop responding to ECT
after the third to the tenth course of treatment in the same way that some patients may “poop out”
with use of some antidepressants.
Although stimulants are occasionally quite helpful in the treatment of recent-onset depressions in
elderly patients with medical problems, they often only induce agitation in treatment-resistant
elderly depressed patients. We have seen some benefits of adding 100–200 mg in the morning of
modafinil (Provigil) to standard antidepressants in geriatric patients. Alexopoulos (2005) has
suggested that some late-life depression that is characterized by problems with executive function
and white matter changes might respond better to dopamine agonists and perhaps modafinil.
Another presumption in the treatment of elderly patients is that anticholinergic drugs increase the
likelihood of delirium. On this basis, desipramine should be safer than amitriptyline, and
fluphenazine should be safer than thioridazine. Our review of the literature on TCA use in elderly
patients suggests, however, that delirium more often occurs in patients taking a TCA-neuroleptic
combination and that this side effect can be transient and relatively easily managed. Again, there
are no adequate controlled trials documenting this issue.
Hypnotics and Anxiolytics
If benzodiazepines are to be used as hypnotics or for daytime anxiety, again use the lowest dose
first to observe whether this dose is adequate and to determine whether the drug is well tolerated.
In general, 3-hydroxy-benzodiazepines such as temazepam and lorazepam are the preferred agents
for geriatric patients because of their lack of active metabolites and simpler metabolism. There is
evidence that benzodiazepine metabolism is slowed in elderly persons, and there is a presumption
that higher cumulative blood levels are associated with behavioral toxicity.
Occasionally, elderly (and young adult) patients complain of excessive morning sedation after
taking slowly metabolized hypnotics like flurazepam. However, there is a good deal of individual
variability in the extent to which this consequence of slowed metabolism causes demonstrable
clinical problems. Nonetheless, the long-acting benzodiazepines such as flurazepam, because of
their long half-lives and tendency toward residual daytime drowsiness, are not particularly good
choices for the treatment of any insomnia. Temazepam is probably the best choice as a
benzodiazepine hypnotic because of its shorter half-life and lack of active metabolites.
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effective agent, it may be less well tolerated than zaleplon, which is much shorter acting and is
probably as effective as zolpidem. Zaleplon has been well studied in geriatric patients and has the
advantage of being able to be taken in the middle of the night, when some patients are most
distressed about not being able to go back to sleep. A dose of 0.5 mg at night or on awakening is
often sufficient. Likewise, eszopiclone may be dosed at 1–2 mg per night. The abuse potential
appears low, and the chance of significant drug interactions or exacerbation of sleep apnea also
appears low.
Trazodone continues to be valuable as a hypnotic in the elderly. At higher doses in geriatric
patients, the risk of orthostatic hypotension increases. Thus, we suggest checking orthostatic blood
pressures at baseline and as the dose is titrated. The most common dosing is 50–100 mg 1–2 hours
before bedtime. Mirtazapine is another fine agent to use as a sleeper. Like trazodone, it carries no
risk of dependence and tends to be well tolerated. A dose of 7.5–15 mg at night works at least as
well as trazodone without the risk of orthostatic hypotension.
Ramelteon may be worth trying before other hypnotics in geriatric patients. Unlike standard
hypnotics, ramelteon is not likely to contribute to confusion or amnesia, nor is it associated with
orthostatic hypotension as is trazodone. It appears to be somewhat less effective for maintaining
sleep.
Mood Stabilizers
Lithium excretion is, on the average, slowed in elderly patients as a consequence of an age-related
decrease in kidney function. Therefore, this drug should be started at low dosages in older
patients—300 mg/day in patients in their 60s and early 70s and 150 mg/day in patients who are
older. Lithium levels and clinical signs of toxicity should be monitored scrupulously. It is our
impression that elderly patients can slip from therapeutic to toxic blood levels more rapidly and
insidiously than can young adult patients. In addition, elderly patients are often taking concurrent
medications that may increase the risk of lithium toxicity, including nonsteroidal anti-inflammatory
drugs (NSAIDs), thiazide diuretics, and angiotensin-converting enzyme (ACE) inhibitors. On the
other hand, lithium can be as effective in some older bipolar patients as it is in younger ones,
although some elderly patients whose condition is of late onset may have an underlying organic
disorder that does not respond well to lithium.
Valproate generally appears better tolerated than lithium in elderly patients. It often takes lower
doses of valproate to achieve adequate serum levels in geriatric patients. We have seen dosages as
low as 250 mg/day appear to result in adequate mood stabilization for some geriatric patients.
However, many more patients will not achieve adequate serum levels with dosages below 750
mg/day.
Gabapentin is well tolerated in geriatric patients but of no utility in the treatment of bipolar
disorder. It may be more useful in geriatric agitation and anxiety states as pregabalin appears to
Other anticonvulsant agents such as oxcarbazepine and lamotrigine have not been adequately
studied in geriatric patients with bipolar disorder but are generally well tolerated. Carbamazepine,
with its potential for interactions with so many medications, is often a poor choice in geriatric
patients.
Antipsychotics
In older patients with chronic schizophrenia, there is a belief that lower antipsychotic dosages are
needed than those used with younger adult patients. There is, again, no real evidence to support
this belief, but there is some evidence that the same antipsychotic dose yields blood levels 1.5–2
times higher in elderly than in younger patients. Cautious attempts at gradually tapering dosage
are indicated in schizophrenic patients older than 60 who are receiving maintenance neuroleptic
treatment. When such patients have stopped their medication and become acutely psychotic,
cautious low-dosage medication (e.g., 0.5–2.0 mg/day of haloperidol or risperidone, or 1.25–5 mgPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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of olanzapine) should be tried for the first week to see whether a clinical response can be obtained
without resorting to high dosages. However, if the patient fails to improve and has a history of
requiring and tolerating a higher neuroleptic dosage, the dose can be gradually raised, again with
monitoring of side effects. Quetiapine, even at higher doses, has a very low risk of EPS and and is
favored by some geriatric psychiatrists.
The use of antiparkinsonian drugs could cause delirium, but leaving the patient exposed to dystonia
or pseudoparkinsonism is equally undesirable; clinicians are forced to feel their way, attempting to
maximize benefit and to minimize adverse effects. This applies equally to the use of antipsychotics
in younger adult patients, but in the elderly, the problems encountered in attempting to achieve the
right balance of medications may be more frequent. Aripiprazole, olanzapine, risperidone, and
quetiapine offer alternatives to standard antipsychotics. The orthostasis that may be secondary to
use of these drugs has occasionally resulted in falls with serious consequences. The anticholinergic
properties of clozapine also tend to be poorly tolerated by geriatric patients. Olanzapine also has
some anticholinergic properties. However, older patients are often able to tolerate and respond to
lower doses of the atypical antipsychotics.
Tardive dyskinesia has been statistically more prevalent in elderly patients, especially women, who
are taking maintenance neuroleptics, but in patients with chronic schizophrenia the dyskinesia
usually has already been present for years and is not a contraindication to using neuroleptics to
achieve relief of psychotic symptoms. Nonetheless, geriatric patients appear to be more vulnerable
to developing some EPS, particularly pseudoparkinsonism, than do younger patients. In the rare
older chronic patient showing new-onset dyskinesia, a trial of withdrawal from neuroleptics is
usually indicated. The concurrent presence of pseudoparkinsonism and dyskinesia in the same
patient is more common in elderly than in other patients.
The use of atypical antipsychotics in patients with dementia has been associated with an increased
mortality from cerebrovascular accidents (CVAs) and other causes. There has been an association
of risperidone, olanzapine, and other atypical antpsychotics with an increased risk of CVAs in
dementia patients. The risk of CVAs in controlled trials of olanzapine in the treatment of dementia
was 1.3% versus 0.4% with placebo. Likewise, the risk of CVAs in controlled trials of risperidone
was 4% versus 2% with placebo. However, a large observational study of 11,400 patients treated
with antipsychotics in the Ontario Healthcare Database failed to find an increased risk of CVAs with
either olanzapine or risperidone in patients over age 66 (Herrmann et al. 2004). In fact, typical
antipsychotics may be associated with the same risks in elderly patients (Trifiro et al. 2006). When
the potential for toxicity is considered along with the relative lack of benefit of antipsychotics in
some carefully done studies (Schneider et al. 2006), the routine use of antipsychotics in dementia
populations should probably be avoided. In cases of behavioral dyscontrol in dementia patients,
nonpharmacological interventions should be attempted first. If those interventions fail, a trial with
an antipsychotic might be attempted, but the utility of such a trial should be reassessed on a
regular basis.
Medications for Dementia
Most elderly patients with mild, moderate, or severe dementia have Alzheimer’s disease, although
some have multi-infarct dementia, a few have both, and some have neither. The best treatment for
dementia is to diagnose a treatable, reversible cause such as vitamin deficiency, hypothyroidism, or
congestive heart failure and to treat the underlying medical condition. The other confounding
diagnosis is pseudodementia secondary to major depression. Some authors believe that depression
can cause dementia in elderly persons, and depression can certainly aggravate mild, preexisting
cognitive dysfunction. Depression probably unmasks some dementias. Thus, “pseudodementias” in
geriatric patients tend to represent early progressive dementias if followed over time. The evidence
is clear that depression should be carefully and thoroughly treated when cognitive impairment and
depression coexist. In recent years, greater attention has been paid to vascular depression, which
may be associated with marked cognitive impairments. Optimal treatments have yet to be defined,
although investigators in this area have suggested that calcium channel blockers and MAOIs mightPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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be useful, perhaps in combination. Data are not yet available as of this writing.
Antidepressants should also be used in patients with strokes or organic mood lability, even if the
depressive syndrome is only partially present. Results from at least 16 controlled trials confirm that
antidepressants are effective in the treatment of poststroke depression and that the benefits
extend beyond mood (Chen et al. 2006). Improvements in activities of daily living (ADLs),
emotional incontinence, and general sense of well-being have been reported benefits of treating
poststroke depression with SSRIs and other agents. The odds favor a substantial improvement over
any worsening of organic deficit, although the dosage should be started low and raised cautiously.
It is clear that patients with behavioral deficits due to strokes who show insomnia, weight loss,
agitation, and inability to participate in rehabilitative programs can do well with TCAs and
presumably with other antidepressants. There are several favorable reports on the use of
nortriptyline for poststroke depression. This strategy was undertaken because nortriptyline is less
likely, at therapeutic blood levels, to produce orthostatic blood pressure changes than are other
TCAs (see below). In addition, a controlled trial showed fluoxetine to be superior to maprotiline in
the treatment of poststroke depression (Dam et al. 1996). In another study (Robinson et al. 2000),
nortriptyline was significantly more effective than fluoxetine or placebo in helping with mood and
anxiety problems but not with cognitive function. Treatment should not be withheld just because a
stroke patient’s dysphoria seems appropriate to the disability: depression appears to be associated
with a high mortality in stroke patients.
Until the advent of tacrine, dementia alone was not an indication for drug therapy. The only drug
previously marketed in the United States for senile symptoms, ergoloid mesylates (Hydergine), was
regularly a bit more effective than placebo in a large number of double-blind, placebo-controlled
studies; however, the effects were weak, different in different studies, and usually only manifest
after 2–3 months, making the marginal utility of this treatment questionable. A variety of other
drugs for dementia, including piracetam, vincamine, lecithin, and oral physostigmine, have been
studied, but so far only a few have been shown to be somewhat useful.
The first drug FDA approved for the treatment of Alzheimer’s disease was tetrahydroaminoacridine
(THA; tacrine). Tacrine was an old drug from Australia, used there to reverse drug-induced coma. It
is a central cholinesterase inhibitor that is thought to act by raising brain acetylcholine levels and
increasing cholinergic brain activity. After an initial very positive study published in the New
England Journal of Medicine (Summers et al. 1986), a controlled multicenter trial of tacrine in
Alzheimer’s dementia was initiated by the National Institute on Aging. Several more recent
controlled studies from the Tacrine Study Group (Davis et al. 1992; Farlow et al. 1992; Knapp et al.
1994) confirmed the utility of tacrine in treating Alzheimer’s disease patients who have mild to
moderate dementia. Tacrine appeared to have a modest effect on the global cognitive deficits that
affect most Alzheimer’s disease patients. Unfortunately, tacrine was also hepatotoxic and is rarely
used now, although it can be obtained through major drug distributors.
Currently, the drug most commonly prescribed for the treatment of Alzheimer’s disease is donepezil
(Aricept). While donepezil is considerably more benign than tacrine, it is probably no more
effective. A number of studies have been completed that demonstrate a clear benefit of donepezil
over placebo in such measures as the Alzheimer’s Disease Assessment Scale (ADAS) or the
Mini-Mental State Exam (Burns et al. 1999; Greenberg et al. 2000). Donepezil may improve
cognitive function by 5%–10% and may improve, though modestly, the quality of life of some
patients and their care providers. In addition to Alzheimer’s disease, donepezil has also been
shown to have mild efficacy in the treatment of other dementias, including Lewy body dementia
and vascular dementias.
Donepezil tends to be well tolerated, with a dose-related increase in side effects. Dosages of 5
mg/day tend to be well tolerated; the most common side effects of the 10-mg dose are nausea,
diarrhea, insomnia, fatigue , muscle cramps, and anorexia. Some adaptation tends to occur over
time to most of these side effects.
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mania (Benazzi and Rossi 1999). Some patients have reported improvement in cognition, even if
they did not have dementia, and some reports suggest that donepezil can help with
medication-induced memory problems (Jacobsen and Comas-Diaz 1999).
Another cholinesterase inhibitor, rivastigmine (Exelon), was recently approved for the treatment of
dementia. Rivastigmine produces a dose-dependent increase in acetylcholine and appears to
bypass hepatic metabolism. Thus, it appears safe for hepatic function. Rivastigmine has a half-life
of 10 hours and is more centrally active than peripheral in its effects on the cholinergic system, a
feature that makes it reasonably tolerated. Gastrointestinal upset is the most common side effect.
There have been two large studies demonstrating the superiority of a dosage of 6–12 mg/day over
placebo in the treatment of Alzheimer’s dementia (Jann 2000). It may be somewhat better
tolerated than donepezil in some patients. Rivastigmine is reported to produce fewer and less
severe gastrointestinal effects, including diarrhea, than donepezil; however, it does not appear to
be any more effective than donepezil.
Galantamine (Reminyl) was the next cholinesterase inhibitor, after rivastigmine, on the U.S.
market. Galantamine’s mechanism of action is a variation on the theme of acetylcholinesterase
inhibitors. This agent is a competitive inhibitor of acetylcholinesterase and allosterically modulates
nicotinic receptors to enhance cholinergic transmission. This mechanism may theoretically give
galantamine some advantages over other acetylcholinesterase inhibitors, but none as yet have
been demonstrated. What has been proven is that galantamine is more effective than placebo in
treating the cognitive deficits of Alzheimer’s disease and that these effects are sustained for at
least 12 months. The drug seems to be reasonably well tolerated at doses of 24–32 mg/day, with
nausea in up to 40% of treated patients and diarrhea in up to 19% of patients. No significant
effects were seen on liver function or any other laboratory tests.
In 2003, memantine (Namenda) became the first drug approved for moderate to severe
Alzheimer’s disease. Memantine is a moderate N-methyl-D-aspartate (NMDA) antagonist that is
thought to mitigate the toxic effects of increased calcium flow into neurons by blocking NMDA
receptors. This blockade then reduces the neurodegenerative effects caused by lower glutamate
levels and increased calcium influx in Alzheimer’s disease. Memantine appears to improve cognition
and ADLs significantly more than placebo in patients with moderate or more severe dementia
(Reisberg et al. 2003). Importantly, memantine also appears to modestly reduce the amount of
time caregivers must spend with an Alzheimer’s patient. In addition, patients who are already
taking a cholinesterase inhibitor, such as donepezil, appear to improve with the addition of
memantine to the regimen (Tariot et al. 2004).
Memantine has been quickly adopted in clinical practice not because it is dramatically efficacious
but rather because it is impressively benign. In clinical trials, the rate of side effects was not
different than the rate with placebo. In fact, no side effect occurred in more than 5% of patients at
statistically different rates than with placebo. The most commonly reported side effects were
dizziness, confusion, headaches, and hallucinations.
Memantine is not a potent inhibitor or dependent substrate of any CYP enzyme. As a result, it has
few drug interactions. The only condition known to substantially affect serum levels of memantine
is alkaline urine. A urine pH > 8, such as caused by urinary tract infections or carbonic anhydrase
inhibitors, will substantially reduce the clearance of the drug and may be associated with increased
side effects.
Memantine is usually started at 5 mg/day, with a target dosage of 20 mg/day. We have generally
had no trouble increasing the dosage by 5 mg per week until the patient is taking 10 mg bid. While
many patients will tolerate a more rapid titration, it is unclear whether there are any advantages to
more rapid titration.
It is nice for the clinician to have options, but it is unlikely that any acetylcholinesterase inhibitor
with or without memantine will produce anything more than moderate benefits for the cognitive
function and behavioral difficulties of most dementia patients. Donepezil is currently the firstPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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choice for most clinicians only because it is the best studied and there is no evidence yet that the
newer agents are any more efficacious. Memantine appears to be an important additional option for
patients. However, we appear to be a long way from having interventions that substantially affect
the course of the disease or the quality of life of Alzheimer’s patients.
Medications for Agitation
Patients with chronic dementia often show agitation, irascibility, night wandering, paranoid
ideation, or hallucinations and become major management problems at home or in psychiatric
hospitals or nursing homes. Behavioral dyscontrol represents one of the most common reasons
geriatric patients are placed in nursing homes. Many of these patients were routinely treated with
low-dose, typical antipsychotics such as haloperidol, often with dubious benefit. A review of the
few controlled studies in this area suggested that only a third of these patients clearly benefit from
low-dose (typical) neuroleptics (Cole 1990).
More recent studies have also cast doubt on the utility and safety of atypical antipsychotics in
treating behavioral problems in dementia patients (see “Antipsychotics” subsection earlier in
chapter). In our own experience, thioridazine is not better tolerated than low doses of more potent
antipsychotics; all typical antipsychotics show an unfortunate tendency to cause
pseudoparkinsonism and akathisia in the elderly. These problems, plus the increased risk of tardive
dyskinesia and the probably increased risk of confusional states when antiparkinsonian drugs are
added, often make typical antipsychotics unsatisfactory drugs in treating agitated patients with
dementia. We had found low doses of atypical antipsychotics (0.5–1 mg of risperidone or 2.5–5 mg
of olanzapine) sometimes helpful in controlling the agitation and psychosis associated with
dementia. These tend to produce few, if any, EPS at low doses. However, as described previously,
the recent CATIE study (see Schneider et al. 2006) failed to show much benefit for olanzapine,
risperidone, or quetiapine over placebo in terms of efficacy, while these agents had much more side
effects.
There are a number of other options for treating agitation in patients with dementia. First, treating
the underlying dementia with an acetylcholinesterase inhibitor often helps with behavioral
problems associated with dementia. Thus, the acetylcholinesterase inhibitors should be tried first.
We have had good success with treating some agitated depressed patients with moderate dosages
of valproate (500–1,250 mg/day) (Schatzberg and DeBattista 1999). However, many geriatric
patients do not tolerate higher doses of Depakote. Tariot’s group first reported that the maximum
tolerated dosage in this population is about 800 mg/day, or 11.5 mg/kg per day (Profenno et al.
2005). Also, a recent multicenter trial involving 153 patients failed to find valproate at a mean
dosage of 800 mg/day to be significantly more effective than placebo in reducing agitation in
nursing home patients (Tariot et al. 2005). A number of studies have also demonstrated the utility
of carbamazepine in the treatment of agitated dementia patients (Gleason and Schneider 1990).
There is one controlled trial in which a modal dose of 300 mg of carbamazepine was significantly
more effective than placebo in reducing agitation in dementia patients (Tariot et al. 1998). We still
tend to prefer valproate over carbamazepine because carbamazepine tends to be more poorly
tolerated, has a lower therapeutic index, and has more drug interactions in these elderly patients,
who tend to be on multiple drugs.
Newer anticonvulsants, such as gabapentin, pregabalin, and tiagabine, make intuitive sense for the
treatment of agitation but are largely untested. As with benzodiazepines, there has been the
suggestion that gabapentin can induce agitation in some brain-injured patients but can help others
(Goldenberg et al. 1998; Miller 2001). Probably some patients would respond to a benzodiazepine,
preferably oxazepam, because of its simple metabolism and low abuse potential. This drug at least
offers hope of an early response when the dose is adjusted properly. Many dementia patients
become confused on benzodiazepines, and we now tend to prefer atypical antipsychotics and
valproate over benzodiazepines.
Other drugs have been the subject of individual case reports. Propranolol had been the most widely
studied, but mainly for agitation and assaultiveness in nonelderly brain-damaged patientsPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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(Greendyke and Kanter 1986; Greendyke et al. 1989; Weiler et al. 1988). Some case reports have
suggested that agitation decreases as soon as the right dosage of propranolol is reached, but most
studies report improvement after a month of taking the right dosage. In the hospitalized, agitated,
restless, irascible dementia patient, a month is a very long time, and propranolol carries the risk of
orthostatic hypotension, with resulting falls. If it is to be tried in elderly patients, the starting
dosage should be 10 mg bid, and dosage should be increased in increments of 10–20 mg every 2
days to 200 mg/day, stopping at lower dosages if hypotension or other side effects occur.
Propranolol can cause delirium. Glassman et al. (1979) showed that orthostatic hypotension due to
TCAs is far worse in cardiac patients taking multiple cardiac medications than in medically healthy
depressed patients. The same is likely with propranolol—it probably should not be tried in patients
taking multiple cardiac or other medications.
There are a number of studies on the helpfulness of trazodone and buspirone in treating agitated
elderly patients with dementia (Colenda 1988; Lebert et al. 1994; Pinner and Rich 1988; Sultzer et
- 2001). The latter is used quite commonly in some nursing home settings at dosages of 10–45
mg/day More recently, controlled trials of SSRIs, such as citalopram at approximately 20 mg/day,
have demonstrated benefits for controlling behavioral outbursts in patients with dementia.
Psychosocial measures may be more useful than drugs in treating agitation in elderly patients with
dementia. Simple interventions such as keeping the patient oriented with a calendar and clock and
keeping the lights on can substantially reduce agitation in dementia patients. Also, looking for and
treating concurrent medical problems such as a urinary tract infection will often do more than any
pharmacological treatment for agitation. Better studies of more kinds of drug therapy in elderly
patients are needed, but in their absence, clinicians have to cautiously try to do their best with
available measures.
MENTAL RETARDATION
As with elderly patients with dementia, institutionalized mentally retarded persons have been
treated routinely for decades with antipsychotics, such as small doses of haloperidol or risperidone,
for a wide range of behavioral disorders. Many patients with even mild intellectual deficits end up
taking either antipsychotics or mood stabilizers at some point to control behavioral problems (Haw
and Stubbs 2005). Court decisions have mandated evaluating such patients while they are not
taking medications, and it now appears that only a fraction of those receiving long-term
antipsychotic medication are clinically better with them than without them.
Antipsychotic-responsive retarded patients have not been well characterized, but it seems probable
that some show psychotic symptoms that would qualify for a diagnosis of schizophrenia. Since the
mid-1990s, the atypical antipsychotics have been increasingly employed for the management of
behavioral dyscontrol in mentally retarded and brain-injured patients. The evidence has
accumulated that agents such as risperidone appear to be useful in both the acute and the
long-term management of disruptive behavior, affective symptoms, or self-injurious behavior in
patients with subaverage intelligence (Biederman et al. 2006; Reyes et al. 2006b; Shedlack et al.
2005).
A general principle in the treatment of mentally retarded patients may be useful as a guideline.
Such patients often show aberrant behaviors (e.g., disrobing, jumping, poking fingers in eyes) that
can increase dramatically when they become psychiatrically upset. Counting (monitoring) these
target behaviors can be a useful guide to treatment effect in often nonverbal patients. The real
diagnosis may have to be inferred from changes in vegetative symptoms such as sleep, appetite,
and motor activity or from family history of psychiatric disorders. All this gives a trial-and-error
quality to the drug therapy of behaviorally disturbed mentally retarded patients, reinforcing
Sovner’s (1989) practice of monitoring target behaviors or symptoms before and during trials. It
may take a few weeks to be sure any given drug is or is not useful.
Some articles have documented the existence of depressive and bipolar disorders that manifest
somewhat atypically in relatively or completely nonverbal patients (Sovner and Hurley 1983). Such
patients are appropriate candidates for treatment with standard antidepressants or moodPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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stabilizers.
If one accepts that overactive, turbulent, and episodically violent behaviors toward others or self
are usually not a manifestation of psychosis in retarded patients, or if it has been empirically
determined that these are not antipsychotic responsive behaviors, what then? Candidate drugs
include atypical antipsychotics, SSRIs, valproate, buspirone, propranolol, gabapentin, and
carbamazepine. None of these have been the subject of placebo-controlled clinical trials in
disturbed retarded patients. However, all have been the subject of small open trials with reported
sustained, if often delayed, benefit in the patients described here.
In addition to the antipsychotics, lithium carbonate and valproate have among the best credentials
as antianger drugs in a variety of psychiatric populations. If the patient has a seizure disorder,
shifting to carbamazepine or valproate seems sensible. Nadolol is of theoretical interest because it
is a -blocker that does not cross the blood-brain barrier and because it is hypothesized to decrease
episodic violence by peripheral action on muscles. Propranolol requires more titrating (30–480
mg/day) to determine an effective dosage, and it can cause hypotension, bradycardia, and
delirium. The desirable monitoring of vital signs before each dosage greater than 120 mg/day may
be impossible in some residential facilities.
Buspirone has been useful at dosages of 15–60 mg/day, but onset of clinical action appears to be
delayed. Various experts inform us that buspirone is less useful in treating more violent retarded
patients. Preliminary data show that the SSRIs may be effective in such patients. Further
discussion of many of these drugs is found in Chapter 3 (“Antidepressants”), Chapter 4
(“Antipsychotic Drugs”), and Chapter 5 (“Mood Stabilizers”).
In patients with a seizure disorder, in the presence or absence of mental retardation, there is a
worry that psychiatric drugs, including TCAs and neuroleptics, may lower the seizure threshold and
increase the likelihood or frequency of convulsions. There is no firm evidence that this occurs.
Maprotiline, imipramine, and amitriptyline have been more often connected with seizure
occurrences in nonretarded depressed patients in our experience, but these drugs were also the
most commonly used TCAs in the McLean Hospital system at the time seizures were seen.
Trazodone is least likely to affect seizure threshold. Bupropion and clomipramine have also been
associated with seizures. There is a belief that haloperidol and molindone, among the typical
antipsychotics, are least likely to affect seizure occurrence. In our experience, chlorpromazine and
loxapine are occasionally associated with seizures, and seizures are more of a problem with
clozapine (see Chapter 4). In patients with a known seizure disorder that is adequately treated
with anticonvulsants, it is relatively unlikely that any of the standard psychiatric drugs will make a
clinically important difference in seizure frequency. In retarded patients taking phenytoin,
phenobarbital, or primidone for seizure control, there is a real possibility that the seizure
medication may be causing cognitive dysfunction. It may be worth shifting the patient to
carbamazepine to determine whether the patient may function better on that relatively different
medication.
Stimulants may also be worth a trial in hyperactive retarded patients who are under close clinical
observation. Stimulants have the advantage of causing clear clinical effects (improvement or
worsening) within a few hours or days of reaching an adequate dose; therefore, the trials of a
stimulant may be completed in 1–2 weeks.
MEDICAL CONDITIONS
Some psychiatric syndromes are caused by or strongly associated with medical disorders. Others
are commonly associated with medications used to treat medical or neurological conditions. On the
other hand, some medical conditions and some drugs used to treat medical conditions complicate
the use of standard psychoactive drugs to treat coexisting psychiatric disorders.
Psychiatric Disorders Resulting From Medical Illness
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thyroid or adrenal cortical dysfunction, uremia, cancer of the pancreas, and any metastatic
carcinomatosis sufficiently often to make it worth ascertaining whether these conditions exist in
depressed patients. Other, more obvious conditions, such as strokes, multiple sclerosis, lupus
erythematosus, and Parkinson’s disease, are often associated with depression, as well as with
organic brain dysfunction.
Chronic pain syndromes, including headache and low back pain, are so confounded with depressive
syndromes that primary antidepressant therapy is often indicated and effective. For some medical
conditions such as hypothyroidism, treating the underlying condition is the first order of business.
For others, the presence of an untreatable medical or neurological condition is not per se a
contraindication to standard antidepressant therapy.
Hyperthyroidism, caffeinism, hypoglycemia, temporal lobe epilepsy, paroxysmal tachycardias, and
pheochromocytoma can all mimic panic disorder and should be ruled out. A medical reevaluation is
indicated if standard drug therapies fail. A review by Raj and Sheehan (1988) suggested some
useful tips for making such key differential diagnoses. For example, attacks of paroxysmal atrial
tachycardia generally begin and end more abruptly than do panic attacks and produce heart rates
of 140–200 bpm. In contrast, heart rates in panic disorder rarely exceed 140 bpm. In
pheochromocytoma, anxiety is only the fourth most common symptom, and many patients with this
condition experience tachycardia and increased blood pressure without becoming unduly fearful; in
this disorder there is often an increased familial prevalence of neurofibromatosis and café au lait
spots.
Hyperthyroidism is associated with sleep disturbance, heat sensitivity, and a more enduring
tremor, among other symptoms. Finally, temporal lobe epilepsy may represent a more difficult
diagnostic dilemma. In almost 25% of patients with this disorder, anxiety occurs during the aura or
interictally. However, such patients frequently also complain of other symptoms—for example,
perceptual distortions and lapses of concentration. In assessing patients with possible panic
disorder, a routine medical history and physical examination should be obtained. Laboratory tests
should be ordered as needed to rule out suspected conditions.
There is now a growing series of very positive case reports on the use of stimulants—mainly
methylphenidate at a dosage of 10 mg once or twice a day—in patients with serious medical or
surgical illnesses on medical services. These patients were noted on psychiatric consultation to be
depressed, retarded, even almost mute, losing weight, not eating, unable to cooperate in
treatment, withdrawn, and hopeless. Stimulants can produce relief in a day or two and can often be
discontinued in 2–4 weeks, once the patient is generally improving. Of the 17 such case reports,
none describe any serious side effects. By inference, elevated pulse or blood pressure is not a
problem. Despite the appetite-reducing effect of stimulants in overweight subjects, these medically
ill patients rapidly regain weight while taking methylphenidate. Sometimes stimulants are used
because TCAs are contraindicated, but the results are positive enough for stimulants to be
considered first-choice drugs in treating these patients. Standard antidepressants rarely improve
mood or functioning in a few days.
Depression following stroke has received some special study in recent years. It is clear that
depression following CVAs occurs in about half the patients affected and can be relieved by
antidepressants. In fact, the majority of studies of antidepressants in the treatment of poststroke
depression have found significant benefits in mood and behavior and even improvement in
activities of daily living (Chen et al. 2006). There have been several controlled studies, one of
nortriptyline (Lipsey et al. 1984), one of trazodone (Reding et al. 1986), and one of fluoxetine
(Dam et al. 1996). Nortriptyline was generally effective, but 3 of the 17 patients studied developed
delirium (Lipsey et al. 1984). Patients treated with medication longer and those with plasma levels
over 100 ng/mL did better. Trazodone was less effective relative to placebo, but significant positive
effects were found in dexamethasone nonsuppressors and patients with higher levels of depressive
symptoms (Reding et al. 1986). Slow, cautious dosage increases are best with both drugs to avoid
adverse effects. Fluoxetine (20 mg/day) appeared to substantially facilitate recovery in poststrokePrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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patients who were undergoing rehabilitation (Dam et al. 1996). In this study of 52 severely
disabled hemiplegic patients, fluoxetine-treated patients showed significant improvements in
depression, ADLs, and neurological deficits relative to both maprotiline-treated patients and
patients receiving placebo. In fact, maprotiline seemed to hinder rehabilitation, whereas fluoxetine
generally helped a variety of indices of recovery in these poststroke patients treated for 3 months.
Fluoxetine may also help with the emotional incontinence that often occurs after a stroke
(Choi-Kwon et al. 2006). ECT has also been reported to be effective in poststroke depression. Most
patients with cognitive impairment before ECT had improved cognitive functioning after ECT. In
contrast, Robinson et al. (2000) reported that nortriptyline was more effective than fluoxetine or
placebo in poststroke depression. As indicated earlier, sertraline can prevent poststroke
depression.
Many psychiatric disorders may be seen in patients with AIDS, but the prevalence of these
disorders is not higher than in carefully matched controls. Studies suggest that subsyndromal
depression is the most common disorder seen in this population, and it is thought that the SSRIs
may be useful in treating these patients. However, some psychiatric conditions can be a direct
consequence of neurological involvement in HIV infection. HIV encephalitis occurs in most AIDS
patients at some point in their illness. Mood and personality changes may occur early in the course
of the encephalitis, and psychosis, mania, and dementia may occur later. Patients with other
neurological consequences of HIV infection, including cerebral lymphoma and toxoplasmosis, often
present with cognitive and psychiatric symptoms. These problems generally occur late in the
progress of the disease.
Zidovudine (formerly azidothymidine, or AZT) is often helpful in reversing the psychopathology
associated with HIV encephalopathy. Antidepressants, lithium, and high-potency antipsychotics
may also help treat HIV-associated psychopathology. However, because AIDS patients tend to be
quite sensitive to the side effects of psychotropic medications, caution must be exercised.
The recent introduction of the protease inhibitors has made a tremendous impact on the treatment
of HIV-positive patients. All the current protease inhibitors are potent inhibitors of the CYP enzyme
3A3/4 and are themselves metabolized by this enzyme. As a result, caution should be exercised
when combining these drugs with nefazodone, fluvoxamine, and St. John’s wort. In addition, one
protease inhibitor, ritonavir (Norvir), also inhibits the CYP enzyme 2D6 and may raise the serum
levels of TCAs and other drugs dependent on this enzyme.
Psychiatric Disorders Associated With Nonpsychiatric Drugs
A variety of older antihypertensive drugs (e.g., reserpine, methyldopa) were sometimes associated
with depression. These drugs rarely are used in current clinical practice. However, propranolol is
commonly used now and has sometimes been associated with major depression. In many instances
the -blockers do not appear to be inducing depression. Rather, high doses of lipophilic -blockers
such as propranolol can induce a lethargy and indifference that is sometimes confused with
depression. Shifting to a thiazide diuretic or to a different, non–centrally acting -blocker (e.g.,
atenolol) can be helpful, or a TCA alone can sometimes adequately treat both depression and
hypertension.
Diazepam has occasionally been associated with increased depression. Both benzodiazepines and
barbiturates can aggravate ADHD. Benzodiazepines may produce memory problems, particularly in
the elderly.
Stimulants can aggravate schizophrenia or mania. Steroids and L-dopa can mimic almost any known
psychiatric syndrome, including delirium, paranoid psychosis, mania, depression, and anxiety.
The whole range of drugs used in treating Parkinson’s disease can cause hallucinosis and
confusion. Sometimes anticholinergic drugs used in gastrointestinal disorders can also cause
anticholinergic confusion and delirium, as can digitalis-like and cimetidine-like agents. It is
impossible to list or predict all the drugs or drug combinations that at some dose in some patient
can elicit or aggravate symptoms of a psychiatric disorder. In a patient receiving several drugs forPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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medical conditions who presents with depression, anxiety, or psychosis appearing after the drugs
were begun, a careful reevaluation of the patient’s pharmacotherapies is necessary. Stopping the
less obviously crucial medications and shifting to less centrally active alternative drugs, when some
medication is necessary, are reasonable steps.
Psychiatric Disorders Complicated by Medical Disorders
Renal Disease
Many medical disorders could have reasonably predictable effects on the pharmacokinetics of
standard psychiatric drugs, but the transition from theoretical data to practical application is often
not exact. In the case of kidney failure and lithium therapy, the facts are clear. If renal clearance is
decreased, lithium excretion will be decreased in a reasonably proportionate manner. In patients
with substantially elevated serum creatinine and blood urea nitrogen who are not in acute renal
failure, very small doses of lithium (e.g., 150 mg/day) can be cautiously begun and titrated in the
same way as in a healthy patient, but more cautiously and with smaller increments. In this
situation, lithium citrate given in milliliter doses could give extra flexibility. Some patients on renal
dialysis may be stabilized on lithium, with a single 300-mg dose after each episode of dialysis. This
dose may maintain an adequate blood level until the next dialysis removes the lithium ions.
Likewise, older patients experience a 30%–40% decrease in glomerular filtration and therefore
require lower starting and maximum doses than younger patients.
The hydroxylated metabolites of TCAs and other psychotropic agents may also be elevated in
elderly patients and in those with advanced renal disease. This suggests that a more gentle
titration of these medications is required in these two groups of patients.
Dehydration states are not uncommon, and they can increase the toxicity of lithium therapy.
Furthermore, there is some evidence that dehydration is a risk factor in the development of
neuroleptic malignant syndrome, although this association is somewhat tenuous. Finally,
dehydration can exacerbate the orthostasis caused by risperidone, clozapine, TCAs, and MAOIs.
Urinary retention can be quite problematic in elderly patients, particularly in males with prostate
difficulties. The most anticholinergic agents, including tertiary-amine TCAs (amitriptyline,
imipramine), low-potency neuroleptics, and antiparkinsonian drugs such as benztropine, should be
avoided if possible in elderly patients.
Liver Disease
When there is liver damage or decreased liver efficiency due to normal aging, the effects are more
complicated. Most drugs are partially metabolized in the liver after absorption from the small
intestine (the first-pass effect). When liver tissue is damaged, many drugs get into the general
circulation at much higher levels. Usually, glucuronidation as a method of drug deactivation is well
preserved, whereas demethylation and other metabolic processes are more readily impaired. This is
why drugs, such as diazepam, that need to be demethylated cause much higher blood levels per
unit dose in cirrhosis, whereas drugs like lorazepam, which are only glucuronidated, are handled
normally. Unfortunately, it is not always clear to even a skilled clinical pharmacologist exactly what
the effect of chronic liver disease on the clinical actions of any particular drug will be.
It is likely that in patients with partial liver failure, standard TCAs such as amitriptyline and
imipramine will be less readily converted to their desmethyl metabolites, nortriptyline and
desipramine. The consequences of this shift—perhaps more sedation, confusion, or anticholinergic
side effects—are less clear. The obvious lesson is to proceed very cautiously; to use blood level
determinations, if available; and to assume that liver damage will markedly increase a drug’s
half-life, making gradual accumulation of higher and higher blood levels quite possible over a
couple of weeks at a constant daily dose. Most psychiatrists find fluoxetine a safe drug to use in
spite of its long half-life.
Lowered blood protein levels, common in liver disease, may also increase free-drug levels, unboundPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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to protein, making a drug more potent at lower total blood levels measured in the conventional
manner. This is less of a problem with venlafaxine, which demonstrates low protein binding.
An overactive liver can also pose problems. Some known drugs, including barbiturates, phenytoin,
carbamazepine, and nicotine, induce hepatic enzymes and increase the rate at which some
psychiatric drugs are metabolized, making higher dosages necessary in order to achieve clinical
results (see Chapter 3: “Antidepressants”; Chapter 5: “Mood Stabilizers”; and Chapter 9:
“Augmentation Strategies for Treatment-Resistant Disorders”). It is also worth noting that even
drug-free patients can show large degrees of biological variability in their natural rates of drug
metabolism. As an example, Glassman et al. (1977, discussed in Chapter 3) found imipramine
levels to vary from 40 to 1,040 ng/mL in depressed patients receiving 2.5 mg/kg of imipramine.
Again, the lesson is that patients taking other drugs for medical reasons may well have an altered
response, based on either increased or decreased hepatic metabolism of the psychiatric drug that
has just been added (not to mention pharmacological interactions such as additive sedation or
additive postural hypotension).
In the likely absence of clear knowledge about the interactions in a particular patient of, for
example, cimetidine, phenytoin, chlorothiazide, and isoniazid with imipramine, the clinician adding
imipramine in a patient taking all these other drugs must be prepared to proceed cautiously but to
use high dosages of imipramine if neither side effects nor clinical response occurs, if blood levels
are low, and if ECG changes are not seen. It has also become evident that a number of psychotropic
drugs may be associated with causing elevations in liver enzymes. The SSRIs, the TCAs,
carbamazepine, and valproate, among other medications, may be associated with increases in
aspartate transaminase (AST; formerly serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine transaminase (ALT; formerly serum glutamic-pyruvic transaminase [SGPT]). The clinical
significance of these elevations remains unclear. However, persisting elevations to greater than
twice the normal levels are of particular concern. There are rare reports of children younger than 2
years who are taking valproate and who have developed fulminant hepatic failure; the risk in adults
appears to be minimal. There are also a few isolated reports of hepatic failure in children that was
believed to be associated with TCA use. In general, it is prudent practice to obtain baseline liver
function tests (LFTs) when initiating therapy with carbamazepine and valproate and to check LFTs
every 6–12 months thereafter.
A number of drugs pose less of a problem in patients with advanced liver disease because they are
less appreciably metabolized by the liver. These include agents such as gabapentin, pregabalin, and
lithium. Transdermal and Zydis selegiline also bypass the liver to a large extent and might be used
in patients with advanced liver disease.
Cardiac Illness
There is accumulating evidence that depression both is a risk factor for coronary artery disease and
significantly increases the risk of mortality in patients who have suffered a myocardial infarction
(MI). In fact, depression in the post-MI period is a stronger predictor of subsequent mortality than
many more intuitive factors such as systolic ejection fraction, which is one measure of the extent of
heart damage. The mechanism by which depression may increase the risk of an MI or subsequent
risk of mortality after an MI is unknown. Current speculation is that depression may increase
platelet binding and therefore clotting or that depression may decrease heart rate responsiveness.
In any case, it would be helpful to know if antidepressant therapy in the post-MI period decreases
mortality. It is evident that sertraline in the post-MI period is well tolerated and effective for
concurrent depression (McFarlane et al. 2001). However, in this small open-label study, it was not
possible to demonstrate significant benefits on coagulation or heart rhythm.
A number of randomized trials have indicated that the SSRIs work at least as well as TCAs and are
better tolerated in heart patients. Studies comparing paroxetine with nortriptyline showed that
both drugs are highly effective but that paroxetine is safer and better tolerated (Nelson et al.
1999).Print: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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In cardiac patients, there has long been a fear that all TCAs are cardiotoxic and likely to cause
disastrous arrhythmias. Although they produce mild tachycardia (an increase of 10 bpm) in
medically healthy depressed patients, their arrhythmogenic potential appears to occur primarily if
the drugs are taken in overdose. The mechanism by which the TCAs and maprotiline affect cardiac
function is a quinidine-like slowing of cardiac conduction. TCAs have an ability to decrease cardiac
irritability and to suppress premature contractions. They are therefore not contraindicated at
ordinary dosages in depressed patients with premature ventricular contractions, and they may well
help both cardiac irritability and depression. Nortriptyline has been shown to be effective and
generally well tolerated in cardiac patients with melancholic depression (Roose et al. 1994). More
recent studies indicate that paroxetine was as effective as nortriptyline in post-MI patients but was
better tolerated from a cardiovascular perspective (Roose et al. 1998).
The TCAs should, however, be used with caution in patients with preexisting conduction defects,
such as bundle-branch block. Patients with first-degree block have a 9% rate of 2:1 atrioventricular
block development when taking TCAs, compared with a 0.7% rate in patients without first-degree
block. TCAs should not be given to patients with known intracardiac conduction delays. This is
particularly so in patients already taking cardiac antiarrhythmic drugs, which act by slowing cardiac
conduction, because additive effects on conduction could be harmful. Not all cardiologists are
aware of the cardiac effects of TCAs, and psychiatrists who collaborate with cardiologists or
primary care physicians may need to do some educating of their consultants.
The other antidepressants with a possible effect on cardiac irritability are trazodone and
venlafaxine. Trazodone does not affect conduction, but it has occasionally (not regularly) been
associated with an increase in premature ventricular contractions (PVCs) and should be avoided in
patients with runs of PVCs or ventricular bigeminies. There has been concern that venlafaxine
overdoses might be associated with a greater risk of mortality, mostly from cardiac events, than
are the SSRIs. Venlafaxine overdoses, often in combination with other drugs or alchohol, have been
associated with QT prolongation, bradycardia, ventricular tachycardia, and other arrhythmias. Thus,
the package insert for venlafaxine was changed at the request of the FDA to reflect this evidence.
The risks appear to be substantially less than with TCA overdoses and may be an artifact of more ill
patients typically being treated with venlafaxine than with SSRIs. However, more careful
monitoring is recommended. Venlafaxine, like the SSRIs, can produce a mild increase in heart rate.
It can also increase diastolic blood pressure. Therefore, patients with current and advanced
congestive heart failure may not be the best candidates for treatment with venlafaxine. Patients
with a history of hypertension may also require increased vigilance when treatment with
venlafaxine is being initiated. In one report, venlafaxine was poorly tolerated cardiovascularly in
nursing home patients (Oslin et al. 2003). Because of these effects, and given the recent report of
British regulators regarding lethality in overdose, the drug should be prescribed cautiously in
vulnerable populations (e.g., elderly patients with cardiac disease).
The SSRIs appear to produce a mild (3-bpm) increase in heart rate in medically healthy depressed
patients. Although these agents have not yet been widely studied in post-MI patients, their possible
use in such patients is suggested by animal studies and by data available in cardiovascularly
healthy depressed patients. In addition, these agents produce milder alterations in blood pressure
than do other antidepressants. However, the SSRIs may slow the metabolism of a variety of
cardiovascular medications, including digoxin, some -blockers, and class 1C antiarrhythmics. The
SSRIs can raise the levels of these other medications by competitive inhibition of the CYP enzyme
2D6 and require close monitoring (Table 12–5). In one study (Roose et al. 1994), fluoxetine was
reported to be less effective than nortriptyline in melancholic cardiac patients, although there are
other data indicating that it does have efficacy and relative safety in cardiac patients with milder
depression. Moreover, paroxetine has been reported to be effective and better tolerated
cardiovascularly than nortriptyline in patients with post-MI depression (Roose et al. 1998).
Table 12–5. Interactions of commonly used psychoactive drugs with cardiovascular medicationsPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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Drug TCA SSRI Antipsychotic Lithium Carbamazepine
calcium channel
blockers
Increase
hypotension
NA Increase
hypotension
Raise or lower
lithium levels,
bradycardia
Increase
carbamazepine
levels
thiazide diuretics May increase
hypotension
NA Increase
hypotension
Increase lithium
levels
NA
-blockers May increase
hypotension
May
increase
-blockers
Increase
antipsychotic
levels
NA Decrease -blocker
levels
reserpine,
guanethidine
Antagonize
antihypertensive
agents
NA Increase
hypotension
NA Unknown
clonidine,
prazosin
Increase
hypotension
NA Increase
hypotension
NA Unknown
1A
antiarrhythmics
Prolong cardiac
conduction
NA Prolong cardiac
conduction
Prolong sinus
recovery time
May decrease
antiarrhythmic
levels
1C
antiarrhythmics
Prolong cardiac
conduction
Increase 1C
levels
May prolong
cardiac
conduction
Prolong sinus
recovery time
May decrease
antiarrhythmic
levels
digitalis Increases digoxin
and TCA levels
May
increase
digoxin
levels
May increase
digoxin levels
Prolongs sinus
recovery time
Unknown
Note. NA = applicable; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
The more significant effect of TCAs and MAOIs is postural hypotension, which can be aggravated
(potentiated) in patients already taking drugs, such as propranolol, that are likely to cause
hypotension as well. Although patients who have stable cardiac disease but are not in congestive
failure probably tolerate antidepressants well, patients taking multiple cardiac drugs are
particularly prone to postural hypotension and other cardiac side effects. For seriously ill cardiac
patients with severe depression, ECT may be the treatment of choice.
Bupropion has been assessed in depressed patients with moderate cardiac disease and seems to be
better tolerated than the TCAs. Even in overdose, apparently bupropion does not typically have a
major effect on cardiac function (Spiller et al. 1994).
Pulmonary Disorders
Patients with pulmonary disorders, including asthma, emphysema, and sleep apnea, are commonly
encountered in psychiatric practice, and some psychotropic medications may present problems in
this population. Benzodiazepines, for example, may be contraindicated in patients with sleep
apnea; the benzodiazepines may relax the airway further and exacerbate already restricted airflow.
Zolpidem may be less likely to produce this problem than the benzodiazepines. In addition,
benzodiazepines reduce the hypoxic response to ventilation and therefore should be used with
caution in patients with chronic obstructive pulmonary disease who retain CO2. Furthermore,
psychotropic medications with significant anticholinergic activity may decrease bronchial
secretions and exacerbate pulmonary disorders. Thus caution should be exercised in treating
pulmonary patients with drugs such as amitriptyline or benztropine.
Many medications used to treat pulmonary problems are affected by concurrent use of some
psychotropic agents. For example, fluvoxamine inhibits the metabolism of theophylline, which canPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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lead to potentially toxic levels. Thus, theophylline levels should be checked frequently if
fluvoxamine must be used concurrently. Conversely, theophylline-like drugs increase the excretion
and lower the serum levels of lithium.
Seizure Disorders
Many psychotropic medications are known to lower the seizure threshold and, therefore, must be
used with caution in patients with a history of a seizure disorder. Most antipsychotics have this
potential, although molindone and thioridazine may be less problematic in seizure disorder
patients. Clozapine, among the antipsychotics, has perhaps the greatest potential for inducing
seizures: up to 5% of patients develop seizures at dosages greater than 600 mg/day. The TCAs and
tetracyclic agents all have some potential for lowering the seizure threshold; amitriptyline and
maprotiline are among the more problematic offenders. Bupropion is probably contraindicated in
patients with a known seizure disorder, because of its dose-related potential for producing
seizures. However, the SSRIs and venlafaxine appear relatively safe in this population.
The anticonvulsants are also associated with a variety of interactions. Carbamazepine is an enzyme
inducer that will lower the serum levels of a variety of drugs, including TCAs, clonazepam, and most
antipsychotics. Oxcarbazepine is a much weaker inducer of the 3A3/4 enzyme. SSRIs, on the other
hand, may substantially increase carbamazepine levels.
Other additive or antagonistic interactions certainly occur. Some of the better-documented ones are
discussed in earlier chapters focusing on specific drug classes.
Pain Disorders
Antidepressants and other psychotropic drugs have long been used in the treatment of a variety of
pain syndromes, including trigeminal neuralgia, peripheral neuropathy, arthritis, myofascial pain,
fibromyalgia, migraine prophylaxis, and the pain associated with some forms of cancer. More than
40 placebo-controlled studies have reported that antidepressants are useful in the management of
pain, independent of whether depression is a part of the clinical picture.
The TCAs have the longest track record and may be the most consistently efficacious group of
psychotropic agents used in the treatment of pain conditions. Tertiary-amine TCAs, particularly
amitriptyline, imipramine, and doxepin, have been well studied and found to be effective for a
variety of pain conditions. Initially, it was thought that the mechanism of action of these drugs was
to increase the peripheral availability of serotonin, which in turn would modulate the pain
response. This explanation does not appear to be correct. Some TCAs, which are more
noradrenergic than serotonergic, also appear to be useful in the treatment of pain, whereas the
SSRIs, which efficiently increase the availability of peripheral serotonin, are sometimes less useful.
For example, a study comparing amitriptyline with citalopram (an SSRI) in the prophylaxis of
chronic tension headaches found that amitriptyline was efficacious but citalopram was ineffective
(Bendtsen et al. 1996). Dosages as low as 25–50 mg/day of amitriptyline or imipramine are
frequently useful in the prophylaxis and treatment of pain problems. However, analgesia of the
TCAs appears to be dose related, so higher doses may be more effective than lower doses.
The SSRIs have been disappointing in the management of pain disorders, although there is some
evidence that they may help with neuropathic pain. Some patients have reported benefit from the
SSRIs for migraine prophylaxis, even though many patients experience a worsening of their
headaches at the initiation of treatment. The results of open-label studies of paroxetine, at 10–50
mg/day, for chronic daily headaches have been encouraging (Foster and Bafaloukos 1994),
whereas findings from double-blind studies have been less promising (Langemark and Olesen
1994).
Venlafaxine and duloxetine, which have a mechanism of action that closely resembles that of the
TCAs, have also been extensively studied in the treatment of chronic pain conditions. Low dosages
of venlafaxine, on the order of 25–75 mg/day, appear to be useful, but, as with the TCAs, higher
dosages may produce more analgesia. In a 6-week double-blind study, venlafaxine XR at dosagesPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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of 150–225 mg/day was signficantly more effective than placebo in reducing diabetic neuropathic
pain. Venlafaxine XR at a dosage of 75 mg/day did not separate from placebo (Kunz et al. 2000).
Preliminary evidence suggests also that the SNRI duloxetine has benefits similar to those of
venlafaxine and the TCAs in the management of neuropathic pain at dosages of 60–80 mg/day.
Duloxetine became the first drug approved for the treatment of pain associated with diabetic
neuropathy in 2004. Both daytime and nighttime pain were substantially reduced by duloxetine as
early as the first week of treatment. The dosages proven effective for diabetic neuropathy in
clinical trials were 60–120 mg/day. Duloxetine has also been reported to be effective in patients
with fibromyalgia, particularly women (Arnold et al. 2004). Duloxetine also appeared to reduce
painful symptoms in depressed patients, including their myalgias and back pain. Thus, duloxetine is
being used with growing frequency in pain clinics. For the patient with chronic neuropathic pain
who is also depressed, duloxetine appears to be a particularly good choice.
Other psychotropic drugs have also been found to be effective in treating pain conditions. As
reported in Chapter 5 (“Mood Stabilizers”), gabapentin and pregabalin have been well studied in
neuropathic pain. Gabapentin at dosages up to 3,600 mg/day is both effective and well tolerated
for many pain patients. As a result, gabapentin has become a standard in most pain specialty
clinics. Pregabalin was also approved for the treatment of diabetic neuropathic pain as well as
trigeminal neuralgia.
Haloperidol and chlorpromazine, in a number of open-label studies, have been found to be useful in
the management of neuropathic pain. Carbamazepine has been efficacious in the treatment of
peripheral neuropathies, and lithium is sometimes used in the treatment of cluster headaches.
A number of common agents used in the management of pain disorders might interact with
common psychotropic medications. For example, tramadol, which is indicated for moderate to
severe pain, is a SNRI, among its analgesic properties. In addition, it is a CYP 2D6 substrate. Thus,
there is the potential for both pharmacokinetic and pharmacodynamic interactions with some
SSRIs, and serotonin syndrome has been sporadically reported with the combination. Opiates,
when combined with CNS depressants (including benzodiazepines), are sometimes associated with
respiratory depression, particularly in overdose. Likewise, carisoprodol (Soma) may interact with
other CNS depressants, including barbiturates and benzodiazepines, to contribute to sedation,
dizziness, and, in overdose, respiratory depression. Meperidine (Demerol) has long been associated
with inducing a serotonin syndrome in combination with MAOIs, and the combination is thus
contraindicated. While MAOIs have been used safely with other narcotics, the interaction with
opiates such as fentanyl is somewhat unpredictable.
CONCLUSION
It would be helpful if our current knowledge of drug actions could be put to precise clinical use in
assessing the effects of adding a new psychiatric drug to a preexisting mixture of medical and
psychiatric drugs. Unfortunately, drugs do not work like sums in an algebraic equation. One would
think, for example, that the action of D-amphetamine, an indirect dopamine agonist, would be
opposed by haloperidol, a reasonably pure dopamine-blocking drug. In practice, however, some
patients feel more lively and functional, without becoming more psychotic, when D-amphetamine is
added to haloperidol. Drugs usually act on several receptors and on both pre- and postsynaptic
receptors of a single type, leading to potentially complex effects and interactions. The clinician is
often faced with treating schizophrenia, agoraphobia with panic, or depression in a patient with
several medical problems. This kind of situation requires drug therapy for the medical problems
that is likely to influence the metabolism or absorption of a psychiatric drug or to have additive,
antagonistic, or (more likely) unknown effects in combination with the most appropriate psychiatric
drug treatment.
All drug therapy consists of a series of empirical clinical trials; treatment of medically ill patients
simply presents more complicated empirical trials. The psychiatrist can try to guess at the more
probable ways in which the new drug will act or be affected by the patient’s medical disease andPrint: Chapter 12. Pharmacotherapy in Special Situations http://www.psychiatryonline.com/popup.aspx?aID=239376&print=yes…
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ongoing drug therapies, but it is likely to be only guesswork. If there are semipredictable adverse
interactions, one can either try to avoid them by choosing the psychiatric drug least likely to cause
trouble or proceed cautiously, with close monitoring of the patient for predictable and
unpredictable side effects, in collaboration with the physicians managing the patient’s
nonpsychiatric disorders. One worries that medically ill patients will be very fragile and easily
become toxic while taking psychiatric drugs, but it is likely that this is not a general problem; some
patients may develop problems, whereas others tolerate psychiatric drugs unusually well.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Pharmacotherapy in Diverse Populations
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Understanding Diverse Patient Populations
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Pharmacokinetics and Pharmacodynamics Variations
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Cultural Competency in Pharmacotherapy
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Quiz: Key Concepts in Pharmacotherapy for Diverse Populations
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Ethical Considerations in Pharmacotherapy
Understanding Pharmacokinetics and Pharmacodynamics across Populations
Pharmacotherapy Considerations for Pediatric and Geriatric Patients
Addressing Pharmacotherapy Challenges in Pregnant and Lactating Women
Advanced Strategies in Personalized Pharmacotherapy
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