THERAPEUTIC INDICATIONS

Mood Disorders The primary indication for bupropion is the treatment of major
depressive disorder. The IR and SR formulations are effective in inpatients and outpatients.
Under double-blind conditions, bupropion was superior to placebo in treating hospitalized,
depressed patients who had not achieved a satisfactory response with tricyclic agents. Two
open-label studies have revealed significant efficacy for bupropion in outpatients with
nonresponse (with or without intolerance) to tricyclic antidepressants.
The selection of bupropion SR versus SSRIs in the treatment of depression cannot be based
on the presence or severity of associated anxiety symptoms, although its use in depression
cooccurring with panic disorder has not been evaluated.
Bupropion is also commonly used as an adjunct to an SSRI, to reduce the sexual side effects
of the SSRI or to increase the antidepressant efficacy of the SSRI. In both cases, open-label
trials or retrospective chart reviews support this practice, yet double-blind, placebo-controlled
trials are still needed.
Bupropion has been used in open-label trials and a small, double-blind, controlled trial in
addition to mood stabilizers with the treatment of the depressed phase of bipolar disorder.
Bupropion may be associated with a lower likelihood of inducing manic or hypomanic states
in patients with bipolar disorder. However, this contention rests largely on a small number of
open studies of patients with bipolar disorder treated over time with bupropion. In a double-
blind, randomized trial, bupropion was less likely than desipramine (Norpramin) to induce
mania within 8 weeks of treatment in bipolar disorder; all patients were taking mood stabilizers.
Another study found significantly better improvement in bipolar or atypical depression
compared to that with so-called typical depression. However, secondary mania has been
reported with bupropion, as well as with all other antidepressants. Bupropion should be used
cautiously in bipolar disorder, and patients should be monitored closely.
Whether bupropion induces rapid cycling is not known, but a recent report suggests efficacy
for bupropion in six rapid-cycling bipolar II disorder patients, with sustained effects for as long
as 2 years. The efficacy and safety of bupropion in psychotic depressions have not been
evaluated. An open series suggests efficacy and tolerability for dysthymic disorder.

Smoking Cessation Bupropion SR is marketed under the name Zyban, which is FDA
approved for smoking cessation. Better effects may be found when Zyban is combined with
behavioral modification and, in some cases, nicotine replacement therapy. Zyban should not
be used in combination with bupropion (Wellbutrin) IR or SR. The same adverse reactions are
shared by Zyban and Wellbutrin SR. Zyban may be effective in repeated attempts at smoking
cessation if the initial attempt fails. Subjects who were continuously abstinent in the longer-
term treatment for smoking cessation exhibited a mean absolute weight gain that was inversely
related to bupropion dosage.

Attention-Deficit/Hyperactivity Disorder Neither bupropion IR nor SR is FDA approved

for ADHD. However, several studies are suggestive of efficacy in pediatric, as well as adult,
patients with ADHD. Most clinicians take the available data to suggest efficacy in ADHD,
albeit at a level equal to or a bit less than that achieved with classical stimulants. Bupropion
may exacerbate comorbid tics in these patients.

PRECAUTIONS AND ADVERSE REACTIONS

Bupropion is generally well tolerated. The newer SR preparation appears to have some
advantages with regard to potential adverse effects. In larger trials of bupropion SR in
depressed outpatients, the most commonly reported side effects were headache, nausea, dry
mouth, and insomnia. Sweating and constipation were also reported to be more common on
higher (300 mg per day) doses. The discontinuation rates due to adverse events for bupropion
SR in acute phase treatment trials in depressed outpatients are 7 to 11 percent. Clinically,
agitation, tremor, and insomnia are the most common adverse events that limit bupropion dose
increases.
Some potential side effects are similar to those reported for psychostimulants or other DA
agents. Unlike many other antidepressants, sedation and weight gain are rarely a problem with
bupropion, which is likely due to its lack of serotonergic, anticholinergic, and antihistaminic
effects. Early studies with bupropion IR found that one of the most common reasons for
discontinuation was excitement or agitation. Clinical impression suggests that these adverse
events are less likely with bupropion SR. Psychotic symptoms, especially in the elderly, albeit
rare, have been described in a number of case reports, although frequently with complicating
factors, such as prior psychosis or bipolar illness, or concomitant medications, such as lithium
(Eskalith) or benzodiazepines. Less common but serious adverse effects that have been
reported include acute delirium, catatonia, and parkinsonian symptoms. Coadministration of
bupropion with other DA agents (e.g., amantadine [Symmetrel]) may increase the likelihood
of neurotoxic effects. There is a report of the development of compulsive ordering rituals in a
7-year-old boy 4 weeks after bupropion was added to d-amphetamine treatment.
Although bupropion may cause small increases in blood pressure, it has not been associated
with orthostatic hypotension or electrocardiogram (ECG) changes. In contrast to SSRIs, sexual
dysfunction is much less common, and, in fact, bupropion has been used to treat SSRI-induced
sexual side effects.
The risk of seizures for bupropion SR at doses of 100 to 300 mg is 0.1 percent, which is
comparable to other antidepressants. A large, open-label, surveillance study of more than 3,000
depressed patients treated with bupropion SR, as much as 300 mg per day, found a seizure rate
of 0.06 percent during an 8-week acute phase, with a cumulative seizure rate in the acute and
1-year continuation phase of 0.1 percent. Of the three patients who experienced a seizure, two
had predisposing factors. This risk is noted in the package insert to rise to 0.4 percent at the
maximum recommended dose of 400 mg per day, although this may be a high estimate. A
seizure rate of 0.4 percent was also found in earlier studies using bupropion IR at doses of 300
to 400 mg per day. Although this seizure rate is certainly of clinical significance, it is not
dissimilar to seizure rates of tricyclics when used at higher doses. Careful evaluation for seizure
risk factors, such as past history of seizures, alcohol withdrawal, and organic brain disease, is
recommended before beginning bupropion treatment. Should bupropion treatment be indicated
in at-risk individuals, slow titration and conservative dose maximums are advocated to
minimize seizure risk.
In overdose, bupropion appears to be less lethal than other tricyclics. Nevertheless, serious
consequences, including hypotension, acidosis, sinus tachycardia, and seizures that require
intensive medical managements, have been reported, as have fatal drug overdoses.

DRUG INTERACTIONS
Bupropion is extensively metabolized by the liver through the CYP system. CYP 2B6 is the
principal isoenzyme that metabolizes bupropion to hydroxybupropion. Bupropion and
hydroxybupropion are inhibitors of CYP 2D6 in vitro. Toxicity between bupropion and
fluoxetine and between bupropion and tricyclics has been reported, likely due to the effects on
the CYP 2D6 system. The package insert recommends caution when bupropion is used in
conjunction with medications that are metabolized through the CYP 2D6 isoenzyme.
Carbamazepine (Tegretol) seems to induce bupropion metabolism.
 Bupropion, like most antidepressants, is contraindicated in patients taking an MAO inhibitor
(MAOI), and a 14-day wash-out period is recommended before initiating bupropion. Additive
effects may be expected with other DA agents, such as antiparkinsonian medications, as well
as agents that may lower the seizure threshold.

LABORATORY INTERFERENCES
Bupropion may lead to false-positive test results for amphetamine urine toxicology screening
tests. There is no overall effect on other laboratory values, although one report found a 10 to
14 percent decrease in white blood cell counts over the first 2 months of therapy with
bupropion. There is no need to routinely monitor hematological indices during treatment with
bupropion.

DOSE AND ADMINISTRATION

Bupropion SR is available in 100-, 150-, and, recently, 200-mg tablets. The manufacturer
recommends dosing of bupropion SR to begin at 150 mg per day given as a single daily dose.
If tolerated, the dose can be increased to 150 mg twice a day as early as day 4, with at least 8
hours between twice-daily doses. If adequate response does not occur, bupropion SR can be
increased to a maximum of 400 mg per day (200 mg twice a day). Reduced dosing is
recommended in patients with liver or renal disease. For the elderly, some investigators have
advocated reduced doses with slower titration because of the concern of metabolite
accumulation and reduced renal clearance. One positive trial of bupropion SR in the elderly
began treatment at 100 mg per day and increased to 200 mg per day in divided doses on day 8,
with a maximum daily dose of 300 mg per day.
Dosing regimens for children and adolescents are not firmly established. Several trials with
bupropion in ADHD patients were conducted with the IR formulation at doses generally lower
than those used in adults. As with other antidepressants, trials of several weeks or longer are
necessary to gauge full response. As mentioned previously, for patients being treated for
nicotine dependence, bupropion SR should be started at least 1 week before the planned quit
date.
CONCLUSION
Bupropion is an antidepressant with pharmacological properties that continue to be relatively
unique. The primary mechanisms of action appear to be modulation of dopamine, NE, and,
perhaps, nicotinic pathways with minimal direct effect on serotonergic action.
Bupropion's minimal effect on anticholinergic, -adrenergic, muscarinic, and histaminergic
receptors likely accounts for the absence of many side effects commonly associated with other
antidepressants. The major treatment-limiting side effect for bupropion tends to be related to
overstimulation experienced in some patients as agitation or insomnia. The risk of seizures
with bupropion SR is approximately 0.1 percent at as much as 300 mg per day, which is
comparable to other antidepressants. In contrast, claims that bupropion is less likely to provoke
manic episodes in susceptible individuals require additional support with larger numbers of
patients before this can be reliably substantiated.

SUGGESTED CROSS-REFERENCES
Mood disorders are discussed in Chapter 13, nicotine-related disorders are discussed in Section
11.9, and other antidepressant pharmacotherapies are discussed in other sections of Chapter 31.

31.13: Buspirone
James Hudziak M.D. and G. Scott Waterman M.D.

INTRODUCTION AND HISTORY

Buspirone (BuSpar) is a member of the azaspirone class of drugs. Although its precise
mechanism of therapeutic action is not fully understood, it is distinct from that of barbiturate,
propanediol, and benzodiazepine anxiolytic agents. It does not have hypnotic, muscle relaxant,
or anticonvulsant properties. It has negligible affinity for the -aminobutyric acid
(GABA)benzodiazepinechloride ionophore receptor complex. It does, however, bind to
serotonin (5-hydroxytryptamine [5-HT]) type 1A (5-HT1A) receptors and has moderate affinity
for dopamine type 2 (D2) receptors in vitro.
CHEMISTRY
Buspirone's chemical designation is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-
azaspiro[4,5]decane-7,9-dione monohydrochloride (Fig. 31.13-1). It is structurally unrelated to
the barbiturate, propanediol, or benzodiazepine anxiolytics or the currently available
antidepressants.

FIGURE 31.13-1 Molecular structure of buspirone (BuSpar).

PHARMACOLOGICAL ACTIONS
Pharmacokinetics
Absorption Following rapid and almost complete absorption after oral
administration, buspirone undergoes extensive first-pass metabolism, resulting in
approximately 4 percent of the parent compound being found in general circulation. Peak
plasma concentrations of 1 to 6 ng/mL are achieved within 40 to 90 minutes after an oral dose
of 20 mg. In healthy adult subjects, linear kinetics are observed for single doses ranging from
10 to 40 mg. Nonlinear pharmacokinetics are observed after multiple-dose oral administration.
As the dose increases, or as the frequency of dosing is increased, the plasma concentrations are
higher than those predicted in the single-dose studies. Absorption of buspirone is delayed by
food ingestion, and the amount of unchanged buspirone reaching the systemic circulation is
increased. There is no evidence of increased adverse events or altered efficacy of buspirone
due to food intake.

Distribution Results from animal studies indicate that buspirone is widely distributed
after intravenous (IV) administration. Higher concentrations are observed in the lung, kidney,
and adipose tissue than in plasma or brain. The active metabolite of buspirone (1-
pyrimidinylpiperazine [1-PP]) accumulates in the brain at concentrations four- to fivefold
higher than plasma concentrations. A volume of distribution of 5.3 L/kg in healthy adults
results after IV administration of buspirone.
 Roughly 95 percent of buspirone is bound to the plasma proteins albumin and 1-acid
glycoprotein, yet it does not displace other highly bound ligands, such as phenytoin (Dilantin),
propranolol (Inderal), or warfarin (Coumadin). Buspirone does not displace digoxin (Lanoxin),
although this finding is from in vitro studies.

Metabolism and Elimination Following extensive hepatic metabolism, buspirone and

its metabolites are excreted in the urine (29 to 63 percent) and in the feces (18 to 38 percent).
In vitro studies of the metabolism of buspirone indicate that two major metabolites result via
different processes. These are the inactive 5-hydroxybuspirone (5-HB) via hydroxylation and
the pharmacologically active 1-PP via oxidative dealkylation. Animal studies reveal that 1-PP
is 20 to 25 percent less potent but is 15 to 30 times more concentrated in the brain than
buspirone.
The elimination half-life of buspirone is 2 to 11 hours after a single dose of 10 to 40 mg.
For 1-PP, the elimination half-life is 6 hours after a 20 mg dose. Patients with renal impairment
or cirrhosis may require lower doses of buspirone, because the elimination half-life in
individuals with those conditions is prolonged. Although the secretion of buspirone, 5-HB, and
1-PP in human milk is unknown, animal studies demonstrate that they are present in measurable
amounts.

Pharmacodynamics
Mechanism of Action Although the actual mechanism of action of buspirone is
unknown, its pharmacological activity most likely involves multiple neurotransmitters,
including the GABA, dopamine, 5-HT, norepinephrine, and acetylcholine systems. Evidence
for each is discussed.

SEROTONIN SYSTEM Buspirone has high affinity for the 5-HT1A receptor in the central
nervous system (CNS), where it acts as a partial agonist or mixed agonist or antagonist. Its
predominant effects appear to be as an agonist at the presynaptic 5-HT1A receptors and as a
partial agonist at postsynaptic 5-HT1A receptors. It is buspirone's ability to inhibit spontaneous
firing of 5-HTproducing neurons in the dorsal raphe nucleus that is thought to account for its
anxiolytic activity. Buspirone is thought to inhibit firing via its effects on somatodendritic 5-
HT autoreceptors. In addition, buspirone's agonist activity at postsynaptic 5-HT1A sites is
thought to account for its antidepressant activity.
 GABA SYSTEM Buspirone anxiolytic properties do not directly interact with the GABA-
benzodiazepine-chloride receptor complex. Buspirone neither stimulates nor inhibits the
binding of benzodiazepines, and benzodiazepine antagonists (e.g., flumazenil [Romazicon]) do
not block its anxiolytic effects. It has been suggested that buspirone may have indirect effects
on the GABA system that may contribute to the anxiolytic effects of this compound.

DOPAMINE SYSTEM Clinical significance for the effects of buspirone on the

dopamine system has not yet been established, yet these effects are thought to be due to its
moderate affinity for D2 receptors in the CNS. The suggested effect appears to be antagonism
of D2 presynaptic autoreceptors, thus increasing dopamine neurotransmission and turnover.
Additional evidence supports the possibility that buspirone blocks the postsynaptic D2 receptor.
Finally, it has been reported that buspirone may also function as a dopamine agonist. Taken
together, the effects of buspirone on the dopamine system are not clearly understood, and it has
been suggested that these effects are of limited importance in the clinical setting.

NOREPINEPHRINE SYSTEM Buspirone's principal metabolite, 1-PP, has central and

peripheral 2-adrenergic receptor blocking activity. The result is increased neuronal activity in
the locus ceruleus and an increase in norepinephrine metabolism. It has been suggested that
buspirone may downregulate 1-adrenoreceptors, as well as decrease striatal concentrations of
norepinephrine and increase concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG).
The net effects of buspirone on the noradrenergic system are unclear, and the clinical
significance of this activity has not been established.

ACETYLCHOLINE SYSTEM Little is known about the interaction of buspirone with

the cholinergic neurotransmitter system. In animal models, it has been demonstrated that
buspirone increases acetylcholine efflux in the hippocampus and decreases acetylcholine in the
striatum. Apparently, buspirone does not directly affect the cholinergic receptors.

Blood Concentrations and Relation to Clinical Action There is no evidence that

plasma buspirone concentration relates to clinical efficacy. Therefore, it is not suggested that
determination of buspirone plasma concentration should be obtained in clinical settings.
CLINICAL STUDIES
Generalized Anxiety Disorder Several multicenter, double-blind, placebo-controlled
trials have established the efficacy of buspirone as an anxiolytic. Studies have compared
buspirone with placebo or other anxiolytic compounds, or both. The other anxiolytic
medications that have served as comparators in buspirone trials have included diazepam
(Valium), clobazam (Frisium), clorazepate (Tranxene), alprazolam (Xanax), lorazepam
(Ativan), oxazepam (Serax), and hydroxyzine (Vistaril). Although these studies were mostly
of patients with generalized anxiety disorder, it is important to note that the majority of them
were performed before the publication of the revised third edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-III-R), when generalized anxiety disorder was
redefined to require a duration of anxiety symptoms of at least 6 months, rather than the
previous third edition of the DSM (DSM-III) requirement of just 1 month. (The 6-month
duration of symptoms is also required for the diagnosis of generalized anxiety disorder in the
fourth edition of the DSM [DSM-IV].) Many of the subjects in those studies therefore may not
have had an anxiety disorder that is as chronic as generalized anxiety disorder is now defined
to be. One recent study compared buspirone with the antidepressant compound venlafaxine
(Effexor), as well as placebo, in patients with DSM-IV generalized anxiety disorder. In that
trial, buspirone performed better than placebo but not as well as venlafaxine.
Although some studies failed to demonstrate the superiority of buspirone over placebo or
the comparability of buspirone with another anxiolytic agent, or both, a metaanalysis of
placebo-controlled comparisons of buspirone with benzodiazepine compounds, comprising
eight studies and 735 subjects, showed that the efficacy of buspirone was comparable to that
of benzodiazepines in the treatment of DSM-III generalized anxiety disorder. However,
anxious patients who have been treated with a benzodiazepine compound within 1 month of
initiating therapy with buspirone tend to respond less well to buspirone. Response of anxiety
symptoms to buspirone generally requires at least 2 weeks of treatment, and continuing gradual
improvement may extend over several more weeks. Benzodiazepines may be more helpful than
buspirone in ameliorating somatic symptoms of anxiety, although they appear equally effective
in reducing cognitive symptoms of anxiety.

Other Anxiety Disorders Other anxiety disorders for which the usefulness of buspirone
has been evaluated include panic disorder, social phobia, posttraumatic stress disorder (PTSD),
and obsessive-compulsive disorder (OCD). Although one placebo-controlled study of
buspirone in patients with panic disorder who were receiving cognitive behavioral therapy
found transient beneficial effects of the drug on measures of anxiety and avoidance, two other
controlled trials in panic disorder have not found buspirone to be effective. Open-label trials of
buspirone have suggested efficacy in the treatment of social phobia, although double-blind,
placebo-controlled studies have not. Uncontrolled observations suggest that buspirone may
have some beneficial effects in PTSD.
In OCD, evidence for the efficacy of buspirone, as monotherapy or as an augmenting agent,
is sparse and conflicting. A small placebo-controlled comparison of buspirone and
clomipramine (Anafranil) as monotherapies found similar degrees of improvement for the two
drugs. Other reports, however, have not found buspirone effective for OCD. Open-label trials
have found buspirone effective in augmenting the antiobsessional effects of serotonergic
antidepressant medications in adult and pediatric samples. Controlled studies have examined
the use of buspirone when added to therapy with fluoxetine (Prozac), fluvoxamine (Luvox),
and clomipramine and have failed to find added benefit in patients with OCD.

Major Depressive Disorder As with OCD, buspirone has been studied as a

monotherapy for major depressive disorder and as an augmenting agent in patients whose
depressions have failed to respond adequately to pharmacotherapy with standard antidepressant
medications. Controlled trials have examined the efficacy of buspirone in the treatment of
major depressive disorder and have found it to be superior to placebo on measures of depressive
and anxious symptoms. Doses may need to be relatively highnear or, in some instances, greater
than the manufacturer's recommended maximum daily dose of 60 mgfor buspirone to be useful
as a single antidepressant agent. Open-label studies and case reports have (although not
unanimously) found buspirone to be helpful as an augmenting medication in major depressive
disorder. Two randomized, double-blind, placebo-controlled trials have investigated this use
of buspirone over the recent past. In one, no significant difference was found between
buspirone and placebo when added to ongoing therapy with paroxetine (Paxil) or citalopram
(Celexa). In the other, patients randomized to buspirone augmentation of selective serotonin
reuptake inhibitor (SSRI) therapy showed a greater reduction of depressive symptoms
compared to placebo-treated patients after the first week, but no such difference existed at the
end of the 6-week study period. However, among patients whose depressive symptoms were
severe on study entry, buspirone augmentation was significantly superior to placebo.
Other Uses
Alcohol Use Disorders Buspirone has been extensively studied in the treatment of
alcohol dependence. A placebo-controlled trial showed marked improvement in alcoholics and
control subjects. These differences were found in multiple measures of psychopathology but
not in measures of alcohol consumption. In fact, the evidence indicated that there were no direct
effects on craving and consumption independent of anxiety. A recent study that tested the
effects of buspirone, lithium (Eskalith), and placebo on alcoholic's craving and consumption
of alcohol similarly found no effects of medication relative to placebo. Multiple studies have
suggested that buspirone is best used in alcoholics with comorbid anxiety problems. The results
of those studies have been mixed. Three of four double-blind, placebo-controlled studies
reported that buspirone was an effective agent to use in alcoholics with anxiety. Those studies
reported significant gains in treatment retention, decreases in alcohol craving, slower return to
heavy alcohol consumption, fewer daily drinks during aftercare, and marked reduction in
anxiety and depressive symptoms. The fourth study of alcoholic veterans in aftercare showed
no differences between patients and placebo. The reasons for these differences are unclear.
Other advantages of buspirone in anxious alcoholics include reduced sedation and impairment
in subjects who were receiving buspirone or alprazolam, plus or minus ethanol. Subjects in the
buspirone group were less sedated and less impaired. Although the literature is mixed, it
appears that buspirone is well tolerated and is associated with improvement in a number of
behavioral measures in alcoholics who experience comorbid anxiety.

Psychosis Buspirone has no known antipsychotic activity in humans. Multiple open

clinical trials evaluated the efficacy of buspirone in schizophrenic patients with no clear
evidence of improving positive or negative symptoms. Buspirone's dopaminergic activity led
to many animal studies, and one study in which extremely high doses of buspirone (a mean of
1,470 mg daily) had transient antipsychotic effects. In typical doses, however, no antipsychotic
effects have been reported.
Buspirone has also been tested as a possible treatment of neuroleptic-induced akathisia. It
had no effect in 60 percent, a positive effect in 20 percent, and a negative effect in 20 percent
of patients with that syndrome. Thus, buspirone is thought to be of limited value in the
treatment of neuroleptic-induced akathisia.
 Aggression Buspirone has been tested in a number of studies as an antiaggression agent.
Animal studies indicated that buspirone was an effective anticonflict compound. In a placebo-
controlled trial, buspirone was demonstrated to reduce aggression and anxiety in five of six
developmentally delayed, mentally retarded subjects. A study in patients experiencing
traumatic brain injury revealed that treatment with buspirone was associated with improvement
on the Neurobehavioral Rating Scale. In subjects with brain damage and aggression, nine of
ten patients had some improvement while on buspirone. Among patients who showed
significant (50 percent) reductions in their symptom scores, doses of buspirone were relatively
high (an average of 50 mg per day). In an open-label study of 25 hospitalized children with
severe aggression, buspirone was of limited usefulness. In fact, 24 percent of the children had
worsening of aggression and agitation or developed euphoric mania. In children who tolerated
buspirone, there was a 52 percent reduction in depressive symptoms, a 29 percent reduction in
aggression, and 86 percent less time in seclusion. However, only three of the original 25
children improved sufficiently to continue buspirone after the study. Buspirone's role in the
management of aggression is unclear, but it may have specific benefits in aggressive or anxious
patients who are developmentally delayed, are mentally retarded, or have had traumatic brain
injury.

Attention-Deficit/Hyperactivity Disorder Patients with ADHD commonly

experience comorbid anxiety and are aggressive. As a result, there was some interest to test
buspirone in ADHD. In an open clinical trial of 12 children, buspirone was reported to lead to
significant improvement in hyperactivity, impulsivity, inattention, and disruptive behavior in
all of the children. Buspirone was associated with few side effects and, reportedly, the children
had the return of symptoms, once buspirone was discontinued. In a report, buspirone was also
effective in reducing oppositional defiant disorder symptoms in children who also had ADHD.
As both of these studies were open-label, controlled clinical trials are necessary before the role
of buspirone in ADHD is understood.

Pervasive Development Disorders Early case reports described improvement in

hyperactive behavior in two of four children whose primary diagnoses were autism. This
research was extended to 22 subjects with pervasive developmental disorders. In an open-label
trial, 16 (nine of whom showed marked responses and seven of whom showed moderate
responses) of the 22 subjects were classified as responders and continued in buspirone
treatment for a full year. The main benefits were reduction of irritability and anxiety, with
improvement coming as early as 6 to 8 weeks. A 3-week double-blind, placebo-controlled
crossover trial with buspirone in a single autistic child found the drug to be safe and effective
in reducing hyperactivity. Controlled trials are necessary to understand the role of buspirone in
autism and other pervasive developmental disorders.

Premenstrual Disorder Two controlled trials found buspirone to be more effective than
placebo in reducing somatic and psychic symptoms associated with premenstrual syndrome.
No studies have compared buspirone to SSRIs (approved for the treatment of premenstrual
dysphoric disorder), so the efficacy of buspirone compared to approved agents remains unclear.

Somatoform Disorders Buspirone has been reported to be modestly effective in chronic

tension headaches and in SSRI nonresponders with body dysmorphic disorder. A role for
buspirone in the treatment of classic somatoform disorders has not been demonstrated.

Sexual Dysfunction Three studies report on the usefulness of buspirone as an antidote

to SSRI-induced sexual dysfunction. In a retrospective study, buspirone was effective in
alleviating sexual dysfunction in 11 of 16 patients who were treated with SSRIs. A randomized,
placebo-controlled study of buspirone or amantadine (Symmetrel) revealed that neither was
superior to placebo in reversing symptoms of sexual dysfunction. A second controlled study
reported buspirone to be superior to placebo in reversing sexual dysfunction, with women
benefiting more than men. The response was reported to be obvious during the first week of
treatment, with no further improvement evident thereafter. It appears that buspirone may be a
useful agent in some patients who experience sexual dysfunction induced by SSRIs. It is
unclear which patients are responders.

Nicotine Dependence A placebo-controlled trial of the efficacy of buspirone in

smoking cessation followed multiple open-label studies that reported mixed results, with
abstinence rates varying from 36 to 88 percent in the buspirone groups, compared to 16 to 89
percent in placebo groups. The controlled trial tested buspirone against placebo in a double-
blind format. One hundred patients were studied (51 with buspirone, 49 with placebo), and
outcome measures included rates of cessation and severity of withdrawal symptoms. Buspirone
did not differ from placebo in rates of cessation or in minimizing withdrawal symptoms.
EFFECTS ON SPECIFIC ORGANS AND SYSTEMS
Nervous System The most commonly encountered adverse effects of buspirone are those
that relate to the CNS. They include dizziness, nervousness, headache, light-headedness, and
disturbed dreams. Extrapyramidal symptoms and akathisia have been reported in association
with buspirone but appear to be rare.

Gastrointestinal System Nausea is sometimes reported by patients taking buspirone.

Cardiovascular System The frequency of symptoms referable to the cardiovascular

system in patients taking buspirone did not exceed that of placebo-treated patients.

Dermatological Effects Adverse dermatological effects with buspirone have been rare.

Endocrine System Acute administration of buspirone has several neuroendocrine effects.

Nonetheless, adverse effects of ongoing buspirone administration that are referable to the
endocrine system, such as galactorrhea and thyroid abnormalities, are rare.

Other Systems Buspirone has not been associated with other frequently occurring
adverse effects.

THERAPEUTIC INDICATIONS
The U.S. Food and Drug Administration (FDA) has approved buspirone's indication for the
management of anxiety disorders or the short-term relief of the symptoms of anxiety. The FDA
has judged that its efficacy in treating patients whose diagnoses roughly correspond to
generalized anxiety disorder has been demonstrated. Although, as noted previously, buspirone
has been used in a number of different contexts, its use in the treatment of anxiety is its only
FDA-approved indication.

PRECAUTIONS AND ADVERSE REACTIONS

Buspirone is contraindicated in patients with known hypersensitivity to it. Because
metabolism or excretion of the drug may be compromised in the presence of hepatic or renal
dysfunction, doses may need to be reduced in patients with liver or kidney disease.
 In placebo-controlled clinical trials, commonly occurring adverse effects associated with
buspirone to a greater extent than with placebo included dizziness, nausea, headache,
nervousness, light-headedness, and agitation. A seizure reportedly occurred in a patient with
OCD for whom buspirone was prescribed in an effort to augment the effects of an SSRI
compound. Administration of buspirone may be associated with an increased risk of mania or
hypomania in bipolar patients.
Buspirone is not cross-tolerant with benzodiazepines, barbiturates, propanediols, or alcohol.
Although buspirone administration during benzodiazepine taper may ameliorate the symptoms
of benzodiazepine withdrawal, such withdrawal should nonetheless be gradual. Buspirone
should not be abruptly substituted for benzodiazepines in patients who have been taking
benzodiazepines for significant periods of time.
Rodent studies with buspirone have found no evidence of carcinogenicity, teratogenicity, or
fertility impairment. Buspirone does not appear to be associated with deoxyribonucleic acid
(DNA) damage or chromosomal anomalies. The FDA use-in-pregnancy rating for buspirone is
category B (no evidence of risk in humans), although there are no data to support the safety of
buspirone in human pregnancy. Buspirone and its metabolites are excreted in milk in rats and
are likely excreted in human milk as well.

DRUG INTERACTIONS
Concurrent administration of buspirone with monoamine oxidase inhibitor (MAOI)
antidepressant compounds has been associated with blood pressure elevations. Buspirone has
been found to increase haloperidol (Haldol) serum concentrations when the two drugs are
coadministered. Buspirone is highly protein bound, raising the possibility that it may displace
other drugs from protein binding sites. In vitro, it does not displace tightly protein-bound drugs,
including phenytoin, propranolol, and warfarin, although there is a report of prolongation of
prothrombin time in a patient for whom buspirone was added to a regimen that included
warfarin, as well as phenytoin, phenobarbital (Barbita), digoxin, and L-thyroxine. Buspirone
may displace from protein-binding sites less tightly bound drugs, such as digoxin, although the
clinical significance of that is not known.
Adding buspirone to diazepam did not affect pharmacokinetic parameters for the parent
compound (diazepam) but did increase nordiazepam concentrations. Administering buspirone
with the hypnotic benzodiazepines triazolam (Halcion) or flurazepam (Dalmane) did not
increase the duration or intensity of the sedating effects of those compounds. Substances that
inhibit the activity of the cytochrome P450 3A4 isoform (e.g., erythromycin [E-Mycin],
itraconazole [Sporanox], nefazodone [Serzone], and grapefruit juice) increase buspirone
plasma concentrations.

LABORATORY INTERFERENCE
Buspirone has not been reported to interfere with clinical laboratory values.

DOSAGE AND ADMINISTRATION

Buspirone is prepared as buspirone hydrochloride. It is available in 5-, 10-, 15-, and 30-mg
tablets. The 15- and 30-mg tablets are scored so that they can be bisected or trisected. The usual
initial adult dose is 10 to 15 mg per day in two or three divided doses. The dose may be
increased in increments of 5 mg per day at intervals of 2 to 3 days. Divided doses totaling 30
to 60 mg per day, as tolerated, are commonly required for optimal therapeutic response.

SUGGESTED CROSS-REFERENCES
Anxiety disorders are discussed in Chapter 14, mood disorders are discussed in Chapter 13,
substance use disorders are discussed in Chapter 11, and benzodiazepine anxiolytics are
discussed in Section 31.11.

31.14: Calcium Channel Inhibitors

Steven Dubovsky M.D.

HISTORY
The complex psychobiology of mood disorders is unlikely to be explained by changes in a
single neurotransmitter or receptor. Intracellular messengers, on the other hand, regulate
multiple aspects of neuronal function, and abnormal regulation of one messenger can have
multiple downstream effects on affective, cognitive, and behavioral systems. The intracellular
calcium ion is particularly interesting in this regard, because it regulates activity of
neurotransmitters, such as serotonin and dopamine, and has a biphasic action (Fig. 31.14-1).
Moderate increases of free intracellular calcium ion concentration ([Ca2+]i) stimulate cellular
activity, whereas greater elevations inhibit the same functions. A hyperactive intracellular Ca2+
signal that contributes to the activation of mania at the same time that it suppresses behavioral
and other affect regulation systems could explain why so many bipolar patients have rapid
fluctuations between mania and depression or experience both states at the same time.
Correction of hyperactive intracellular calcium signaling could also explain why treatments
such as lithium (Eskalith) can improve mania and bipolar depression.

FIGURE 31.14-1 Intracellular calcium ion signaling. Intracellular calcium ion concentration
([Ca2+]i) is increased by entry into the extracellular space and by release from intracellular
stores. Calcium enters the cytosol through receptor operated (e.g., N-methyl-d-aspartate) and
potential-dependent ion-specific channels, as well as in exchange for intracellular sodium.
Stimulation of a variety of G-protein-associated receptors (e.g., serotonin type 2, dopamine
type 2) activates turnover of the membrane phosphoinositol system, with production of inositol
triphosphate (IP3) and diacylglycerol (DG). IP3 releases calcium ions from intracellular stores,
and DG draws protein kinase C (PKC) to the cell membrane, where it is activated by Ca2+.
Moderate increases of [Ca2+]i stimulate cellular processes by activating PKC and a variety of
other enzymes that are activated by the calcium-calmodulin (CaM) complex; greater increases
suppress the same processes. CBZ, carbamazepine; CCB, calcium channel blocker; Li, lithium;
NL, neuroleptic; PIP2, phosphatidylinositol biphosphate; PLC, phospholipase C; TCA,
tricyclic antidepressant.
 Free intracellular Ca2+ concentration is normally regulated tightly at approximately 100
nmol, or 0.0001 of the Ca2+ concentration in the extracellular fluid. Elevations of resting
[Ca2+]i, as well as of [Ca2+]i stimulated by agonists that have included thrombin, platelet-
activating factor, and serotonin, have been found in blood platelets, lymphocytes, and
lymphoblasts of affectively ill manic and bipolar depressed patients but not in platelets of
bipolar patients who are euthymic after treatment with various medications or
electroconvulsive therapy (ECT). Some investigators have found greater serotonin-stimulated
increases in platelet [Ca2+]i in unipolar depressed patients than in controls, with blunting of the
excessive intracellular signal by serotonin reuptake inhibitors, but most studies find that
elevated resting and agonist stimulated increases in [Ca2+]i in peripheral cells are specific to
bipolar disorder, occurring with equal frequency in mania and bipolar depression.
Elevated [Ca2+]i in bipolar mood disorders may be the effector arm of a number of upstream
changes. One consistently reported finding in peripheral cells of patients with bipolar disorder
is hyperactivity of a G protein, which is antagonized by long-term lithium treatment. Membrane
phosphatidylinositol (PI) turnover, which is linked to a variety of receptors, including serotonin
type 2 (5-HT2) and dopamine type 2 (D2) receptors, may be primarily increased or it may be
increased by a hyperactive G protein; in either case, this would result in increased release of
stored intracellular calcium or increased activity of protein kinase C (PKC)dependent
processes, or both. Preliminary studies suggest that brain PKC activity may be primarily
increased in bipolar disorder. Calcium influx from the extracellular space may be increased by
hyperactivity of calcium channels or by increased exchange of intracellular sodium for
extracellular calcium. Interventions that act at any point in the cascade of intracellular calcium
mobilization or action could compensate for dysregulation at other points in the cascade.
In vitro incubation with lithium and carbamazepine (Tegretol) lowers platelet and
lymphocyte [Ca2+]i significantly in ill bipolar patients but not in controls or euthymic bipolar
patients. Lamotrigine (Lamictal), another medication that is being found useful in bipolar
disorder, also has calcium antagonist properties. Attenuation of hyperactive intracellular
calcium signaling by antimanic drugs may have a number of different mechanisms (Fig. 31.14-
1). Lithium inhibits a crucial step in membrane PI turnover (inositol-1-monophosphatase),
which could reduce production of inositol triphosphate (IP3), thereby decreasing calcium
mobilization from intracellular stores; this possibility is suggested by the finding that lithium-
treated bipolar patients, but not controls, have reduced platelet phosphatidylinositol
biphosphate (PIP2). Lithium may also interfere with calcium channel activity or may enhance
calcium efflux, perhaps through an effect on sodium flux. Carbamazepine inhibits Ca2+ currents
in a variety of models, and the time course of suppression of calcium-dependent potentials is
comparable to that produced by the calcium channel inhibitor verapamil (Calan, Isoptin).
Lamotrigine also inhibits calcium channels.

CHEMISTRY
Different classes of calcium channel inhibitors (calcium channel blockers [CCBs]) have
significantly different structures (Fig. 31.14-2), leading to differential activity in various tissues
that depends on interactions with ion-specific channels in the neuronal membrane. Verapamil,
the first calcium channel antagonist to be introduced, was synthesized in 1962. A phenyl
alkylamine derivative of papaverine (Pavarine), verapamil was found to have negative
inotropic effects that, in 1967, were postulated to be due to reduction of excitation-contraction
coupling caused by inhibition of calcium influx into cardiac cells. Three additional classes of
CCBs have been developed (Table 31.14-1). Because of their heterogeneity of structure and
action, these medications are not interchangeable. However, they all have the capacity to
reduce excessive excitability of diverse cellular systems.
Verapamil and diltiazem (Cardizem) are crystalline powders that are soluble in water and
chloroform. Nifedipine (Procardia) is insoluble in water, but it is soluble in ethanol.
Nimodipine (Nimotop), a 1,4-dihydropyridine (DHP) that is insoluble in water but is highly
lipophilic, has two closely related congenersisradipine (DynaCirc) and amlodipine (Norvasc).
Amlodipine is a white crystalline powder that is slightly soluble in water and ethanol.
FIGURE 31.14-2 Structure of some calcium channel inhibitors.
Table 31.14-1 Calcium Channel Inhibitor Classes
Class Examples
Phenyl alkylamine Verapamil (Calan, Isoptin), norverapamil
1,4-dihydropyridine Nifedipine (Procardia), nicardipine (Cardene), nimodipine (Nimotop),
(DHP) amlodipine (Norvasc), isradipine (DynaCirc), nitrendipine
Benzodiazepine Diltiazem (Cardizem)
Diphenylpiperazine Flunarizine (Sibelium), cinnarizine

PHARMACOLOGICAL ACTIONS

Pharmacokinetics
Absorption The CCBs are nearly completely absorbed after oral administration
(Table 31.14-2), but bioavailability is decreased by extensive first-pass hepatic and probably
intestinal metabolism. First-pass metabolism also results in considerable interindividual
variability in blood level at a given dose. As noted in Table 31.14-2, oral bioavailability of the
CCBs is less than that of other drugs used to treat mania, but effective concentrations for their
primary indication are an order of magnitude lower. Optimal serum concentrations for mood
disorders have not been investigated.
Verapamil is metabolized by D-dealkylation and O-demethylation to at least 12 metabolites.
One of these, norverapamil, has approximately 20 percent as much cardiovascular activity in
animal models and a half-life of 10 hours. Diltiazem, which is metabolized by O-deacetylation
or N-demethylation, has active metabolites that do not appear to be clinically important.
Nifedipine, nicardipine (Cardene), and most of the other dihydropyridines have inactive
metabolites. The majority of people are rapid metabolizers of nifedipine and possibly other
DHPs; approximately 17 percent are slow metabolizers.
Table 31.14-2 Comparative Chemistry of Some Calcium Channel Blockers and Some
Mood Stabilizers
Plasma Effective
Oral Protein Volume of Elimination Concentration for
Availability Binding Distribution Half-Life Primary
Drug (%) (%) (L/kg) (hrs) Indication

Verapamil 22 8 90 5.0 2.1 4.0 1.5 40120 ng/mL

(Calan, Isoptin)
Diltiazem 44 10 78 3.0 1.2 6.0 1.2 Unknown
(Cardizem)
Nifedipine 50 13 96 0.8 0.22 3.0 1.3 2767 ng/mL
(Procardia)
Lithium 100 0 0.8 0.34 22.0 8.0 0.51.5 mEq/L
(Eskalith)
Carbamazepine 70 74 1.4 0.4 15.0 5.0 412 g/mL
(Tegretol)
Divalproex 100 93 0.2 0.07 14.0 2.2 50125 g/mL
(Depakote)

Distribution Peak plasma levels of the majority of calcium channel blocking agents
are achieved within 30 minutes to 3 hours after oral dosing, but amlodipine does not reach peak
plasma concentrations for 6 hours. All CCBs are extensively bound to plasma proteins. Most
CCBs are excreted in breast milk. Verapamil and norverapamil can be recovered from human
cerebrospinal fluid (CSF) after oral administration, and the concentration of phenyl
alkylamines in the brain is sufficient to be protective after cerebral ischemia in rats. However,
the more lipophilic nimodipine crosses the bloodbrain barrier more readily.

Elimination Most CCBs have elimination half-lives in the range of 1.3 to 6.0 hours,
except for amlodipine, which has a half-life of 35 to 50 hours. Although amlodipine can be
given once daily, the short half-lives of most CCBs require multiple daily doses. However,
because repeated administration saturates hepatic metabolizing enzymes, bioavailability and
half-lives increase with chronic administration, and the dosing interval can be increased.
Pharmacodynamics
Mechanism of Action Calcium ions enter the cytosol through receptor-operated
channels gated by receptors for hormones and transmitters, such as the excitatory amino acids,
and through PDCs gated by membrane potential. Additional pathways for calcium entry
include leak through an ungated channel and exchange of extracellular calcium ions for
intracellular sodium ions (Na+) (Fig. 31.14-1). Under physiological conditions, PDCs can be
regulated by receptor-mediated events, such as the production of inositol triphosphate, and
receptor operated channels can be gated by voltage dependent events. In addition, extracellular
Ca2+ entering the cell may release calcium ions from intracellular stores, and trigger amounts
of calcium ions released from intracellular stores may facilitate calcium channel opening. Even
subtle alterations of the function of one kind of calcium channel therefore may have significant
effects on the overall balance of calcium-dependent cellular activity.
Calcium channel blocking agents interact with the potential-dependent channel (PDC). This
type of channel consists of five allosterically linked subunits, termed 1, 2, , , and ; the 1
channel has a hydrophobic region that spans the cell membrane and outlines the actual calcium
pore (Fig. 31.14-3). In the brain, potential-dependent calcium channels are localized in regions
rich in synapses, perhaps because high [Ca2+]i must be produced rapidly to regulate
neurotransmitter release. Endogenous regulators unrelated to neurotransmitters appear to
modulate PDC gating and CCB binding and may be altered in disease states.
Four subtypes of PDCs have been identified. The L (long-lasting) channel, the only PDC
shown definitely to bind CCBs, requires significant depolarization for Ca2+ entry and
inactivates slowly. L-type calcium channels do not participate directly in neurotransmitter
release, but they play an important role in determining neuronal excitability. The T (transient)
channel is activated by small depolarizations and inactivates rapidly. T-type calcium channels
may be involved in the action of ethosuximide (Zarontin), valproic acid (Depakene), and
divalproex (Depakote) in the treatment of absence seizures. The N (neither L nor T) channel,
which is primarily found on central nervous system (CNS) neurons, is unresponsive to CCBs.
A rapidly inactivating P (Purkinje cell) channel identified in cerebellar Purkinje cells is
insensitive to the DHP CCBs. N and P channels may participate in release of neurotransmitters
in response to the action potential, whereas the role of L channels is less certain. Studies of
actions of specific CCBs on L channels may be complicated by differential binding of CCBs
by the same channels in different tissues, alteration of findings by slight changes in
experimental conditions, and difficulty distinguishing between N and L channels.
 Calcium channel inhibitors (CCBs) reduce Ca2+ influx through L (long-acting)type
potential-dependent calcium channels. At least four and possibly seven or more distinct binding
sites for different classes of CCBs exist on the L channel 1 subunit, allosterically linked to
each other and to the Ca2+ gating site. Different CCBs therefore may have different spectra of
action. For example, nimodipine also has anticonvulsant properties that could contribute to
activity in different syndromes than CCBs that are not anticonvulsants. The intracellular action
of the calcium ion (Ca2+) may also be inhibited by substances that enhance efflux, intracellular
storage, or binding of Ca2+ to inactivating proteins or that activate second messengers with
contradictory actions. However, the CCBs are the only drugs in widespread clinical use for
their calcium antagonist activities.

FIGURE 31.14-3 Structure of the calcium channel blocker binding site. BP, benzodiazepine
binding site; DHP, 1,4-dihydropyridine binding site; DPP, diphenylpiperazine binding site; O,
other calcium channel blocking agent binding sites; PA, phenyl alkylamine binding site.

Calcium channel blocking agents bind primarily to L channels. Nimodipine, nicardipine,

methoxyverapamil, flunarizine (Sibelium), and cinnarazine may also antagonize T channels,
and a phenyl alkylamine binding site exists on the inner mitochondrial membrane. At least four
and possibly seven or more distinct binding sites have been identified for the 1 subunit,
allosterically linked to each other and to the Ca2+ 1 subunit CCB binding site. The other
subunits, and possibly the other endogenous circulating factors, can alter the conformation of
the 1 subunit, changing the affinity of the L channel for a given CCB.
Thus far, four separate genes coding for the 1 subunit have been identified, producing
different versions of CCB binding sites. Depending on the distribution of binding sites for a
given chemical class of CCBs, that class may be more or less active in a particular tissue or
region. Variations in CCB structure produce variations in potency at different L channels in
different tissues. For example, dihydropyridines are more selective for vascular tissue, whereas
verapamil and diltiazem have more prominent antiarrhythmic properties.
Several additional features of the calcium channel contribute to activity profiles of CCBs of
different structure. Along with allosteric regulation and the influence of circulating modulators,
membrane potential determines the conformation and, therefore, the affinity of CCB binding
sites. Dihydropyridine binding is enhanced by membrane depolarization, the CCB stabilizing
the channel in an inactivated state. Most DHPs are uncharged at physiologic pH and easily gain
access to the receptor through the cell membrane if it is sufficiently depolarized. Charged
DHPs, such as amlodipine, have slower onsets of action because of interactions with negatively
charged phosphate head groups in the cell membrane. Verapamil and diltiazem, which are also
charged at physiological pH, gain access to the receptor through open channels and therefore
are more active when channel openings are more frequent. The activity dependence of charged
and uncharged CCBs makes these drugs much more potent in hyperactive tissue than in normal
tissue. As a result, actions measured in normal cell preparations may not reflect activity in
pathological states.
Several objections can be raised to the hypothesis that attenuation of excessive rises in
[Ca2+]i is a primary mechanism of action of CCBs in bipolar illness. First, as noted previously,
L channels do not appear to be involved in the action potentialdependent release of
neurotransmitters. However, neurotransmitters activate L channels, making them an important
component of neuronal signaling, and it is not certain that neurotransmitter dysfunction is the
primary pathophysiology of mood disorders anyway. Similarly, low concentrations of CCBs
do not affect neurotransmitter release or neuronal Ca2+ currents, because depolarization in these
cells is normally too brief to permit sufficient binding of the CCBs, but higher concentrations
of CCBs may alter neuronal activity in other fundamental ways, and CCBs have significant
effects on neurons with prolonged or marked depolarization. This may be why the effects of
antimanic drugs, such as lithium, on [Ca2+]i are evident in hyperactive peripheral cells from
bipolar patients but not in normally active cells from controls.
It could also be argued that it is the anticonvulsant property of some CCBs and not their
effect on Ca2+ currents that accounts for their antimanic activity. Nimodipine, a CCB with
definite anticonvulsant properties, seems particularly useful in the treatment of mood disorders,
although this may be more a function of its high lipid solubility. Although reduction of neuronal
excitability does convey anticonvulsant effects to the CCBs, these effects do not appear to be
in proportion to their antimanic potential. In addition, the anticonvulsant potency of many of
the CCBs is manifest mainly in animal models and is not as apparent in human epilepsy or
electrically induced seizures.

DESIGN AND INTERPRETATION OF CLINICAL DRUG STUDIES

The first type of calcium antagonist used in psychiatry was calcitonin (Cibacalcin), which
lowers [Ca2+]i by driving Ca2+ into intracellular storage sites. John Scott Carman and Richard
A. Wyatt found that three manic patients had a temporary reduction of agitation after injections
of subcutaneous salmon calcitonin (Calcimar) but not after administration of placebo. In a
subsequent trial, a group of nine patients with so-called chronic psychopathological suffering
accompanied by depression or anxiety but no formal diagnoses felt tranquilized and
demonstrated a reduction of brief psychiatric rating scale scores after receiving an unspecified
dose of salmon calcitonin for 20 days.
The first report of the use of a CCB in the treatment of mania was a double-blind, placebo-
controlled trial of verapamil in a single manic patient. The rationale for choosing this particular
CCB was that it was the only CCB that the manufacturer would make available at a time at
which none of these medications had been approved for use in the United States. Based on
initial positive experience in case reports and open trials, double-blind studies of verapamil in
bipolar disorder have been conducted. Because of lack of interest of CCB manufacturers in
psychiatric applications of the CCBs, there have not been any large, multicenter trials of any
of these medications in mood disorders.
In initial studies, verapamil was superior to placebo and no treatment in the treatment of
mania, and two studies reported equivalent antimanic efficacy with lithium. A 2-week open
trial of diltiazem in seven manic patients, a 3-year follow-up of a bipolar patient for whom
flunarizine was successfully substituted for lithium, a 1-week trial of nimodipine, and a
prolonged double-blind follow-up of three bipolar patients receiving high doses of nimodipine
suggest possible antimanic applications of these medications.
Verapamil has been noted to prevent antidepressant-induced hypomania. Extended follow-
up of a few patients demonstrated the usefulness of nimodipine as maintenance therapy in
bipolar illness, and verapamil also has been found effective in the clinical setting in preventing
affective recurrence. Careful longitudinal observations have suggested possible usefulness of
nimodipine for ultradian cycling and recurrent brief depression. Robert Post's group, which has
pioneered the use of nimodipine in bipolar disorder, found that blinded monotherapy with
nimodipine was more effective than placebo for 10 of 30 patients with refractory, highly
recurrent bipolar and unipolar mood disorders; augmentation of nimodipine with
carbamazepine substantially improved the status of 4 of 14 partial nimodipine responders. The
highly refractory nature of these patients' illnesses and the careful evaluation of response using
Post's life-charting method increase confidence in the results, even though the sample was
small.
In one of two negative trials of verapamil in mania, single-blind lithium produced
significantly more improvement of mania rating scales than verapamil in a 28-day randomized
trial of 40 manic patients. However, doses and frequency of administration of verapamil were
lower than are usually effective, and both groups were still quite symptomatic at the end of the
trial. The second negative study was a random assignment trial of 32 acutely manic patients,
most of them psychotic, to placebo or verapamil given three times per day. Both groups had
similarly slight and statistically insignificant reductions in mania and depression rating scale
scores. However, patients only remained in treatment for a mean of 9.3 (verapamil) to 13.3
(placebo) days, a duration of treatment that would not be considered adequate for any antimanic
drug. Most patients in clinical practice with psychotic mania would be treated with
antipsychotic drugs along with or before an antimanic drug. In addition, although the authors
stated that verapamil doses could be adjusted to as much as 480 mg per day, actual doses
received were not noted, and verapamil may not have been administered frequently enough to
achieve a steady state acutely. Finally, no data were presented to determine whether patients
had been refractory to lithium or other treatments; patients who have responded to verapamil
monotherapy in most studies have also been responsive to lithium.