About Course
Chapter 28. Clozapine
HISTORY AND DISCOVERY
Clozapine has played a critical role in the history of therapeutics for psychosis. When clozapine was
initially developed in the 1960s (following its synthesis in 1958 in Switzerland), there was
skepticism as to whether an agent that barely caused catalepsy in rodents could be an effective
antipsychotic. According to Hippius (1999), there was limited enthusiasm for this drug because it
was inconsistent with the “neuroleptic dogma” that extrapyramidal side effects (EPS) were an
essential feature of an antipsychotic agent. Nevertheless, Hippius and others challenged this dogma
and supported clozapine’s development in Germany. As a result, clozapine was eventually marketed
in a number of countries in Europe.
Enthusiasm about clozapine’s unique profile turned to despair when it was reported that 13
patients in Finland developed agranulocytosis during treatment with clozapine and that 8 of these
patients died (Griffith and Saamerli 1975). This led to a near-halt in research on clozapine and
attempts to switch patients to other agents. However, some individuals demonstrated substantial
deterioration when they were switched (Hippius 1999). These patients were changed back to
clozapine and carefully monitored with regular white blood cell (WBC) counts. It was subsequently
confirmed that clozapine-induced agranulocytosis was reversible. If clozapine was discontinued
before patients developed infections, the drug could be readministered safely (Honigfeld et al.
1998). Moreover, studies revealed that clozapine was particularly effective for patients who were
severely ill and for patients who had failed to respond to treatment with conventional
antipsychotics.
These observations led to attempts to gain approval for clozapine in the United States for patients
who failed to respond to other antipsychotics. This resulted in a multicenter study (Kane et al.
1988; described in greater detail later in this chapter) in which severely ill inpatients with a history
of poor responsiveness to at least three antipsychotics were assigned to a 6-week comparison of
either clozapine or chlorpromazine with benztropine. Clozapine was significantly more effective on
a broad range of psychopathology that included both positive and negative symptoms. This breadth
of improvement suggested not only that clozapine was more effective than chlorpromazine but also
that it was qualitatively different. Another study (Claghorn et al. 1987) evaluated the effectiveness
of clozapine and chlorpromazine in patients with either tardive dyskinesia or EPS. This report also
found that clozapine was superior in a broad range of psychopathology. The completion of these
studies was instrumental in the approval of clozapine by the U.S. Food and Drug Administration
(FDA) in 1990. Approval in the United States was followed by its introduction in a number of other
countries.
The discovery that clozapine was an effective antipsychotic with minimal EPS led to a reassessment
of models for developing antipsychotic agents. This reassessment, in turn, led to the later
development of a new generation of antipsychotics. Moreover, attempts to understand clozapine’s
mechanism of action have had important effects on current views of the pharmacology of
schizophrenia.
STRUCTURE–ACTIVITY RELATIONS
Clozapine belongs to the group of tricyclic antipsychotics known as the dibenzepines. This group is
characterized by a seven-member central ring (Figure 28–1). The antipsychotic dibenzepines
include a loxapine-like group of compounds (the dibenzoxazepines) and a clozapine-like group (thePrint: Chapter 28. Clozapine
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dibenzodiazepines). Substitutions in the clozapine group resulted in the development of both
quetiapine and olanzapine.
FIGURE 28–1. Chemical structure of clozapine.
PHARMACOLOGICAL PROFILE
Animal behavioral models have been of limited use in schizophrenia. The primary problem is that
there is not a well-accepted animal model for psychopathology in schizophrenia. A number of
models—including latent inhibition of the conditioned response, prepulse inhibition, and P50
gating—are being studied, and these models suggest unique properties of clozapine that may be
clinically relevant. The models used in the development of antipsychotics over the years were
empirical models based on dopamine blockade. Criteria for antipsychotic action included the ability
of the agent to cause catalepsy at higher doses as well as its antagonism of stereotypies in animals
resulting from the administration of amphetamine. Although clozapine meets neither of these
criteria, it does block the conditioned avoidance response, suggesting that it has antipsychotic
activity.
One model of schizophrenia is based on the theory that individuals with the disorder are impaired in
their ability to filter out irrelevant internal or external stimuli. Clinically, patients may describe the
experience of being inundated by an excess of stimulation. One method of studying impairments of
gating employs a paradigm known as prepulse inhibition (PPI) of the startle reflex. PPI uses a
stimulus, such as a puff of air aimed at the eye, that evokes a startle response. The prepulse is a
weak stimulus that is presented just prior to the stimulus that elicits a startle. The insertion of the
prepulse inhibits the startle response. The usefulness of this model is supported by the observation
that in comparison with healthy control subjects, patients with schizophrenia (as well as those with
other psychiatric illnesses) demonstrate decreased PPI. Moreover, these PPI deficits correlate with
the severity of thought disorder and psychotic symptoms (Braff et al. 1999).
The PPI model can be used in both rodents and humans. Moreover, as a model of gating
disturbances, it has face validity. In rodents, dopamine receptor agonists, serotonin2 (5-HT2)
receptor agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, and isolation rearing can
result in impairment of PPI (Geyer et al. 2001). Clozapine—as well as other
antipsychotics—restores PPI in rats treated with apomorphine (Swerdlow and Geyer 1993) as well
as rats treated with the NMDA antagonist ketamine (Swerdlow et al. 1998). In addition, clozapine
restores PPI in rats exposed to social isolation (Varty and Higgins 1995). In patients with
schizophrenia, clozapine was superior to typical antipsychotics in normalizing PPI (Kumari et al.
1999).
PHARMACOKINETICS AND DISPOSITION
Peak plasma levels of clozapine are reached approximately 2 hours after oral administration. The
elimination half-life is about 12 hours. Patients will usually reach steady-state plasma
concentrations in less than 1 week. The coadministration of highly protein-bound drugs may lead to
increased free clozapine levels, although the total (free plus bound) levels may be unchanged.Print: Chapter 28. Clozapine
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Clozapine’s volume of distribution is lower than that of other antipsychotic drugs but is nonetheless
large, with a mean of 2.0–5.1 L/kg (range: 1.0–10.2 L/kg).
Clozapine undergoes extensive first-pass metabolism in the liver and gut. Although clozapine is
predominately metabolized by cytochrome P450 (CYP) 1A2, CYP2D6 and CYP3A3 also contribute
(Buur-Rasmussen and Brosen 1999).
Plasma concentrations of clozapine average about 10–80 ng/mL per mg of drug given per kg of
weight. Thus, a typical daily dose of 300–400 mg (about 5 mg/kg) is associated with levels ranging
between 200 and 400 ng/mL. However, there is considerable variability among patients treated
with clozapine. This was demonstrated by Potkin et al. (1994), who administered 400 mg of
clozapine to a group of patients and found a 45-fold variation in plasma concentrations. A number
of studies focused on the clinical implications of this variation in plasma concentrations. These
studies, when taken together, indicate that patients are more likely to do well when their levels are
greater than 350 ng/mL (Bell et al. 1998; Kronig et al. 1995; D. D. Miller 1996; D. D. Miller et al.
1994; Potkin et al. 1994). If patients have not responded after 6 weeks with a plasma level of 250
ng/mL, the clinician should increase the level to approximately 350 ng/mL. High levels, such as
600 ng/mL, are not associated with a greater likelihood of improvement than are moderate levels,
and they may be associated with a higher incidence of side effects. Therefore, patients with high
levels and side effects may benefit from having the dosage reduced. In interpreting plasma
concentrations of clozapine, it is important for clinicians to consider if the laboratory is reporting
just the parent drug or clozapine plus norclozapine. If it is the combination, levels will be higher.
MECHANISM OF ACTION
The explanation for clozapine’s unique effectiveness remains controversial. As mentioned earlier,
clozapine was the first agent to challenge the dogma that antipsychotic efficacy required high
levels of EPS. There are a number of characteristics of clozapine that could explain how it can
reduce psychosis without causing EPS.
Clozapine’s low incidence of EPS could be explained by its low dopamine2 (D2) receptor occupancy
at therapeutic doses. Studies using positron emission tomography (PET) with selective D2 receptor
ligands, such as raclopride, make it possible to determine the proportion of D2 receptors that are
occupied by an antipsychotic in a particular individual at a particular time. These studies found that
conventional antipsychotics are effective when approximately 80% of receptors are occupied
(Farde et al. 1992). Higher levels of occupancy may increase EPS, but they do not result in greater
efficacy. In contrast, clozapine is effective when it occupies 20%–67% of D2 receptors. This
observation may explain two important properties of clozapine: its tendency to cause very little EPS
and the suggestion that its effectiveness is associated with something more than just D2 receptor
occupancy.
It has also been suggested that clozapine’s properties are associated with its combination of
relatively low affinity for D2 receptors and high affinity for other receptors, including 5-HT2A,
5-HT1C, adrenergic, and cholinergic receptors. Most of the attention has focused on clozapine’s high
ratio of 5-HT2A to D2 receptors, because this property is shared by nearly all of the other
second-generation antipsychotics (SGAs). Moreover, serotonin can modulate dopamine neurons in
the substantia nigra, which in turn may decrease EPS. Clozapine also has a very high affinity for the
dopamine4 (D4) receptor. The D4 receptor is widely distributed in the cortex and less so in striatal
areas. However, other agents with high D4 receptor activity have failed to demonstrate
antipsychotic activity.
Another theory—supported by both Seeman (2002) and Kapur and Seeman (2001)—hypothesizes
that the lack of EPS with clozapine and other SGAs is related to their fast dissociation from the D2
receptor. Conventional antipsychotics tend to bind more tightly to dopamine receptors than to
dopamine itself. Nearly all of the SGAs, including clozapine, bind more loosely and tend to come off
the receptor more readily in the presence of dopamine. As a result, these newer agents may block
these receptors more transiently, coming off the receptor to permit more normal dopaminePrint: Chapter 28. Clozapine
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transmission. Another approach to understanding the mechanism of action of clozapine is based on
the finding that acute administration of conventional antipsychotic drugs to rodents leads to an
increase in the firing of dopamine neurons in the substantia nigra and the ventral tegmental area.
However, after 3 weeks of treatment with these agents, there is a decrease in the number of firing
dopamine neurons in both of these areas. This prolonged decrease in firing has been referred to as
depolarization inactivation. Inactivation in the ventral tegmental area has been used to explain the
sustained therapeutic effectiveness of these agents, and inactivation in the substantia nigra has
been used to explain EPS. Clozapine—along with other SGAs—causes inactivation in the ventral
tegmental area, but not in the substantia nigra (Chiodo and Bunney 1983), suggesting that these
agents have different effects in these two brain areas.
INDICATIONS AND EFFICACY
Acute Schizophrenia and Schizoaffective Disorder
Because of its side-effect profile, clozapine is the only available antipsychotic that should not be
administered as a first-line agent for schizophrenia or schizoaffective disorder. However, this does
not mean that clozapine is ineffective in these disorders. Early trials comparing clozapine with
haloperidol and chlorpromazine indicated that clozapine was at least as effective as the other
agents for acutely psychotic patients. In the chlorpromazine comparison (Fischer-Cornelssen and
Ferner 1976), the advantages were most apparent for the more severely ill patients. The
comparison with haloperidol (Honigfeld et al. 1984) was carried out in a more severely ill group of
patients and found a substantial advantage for clozapine. A report by Shopsin et al. (1979)
compared clozapine, chlorpromazine, and placebo in 31 newly admitted patients with acute illness.
Clozapine was found to be superior to both chlorpromazine and placebo. Taken together, these
early studies indicate that clozapine is effective for treatment of a broad range of individuals with
acute psychosis. In China, for example, clozapine is commonly prescribed as a first-line
antipsychotic for acute schizophrenia.
Treatment-Refractory Schizophrenia
As noted above, early studies suggested that clozapine was particularly effective in patients with
more severe treatment-refractory forms of schizophrenia. This was important when it was
discovered that clozapine was associated with a risk of agranulocytosis. Given that clozapine was
viewed as an agent that might be helpful for patients who had failed to respond to other
antipsychotics, a study was designed to test whether there was a role for clozapine in this
population. The result was the design of a multicenter study comparing clozapine with
chlorpromazine in severely ill patients with treatment-refractory schizophrenia (Kane et al. 1988).
Treatment-refractory illness was characterized on the basis of a history of drug nonresponsiveness
and a failure to improve during a 6-week trial of up to 60 mg of haloperidol. Clozapine resulted in
greater improvement in nearly every dimension of psychopathology. Clozapine-treated patients
were less depressed and less anxious. In addition, they demonstrated substantial improvements in
Brief Psychiatric Rating Scale (BPRS) items that measured emotional withdrawal, motor
retardation, and blunted affect. These items may reflect the negative symptoms of schizophrenia
and suggest that clozapine is more effective than conventional antipsychotics in treating negative
symptoms. Thirty percent of the clozapine-treated patients met stringent improvement criteria,
compared with only 4% of those treated with chlorpromazine. However, this study was only 6
weeks in duration and may have underestimated the proportion of patients who improved with
clozapine treatment.
Other studies suggest that the proportion of patients improving with clozapine treatment will be
higher if clozapine is continued for a longer time. For example, a 16-week trial by Pickar et al.
(1992) found a 38% improvement rate. A more recent report (Kane et al. 2001) found that 60% of
patients with treatment-refractory illness improved after a 29-week trial on clozapine.
The early studies of clozapine focused on individuals who had been unresponsive to first-generation
antipsychotics (FGAs) and had subsequently been switched to clozapine. There are a number ofPrint: Chapter 28. Clozapine
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reasons to suspect that the proportions of patients responding to clozapine are lower if patients had
previously been treated with other SGAs. First, failure to respond to an FGA may result from an
inability to tolerate an adequate dose because of EPS. In addition, a number of studies suggest that
patients who fail to respond to FGAs may improve if they are changed to an SGA other than
clozapine. However, comparisons of clozapine and SGAs have yielded results that can be difficult to
interpret. For example, some studies comparing risperidone (Bondolfi et al. 1998) or olanzapine
(Bitter et al. 2004; Tollefson et al. 2001) with clozapine in patients with treatment-refractory
illness suggested that these agents had similar efficacy. Other studies (Azorin et al. 2001; Breier et
- 1999) suggested advantages for clozapine. Volavka et al. (2002) compared clozapine,
risperidone, olanzapine, and haloperidol in patients with suboptimal responses to FGAs. The study
showed advantages for the SGAs over haloperidol on total Positive and Negative Syndrome Scale
(PANSS) scores. Effect sizes for improvement were largest for olanzapine and clozapine, smallest
for haloperidol, and intermediate for risperidone. Clozapine was more effective than the other
medications for negative symptoms.
Two large trials compared clozapine with SGAs in patients with treatment-resistant illness. In the
United States, the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) compared clozapine with risperidone, olanzapine, or quetiapine
in patients with schizophrenia who had failed to respond in an earlier phase of the study because of
a lack of efficacy (Stroup et al. 2006). Clozapine was administered open label, whereas the other
antipsychotics were administered double-blind. Patients assigned to clozapine had the lowest
discontinuation rates, with 56% of patients on clozapine discontinuing treatment, compared with
71% on olanzapine, 86% on risperidone, and 93% on quetiapine. Clozapine-treated patients also
showed greater symptom improvements than those receiving the other agents. Another trial in the
UK, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study—band 2 (CUtLASS-2)
(Lewis et al. 2006), randomly assigned 136 patients who had responded poorly to two prior
antipsychotics to either clozapine or an SGA selected prior to the randomization. Patients who
received clozapine demonstrated greater improvement than those on the comparison drugs.
Chakos et al. (2001) conducted a review and meta-analysis of studies comparing the efficacy and
tolerability of clozapine with that of FGAs and other SGAs in treatment-resistant schizophrenia.
Clozapine was superior to FGAs, but findings for other SGAs were inconclusive. (However, this
study was carried out prior to CATIE and CUtLASS-2, both of which supported superior efficacy for
clozapine.) Despite clozapine’s advantages, a significant number of patients with
treatment-refractory illness do not respond to clozapine. The Chakos et al. (2001) meta-analysis
found that in most studies, fewer than half of the patients with treatment-resistant illness
responded to clozapine. Additionally, many patients who do respond favorably to clozapine continue
to have significant symptoms that impair their functioning in the community.
Taken together, these studies—particularly CATIE and CUtLASS-2—indicate that clozapine has an
important role in the treatment of patients who have failed to respond to either FGAs or other SGAs.
Clozapine’s advantages are clearest in patients who have failed to respond to FGAs but are still
apparent in those who have had an inadequate response to other SGAs. Because clozapine is
associated with a risk of agranulocytosis and other side effects (summarized later in this chapter
under “Side Effects and Toxicology”), patients should probably receive a trial of one or two other
SGAs before receiving a trial of clozapine. Clinical guidelines (Lehman et al. 2004a, 2004b; Marder
et al. 2002; A. L. Miller et al. 2004) differ to a minor degree on the number of trials that should
precede a trial with clozapine, but most recommend at least two agents, one of which is an SGA.
There is a consensus that patients should not be considered to have treatment-refractory illness
until they have received an adequate trial with clozapine.
Hostile and Aggressive Behavior in Schizophrenia
Clozapine may have other advantages for patients with schizophrenia. A number of studies suggest
that clozapine may decrease hostility and aggression, compared with other agents. In a study of
157 inpatients (Citrome et al. 2001), clozapine resulted in greater reductions in the hostility itemPrint: Chapter 28. Clozapine
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from the PANSS than did the FGAs and other SGAs. A study by Chengappa et al. (2003) found
significant reductions in the rates of seclusion and restraint in schizophrenia patients who received
clozapine during the first 3 years after its introduction. Other randomized trials have consistently
found that patients treated with clozapine experience less hostility and fewer aggressive behaviors
than patients on comparators (Essock et al. 2000; Kane et al. 1988). These findings suggest that
clozapine may be of particular benefit to patients with treatment-refractory illness who
demonstrate hostile and aggressive behaviors.
Schizophrenia Patients at High Risk for Suicide
Clozapine may also be a preferred agent for patients with schizophrenia who are at a higher risk for
suicide. Large epidemiological studies have found that mortality from suicide is reduced among
individuals taking clozapine (Reid et al. 1998; Walker et al. 1997). Meltzer and Okayli (1995)
followed patients who were changed to clozapine and found a reduction in the number of serious
suicide attempts as well as in expressed depression and hopelessness. The most convincing study
was a comparison of clozapine and olanzapine in 980 patients with schizophrenia who were
considered at risk for suicide. In that study, clozapine was more effective in reducing the risk of
suicide (Meltzer 2002).
Clozapine may also have advantages for patients with polydipsia–hyponatremia syndrome (Canuso
and Goldman 1999). These patients tend to intoxicate themselves through excessive water
drinking. Hyponatremia may result in seizures.
Schizophrenia With Comorbid Substance Abuse
Although the effectiveness of clozapine in patients with comorbid substance abuse has not been
demonstrated in randomized, controlled trials, there is some supporting evidence from naturalistic
studies. One retrospective study (Green et al. 2003) found that patients treated with clozapine
were more likely than those treated with risperidone to abstain from alcohol and cannabis use. A
prospective study (Green et al. 2007) found that patients treated with clozapine were often able to
reduce their substance abuse. This finding was supported by other prospective studies (Brunette et
- 2006; Drake et al. 2000), indicating that clozapine is effective for reducing substance abuse.
Supplemental Antipsychotic Treatment in Partial Responders to Clozapine
A number of studies have evaluated augmentation strategies for individuals who are partial
responders to clozapine. Paton et al. (2007) reviewed open and randomized, controlled trials in
which partial responders to clozapine received supplemental treatment with another antipsychotic.
Among the controlled trials, three used risperidone as the supplementing agent and one used
sulpiride. The two studies with a duration of greater than 10 weeks favored augmentation, whereas
the briefer studies did not.
Maintenance Therapy in Schizophrenia
Clozapine use has largely been confined to patients with treatment-refractory schizophrenia. As a
result, clozapine has not been studied in the traditional relapse prevention trial in which patients
who are stable are randomly assigned to either clozapine or a comparator. Nevertheless, there are
substantial data supporting the long-term effectiveness of clozapine. Breier et al. (2000) evaluated
the outcomes of 30 patients with schizophrenia who were treated with clozapine for 1 year.
Patients taking clozapine experienced fewer relapses and rehospitalizations than they did in the
year prior to being changed to clozapine. A study in the state hospitals in Connecticut compared
patients who were assigned to clozapine with patients who were maintained on their usual
antipsychotics (Essock et al. 2000). Although clozapine did not result in a greater likelihood of
hospital discharge, patients who were treated with clozapine had a higher likelihood of remaining in
the community following discharge. This finding supports the observation that clozapine is
associated with a reduced risk of relapse, compared with a conventional antipsychotic.
A study from the U.S. Department of Veterans Affairs (VA) Cooperative Studies Program compared
haloperidol and clozapine in patients with treatment-refractory schizophrenia (Rosenheck et al.Print: Chapter 28. Clozapine
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1997). This study was not designed as a relapse prevention trial, but rather as a comparison of the
two agents in individuals who were poor responders to conventional therapy. However, the 1-year
study is somewhat informative about the usefulness of the two drugs in patients living in the
community. Fifty-seven percent of the patients taking clozapine completed the study, compared
with only 28% of the patients taking haloperidol (P <0.001). Using 20% improvement on the
PANSS as the criterion for response, the investigators found that 42% of patients treated with
clozapine and 31% of patients treated with haloperidol were responders (P = 0.09). In addition,
clozapine-treated patients had fewer mean days of hospitalization (143.8 days) compared with
haloperidol-treated patients (168.1 days; P = 0.03).
These studies are encouraging for a number of reasons. First, the VA study (Rosenheck et al. 1997)
addressed the issue of whether clozapine’s advantage in relapse prevention is only an effect of the
monitoring system for agranulocytosis—that is, does the requirement for weekly blood tests act as
a means of assuring compliance? Because the clozapine-treated and haloperidol-treated patients
had the same blood monitoring, the advantage of clozapine appears to be an intrinsic effect of the
drug. Also, clozapine is a drug that has its own discomforting side effects, including sedation,
hypersalivation, constipation, and hypotension. These studies indicate that patients in long-term
treatment are able to tolerate these effects.
Mania in Bipolar Disorder
Given that all available antipsychotics are effective in reducing manic symptoms, it is not surprising
that clozapine is effective in bipolar mania. However, accumulating evidence suggests that
clozapine is particularly effective for manic symptoms that are not responsive to other agents.
McElroy et al. (1991) were among the first to observe clozapine’s unique effects in patients with
bipolar disorder. Subsequent studies have confirmed clozapine’s effectiveness as monotherapy and
as a supplementation medication for mania. In an open-label randomized trial in acutely manic
patients (Barbini et al. 1997), clozapine was as effective as chlorpromazine and had a more rapid
onset. Suppes et al. (1999) randomly assigned patients with schizoaffective and bipolar illnesses to
either supplemental clozapine or treatment as usual during a 1-year open-label trial. Among both
schizoaffective and bipolar patients, those treated with clozapine demonstrated greater
improvements. Other prospective open-label studies (Calabrese et al. 1996; Green et al. 2000)
confirmed clozapine’s effectiveness in refractory bipolar illness. Although the available data support
clozapine’s effectiveness in mania, none of these trials has been double blind.
Depression With Psychotic Features
Limited evidence suggests that clozapine is effective as monotherapy and as an adjunctive
treatment for patients with major depression with psychotic features. This evidence is currently
confined to case reports with relatively small numbers of cases (Ranjan and Meltzer 1996;
Rothschild 1996).
Psychosis in Parkinson’s Disease
Psychosis with delusions and hallucinations occurs in approximately 25% of patients with
Parkinson’s disease (Wolters and Berendse 2001). These symptoms frequently appear in patients
who are receiving dopaminomimetic drugs but may also occur as a result of a cholinergic deficit.
Three double-blind studies (French Clozapine Parkinson Study Group 1999; Jones and Stoukides
1992; Parkinson Study Group 1999; Pollak et al. 2004) found that clozapine at doses as low as
25–50 mg was effective in reducing psychotic symptoms. Moreover, these doses were not
associated with an increase in tremor and rigidity. A report from the American Academy of
Neurology (Miyasaki et al. 2006) recommended clozapine as a preferred agent for psychosis in
Parkinson’s disease.
Schizophrenia in Children and Adolescents
Two randomized, controlled trials from the NIMH have evaluated the effectiveness of clozapine in
childhood-onset schizophrenia. The first (Kumra et al. 1996) compared clozapine and haloperidol inPrint: Chapter 28. Clozapine
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individuals with a mean age of about 14 years who had done poorly on FGAs. Clozapine was
superior for both positive and negative symptoms. A more recent double-blind study (Shaw et al.
2006) compared clozapine and olanzapine in subjects with a mean age of about 12 years. The
results from this study were less clear. Although there were substantial differences favoring
clozapine, the differences were only statistically significant for negative symptoms. The small
sample (n = 12 for clozapine and n = 13 for olanzapine) was a limiting factor for obtaining
statistical significance. Both studies found that this younger population appeared to be particularly
vulnerable to clozapine’s side effects. Nevertheless, these studies suggest an important role for
clozapine in younger patients with schizophrenia with refractory symptoms.
SIDE EFFECTS AND TOXICOLOGY
Hematological Effects
The side effects of clozapine make it one of the most challenging medications for psychiatrists to
prescribe. The main factor that limits its use is the potential serious side effect of agranulocytosis.
Agranulocytosis is defined as a drop in absolute neutrophil count (ANC) to levels below 500/mm3 .
In 1975, there were 17 cases of agranulocytosis in Finland, and widespread use of the medication
for the treatment of schizophrenia was temporarily halted (Amsler et al. 1977; de la Chapelle et al.
1977). Agranulocytosis is a potentially lethal side effect that occurs in less than 1% of patients
treated in the United States (Alvir et al. 1993). In the United States, all patients who are taking
clozapine are entered into a national registry. Through the national registry, patients are prescribed
the medication only if their WBC count shows no signs of clinically meaningful suppression
(Honigfeld 1996). In a review of the morbidity and mortality of clozapine-treated patients
(Honigfeld et al. 1998) over a 5-year period, 99,502 patients were registered through the Clozaril
National Registry. Of these, 2,931 (2.95%) patients developed leukopenia (WBC count =
3,500/mm3 ), and 382 (0.38%) patients developed agranulocytosis (ANC <500/mm3 ). Twelve of
the cases of agranulocytosis (0.012%) were fatal. These findings contrast with the 1%–2%
cumulative incidence expected from the premarketing experience with clozapine. In the United
States, 1,743 patients received the drug in premarketing trials. In addition, this estimate was based
on trials in Europe performed in the 1970s and 1980s (Honigfeld et al. 1998). The encouraging
report by Honigfeld et al. (1998) supports the monitoring system for clozapine as an adequate
measure to prevent agranulocytosis.
The rates of clozapine-induced agranulocytosis in other parts of the world are similar to the rate in
the United States (Gaszner et al. 2002; Helmchen 1989; Jungi et al. 1977). However, it is unclear
what the rates are in parts of the world where generic medication is used and no registry exists.
The onset of agranulocytosis occurs most often during the first 6 months of treatment and is usually
marked by a gradual fall in WBC count, often over several weeks. A precipitous fall within 1 week
can occur but is much less common (Honigfeld et al. 1998). Thus, patients must be monitored with
weekly blood cell counts for the first 6 months and every 2 weeks thereafter. Various investigators
have tried to determine whether there are predictors of clozapine-induced agranulocytosis. Our
group and others examined the possibility that agranulocytosis is immune mediated and thus
preceded by eosinophilia. However, such a relationship has not been supported by our study or by
others (Ames et al. 1996; Hummer et al. 1994). It has been observed that patients of Ashkenazi
Jewish origin (Lieberman et al. 1990) are overrepresented among the cases of agranulocytosis,
prompting researchers to examine whether there may exist a genetic predisposition for a particular
immunohistocompatibility complex and/or immune response (Dettling et al. 2001). No clear
relationship has been found, although speculations about human leukocyte antigen (HLA) types
have been made, particularly HLA B38, in American Jews of Ashkenazi origin who develop
agranulocytosis (Lieberman et al. 1990). In contrast, one Israeli study, composed of patients with
non-Ashkenazi background, did not support this relationship (Meged et al. 1999).
When clozapine treatment is discontinued upon identification of marked leukopenia, patients
usually recover within 14–24 days and without any long-term consequences. However,
rechallenging patients who have experienced agranulocytosis almost always leads to reoccurrencePrint: Chapter 28. Clozapine
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of the problem. The onset of the second episode is more aggressive than the first. In nine patients
who were known to be rechallenged, the average time to onset was 10 weeks shorter (14 weeks)
than the first episode (24 weeks) (Safferman et al. 1992). Agranulocytosis has been successfully
treated by discontinuing the medication, providing supportive measures, and administering
granulocyte colony–stimulating factor, a medication that is commonly prescribed to patients with
medical illnesses that precipitate WBC count suppression (Raison et al. 1994; Weide et al. 1992;
Wickramanayake et al. 1995).
When clozapine first appeared on the market, mandatory monitoring of WBC levels each week was
recommended for all patients taking clozapine. In January 2006, Novartis and the FDA notified
clinicians of modifications to the recommended monitoring schedule for patients receiving
clozapine (available at: www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf).
Under the new monitoring guidelines, when a patient begins clozapine treatment, he or she must
have a baseline WBC count of no less than 3,500/mm3 and an ANC of no less than 2,000/mm3 .
Weekly WBC and ANC levels must be taken for 6 months, at which time the frequency can be
reduced to every 2 weeks, provided that treatment and monitoring have not been interrupted and
WBC counts and ANCs have been within acceptable ranges. After 1 year, monitoring can be reduced
to monthly blood tests. There are specific recommendations for intensified monitoring following
discontinuation of clozapine therapy, particularly if therapy is interrupted because of blood
dyscrasias.
Cardiac Effects
Well-known side effects of clozapine on the cardiovascular system include tachycardia and
orthostatic hypotension. Tachycardia is thought to be attributable to the anticholinergic activity of
the medication, whereas hypotension is due to -adrenergic blockade. Reports of
clozapine-associated myocarditis and cardiomyopathy have raised concern that clozapine may be
associated with other forms of cardiovascular toxicity. In January 2002, Novartis reported that
there had been 213 cases of myocarditis, 85% of which occurred at recommended dosages of
clozapine within the first 2 months of therapy. The presence of eosinophilia in many of the reported
cases indicates that an immunoglobulin E (IgE)–mediated hypersensitivity reaction may be
involved (Killian et al. 1999). Novartis (2002) also reported 178 cases of clozapine-associated
cardiomyopathy, 80% of which occurred in patients younger than 50 years. Almost 20% of the
incidents resulted in death, an alarming figure that may reflect delay in diagnosis and treatment.
The detection of cardiac toxicity is particularly challenging, because its manifestations
(tachycardia, fatigue, and orthostatic hypotension) are frequently observed in clozapine-treated
patients, particularly when alterations in dosage are made (Lieberman and Safferman 1992). The
poor specificity of signs for cardiac toxicity demands that patients with any personal or family
history of heart disease be identified, and the threshold for medical evaluation of patients
developing respiratory and cardiovascular symptoms must be low (Wooltorton 2002). The etiology
of the myocarditis and cardiomyopathy remains unclear at this time.
Sudden death has been associated with both conventional antipsychotic treatment and treatment of
patients with clozapine. A thorough review of the literature examining reports from 1970 to 2004 of
cardiac side effects in patients on clozapine concluded that clozapine is associated with a low risk
(0.015%–0.188%) of potentially fatal myocarditis or cardiomyopathy (Merrill and Goff 2005). The
cause of the sudden death is unclear; it is probably secondary to ventricular arrhythmia and may be
associated with sudden increases in clozapine dosage.
Double-blind clinical trials of antipsychotic medications given to manage agitated behavior in
elderly patients with dementia supported the notion that a greater risk of sudden death is
associated with use of these medications in older populations. As a result, the labeling of all
antipsychotics, including clozapine, was updated to include a boxed warning of this risk. In 2006,
the FDA issued a reminder that off-label use of clozapine for dementia-related psychosis in elderly
patients is associated with an increased risk of sudden death. It is extremely important when
raising the dosage of clozapine that incremental changes do not exceed 50 mg every 2 days (WormPrint: Chapter 28. Clozapine
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et al. 1993). Clinicians must weigh the potential superb clinical benefit of clozapine against these
cardiac risks. We recommend that an electrocardiogram be performed prior to initiation of
clozapine.
For hypotension caused by clozapine, we also recommend a slow upward titration of the medication
and monitoring of orthostatic vital signs during the first weeks of therapy. Patients should be
educated about the risk of orthostatic hypotension and should be taught to rise slowly from supine
positions. Concomitant treatment with -blocking agents may be necessary for persistent
tachycardia. However, the use of -blockers may exacerbate the hypotensive effects of clozapine
and should be used cautiously.
Metabolic Effects
Weight Gain
The metabolic side effects of clozapine are prominent (Henderson 2001; D. A. Wirshing et al. 1998,
1999). Weight gain has been observed in both premarketing and postmarketing trials (Henderson
2001; Simpson and Varga 1974). In patients observed in various clinical trials in our laboratory, the
average weight gain in a 6-month period with clozapine treatment was 6.9 ± 0.8 kg. Allison et al.
(1999) performed a meta-analysis of the weight-gain data in short-term trials of medications. The
average weight gain observed with clozapine was 4.45 kg, which exceeded the weight gain
observed with all of the other medications in the study, including the conventional agent
thioridazine (3.19 kg), a medication known for its weight-gain liability. The weight gain observed
with clozapine seems to occur for a prolonged period of time—up to 40 weeks. In one naturalistic
study, Henderson (2001) observed patients in a clozapine clinic for 5 years and noted weight gain
occurring for up to 46 months in some patients.
Body mass index (BMI; expressed in kg/m2 ), which takes into account a patient’s weight relative to
his or her height, and waist-to-hip ratio (WHR) are important parameters to measure, because they
both are predictors of cardiovascular risk. Obesity is defined as a BMI of 27 kg/m2 . Waist
measurements of 102 cm (or >40 inches) in men and 88 cm (or >35 inches) in women are
indicative of the metabolic syndrome and are strong predictors of diabetes and other medical
complications, including heart disease and sleep apnea (D. A. Wirshing et al. 2002a, 2002c).
Deposition of weight in the abdomen, in excess of weight on the hips (highly correlated with the
development of diabetes), can also be assessed with the WHR. Frankenburg et al. (1998) examined
BMI and WHR in 42 patients treated with clozapine. The majority of patients experienced increases
in both of these parameters. In females, the authors observed an average WHR of 0.8 after 37
months of clozapine therapy, with a significant average increase in BMI from 23.2 to 29.1 kg/m2 (P
= 0.001). Male subjects also gained weight and body mass. After 39 months of clozapine therapy,
the average WHR in males was 0.93, with a significant average increase in BMI, from 26.4 to 29.7
kg/m2 (P <0.001). Both males and females in the sample became obese.
Phase 2 of CATIE provided an opportunity to compare weight gain among patients assigned to
clozapine, olanzapine, risperidone, and quetiapine (McEvoy et al. 2006). The numbers of patients
assessed in the analyses were small, with only 45 patients in the clozapine group, 17 in the
olanzapine group, 14 in the quetiapine group, and 14 in the risperidone group. Although the
differences in weight gain among these agents were not statistically significant, they were
interesting, with patients on clozapine gaining a mean of 0.5 lb per month, compared with 1.0 lbs
on olanzapine, –0.4 lb on quetiapine, and 0.5 lb on risperidone.
Researchers have tried to determine predictors of clozapine-associated weight gain. Of concern is
that adolescents may be among the most vulnerable to this side effect. Theisen et al. (2001a,
2001b) reported that the prevalence of obesity in adolescent patients taking clozapine was 64% (n
= 69). Others have speculated that clozapine-associated weight gain may be genetically
determined, and several candidate genes are being explored (Basile et al. 2001). Numerous
neurotransmitters and receptors are affected by clozapine. Specifically, we noted a logarithmicPrint: Chapter 28. Clozapine
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association between clozapine-associated weight gain and its effect on the histamine1 (H1) system
(D. A. Wirshing et al. 1999). Other researchers have speculated that clozapine interferes with
metabolism by interrupting the feedback loop between leptin, a hormone produced by adipose cells
that should signal satiety to the brain, and neuropeptide Y, a peptide that is thought to stimulate
appetite. Instead, patients treated with clozapine have been observed to have elevated levels of
leptin (Bromel et al. 1998; Kraus et al. 1999; Melkersson and Hulting 2001).
Diabetes
The weight gain observed with clozapine can place patients at risk for significant health problems.
Diabetes is naturally the most concerning potential sequela of this weight gain. Numerous case
reports have linked clozapine with new-onset diabetes (D. A. Wirshing et al. 1998). In Henderson’s
(2001) naturalistic study of 81 patients observed over a 5-year time period, 36.6% of the patients
developed diabetes. The prevalence of diabetes in the United States is estimated to be
approximately 7%, with another 7% of cases undiagnosed. Koller et al. (2001) published the
largest series of case reports submitted voluntarily to the FDA MedWatch Program. The report
revealed that there were 2,424 new-onset cases, 54 of which were cases of diabetic exacerbations
and 80 of which were cases of diabetic ketoacidosis, a potentially life-threatening condition. The
average age of the patients in the report was 40 ± 12 years, and the male-to-female ratio was 2:1.
Diabetes usually occurred within 6 months of starting clozapine. In our review of the peer-reviewed
case literature, there seemed to be a preponderance of African Americans and males (D. A.
Wirshing et al. 1998). As noted by Popli et al. (1997), there is a higher prevalence of
non-insulin-dependent diabetes in African Americans compared with Caucasians in the United
States, and this is likely the result of both nutritional factors and impaired access to health care.
The significance of the overrepresentation of males is unclear but may reflect some hormonal
interaction with glucose metabolism (Andersson et al. 1994)—or, more likely, selection bias, in
which fewer women are placed on novel drugs.
We reviewed the charts of 590 patients taking antipsychotic medications and found statistically
significant shifts in blood glucose among patients treated with clozapine and olanzapine, but not
among patients treated with risperidone and quetiapine (D. A. Wirshing et al. 2002a). Sernyak et al.
(2002) published a study examining the records of more than 30,000 patients in a VA database and
found that the prevalence of the diagnosis of diabetes was higher among patients treated with
novel antipsychotic medications than among patients treated with conventional agents. In
particular, clozapine, olanzapine, and quetiapine were associated with much higher rates of
diabetes than were conventional agents for all age ranges, whereas risperidone was not associated
with a higher diabetes prevalence. The etiology of diabetes in clozapine-treated patients remains
unclear. The most likely mechanism is that clozapine-associated weight gain causes an increase in
insulin resistance.
However, weight gain is often, although not always, seen in patients treated with novel
antipsychotics who develop new-onset diabetes, although a literature review spanning the years
1975–2006 by Newcomer (2006) concluded that antipsychotic medication–associated adiposity is
the main culprit in the development of diabetes. Thus, one potential mechanism of diabetes
induction is an increase in adiposity that, in turn, leads to insulin insensitivity, glucose intolerance,
and, if sufficiently severe, diabetes. This notion is supported by results from a small study by Yazici
et al. (1998), who found that clozapine increased blood glucose, insulin, and C peptide, which
suggests that glucose intolerance was due to increased insulin resistance. It is also speculated that
clozapine directly affects beta cells of the pancreas (D. A. Wirshing et al. 1998). Recent evidence
from animal studies suggests that clozapine dysregulates glucose metabolism by directly impairing
the reaction of islet cells to glucose stimulation (Sasaki et al. 2006). Thus, the etiology of diabetes
may be independent of adiposity, instead reflecting a direct effect of muscarinic blockade on the
pancreatic islet cells.
Much of the information concerning the association of clozapine and diabetes mellitus is based on
case reports, retrospective chart reviews, naturalistic studies, and cross-sectional studies. AlthoughPrint: Chapter 28. Clozapine
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definitive studies have yet to be reported, the evidence is growing that clozapine may significantly
impair glucose metabolism and increase the risk of diabetes in patients with schizophrenia. Diabetic
ketoacidosis, although occurring infrequently, is of concern because of the risk of death. Patients
treated with clozapine should be routinely screened for diabetes and other metabolic abnormalities,
including raised lipid levels. Patients with risk factors for diabetes should be monitored more
closely. Reports and clinical experience suggest that in a case of atypical antipsychotic–associated
diabetes or diabetic ketoacidosis, discontinuation of the antipsychotic agent may result in reversal
of the hyperglycemia and diabetes. During clozapine therapy, we recommend monitoring fasting
glucose, cholesterol, and lipids at baseline and every 6 months thereafter.
Prevention of weight gain with clozapine, through nutrition and diet counseling, is recommended.
Caloric restriction and exercise for 30 minutes per day should be recommended. Screening
questions by physicians that we find useful include the following: “Have you noticed if your belt or
pants size has changed?” “Have you noticed an increase in thirst or urinary frequency?” We
strongly recommend weighing patients at each visit and monitoring blood pressure.
Dyslipidemias
Compelling data indicate that clozapine treatment is associated with dyslipidemias. Ghaeli and
Dufresne (1996) performed a retrospective review of data from 24 male and 15 female patients
treated with clozapine and 13 male and 15 female patients treated with typical antipsychotics
(primarily high-potency agents). All patients had been taking these agents for at least 1 year. Age
and gender of the patient, concomitant medications taken, and antipsychotic dosages were used as
covariates in the analyses. Patients taking clozapine demonstrated significantly higher triglyceride
levels than did patients taking typical agents (mean triglyceride level of 264.6 mg/dL for patients
in the clozapine group vs. 149.8 mg/dL for patients taking typical agents; P <0.001). A
retrospective chart review by Gaulin et al. (1999) compared 117 patients taking clozapine with 45
patients taking haloperidol. The study found significant increases in triglyceride levels for both men
and women taking clozapine—a mean increase from 184.6 mg/dL to 273.4 mg/dL for men (P
<0.01) and from 164.9 mg/dL to 223.3 mg/dL for women (P <0.05).
Spivak et al. (1999) reported on a retrospective data from 70 patients being treated with clozapine
for 6 months. They observed a significant increase in triglyceride levels from 69.6 mg/dL prior to
the initiation of clozapine to 77.3 mg/dL just 6 months after initiation (P <0.05). This suggests not
only that clozapine can increase triglyceride levels but also that it can do so over a relatively short
period of time. Another prospective sample of 8 clozapine-treated patients showed an 11%
increase in triglyceride levels (P <0.05) after 12 weeks of clozapine therapy at an average dosage
of 352 mg/day. No significant changes in total cholesterol, low-density lipoprotein (LDL)
cholesterol, or high-density lipoprotein (HDL) cholesterol were observed (Dursun et al. 1999). More
recently, patients who received clozapine in Phase 2 of CATIE demonstrated greater elevations in
both triglycerides and cholesterol than patients on olanzapine, risperidone, or quetiapine (McEvoy
et al. 2006). However, these differences were not statistically significant.
Our group published the first study to compare multiple SGAs (clozapine, risperidone, olanzapine,
and quetiapine) against each other and against the typical agents fluphenazine and haloperidol in
their propensity to affect lipid parameters (D. A. Wirshing et al. 2002a). This study was a
retrospective review of the charts of 215 patients taking antipsychotics (clozapine, olanzapine,
risperidone, quetiapine, haloperidol, or fluphenazine). Lipid data from 2.5 years before and after
initiation of the target antipsychotic were collected. Covariates used in the analysis included age of
patient, duration of antipsychotic treatment, concomitant use of other medications that could affect
lipids, and initial laboratory values. Patients receiving clozapine or olanzapine demonstrated
statistically significant increases in triglyceride levels compared with the other groups. Triglyceride
levels increased by more than 30% for patients taking clozapine or olanzapine, compared with only
a 19% increase for patients taking risperidone; patients taking haloperidol or fluphenazine
developed decreases in triglyceride levels.
The clinical implications of these findings are thought-provoking—for example, could triglyceridePrint: Chapter 28. Clozapine
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elevation account for the beneficial psychiatric effect of these medications through stabilization of
neuronal membranes? Some authors have suggested that changes in triglycerides may actually
affect serotonergic activity. Diebold et al. (1998) postulated that elevated triglyceride levels cause
increases in brain cell membrane fluidity, which in turn lead to increased presynaptic reuptake of
serotonin and decreased postsynaptic serotonergic function. This effect on triglycerides may
enhance the ability of SGA medications such as clozapine to inhibit serotonergic activity and thus
may contribute to their mechanism of action (Kingsbury et al. 2001). Studies have also shown
correlations between elevations in triglyceride levels and changes in mood. For example, increases
in triglyceride levels have been shown to be associated with decreased hostility (Diebold et al.
1998). Spivak et al. (1998) observed that patients taking clozapine who developed increases in
triglycerides also demonstrated decreases in aggression and suicidal behavior in comparison with
patients taking typical antipsychotics, although the difference was not significant (P = 0.07).
Muldoon et al. (1990) reviewed numerous randomized clinical trials that focused on reducing lipid
levels for primary prevention of coronary artery disease. They concluded that the risk of death due
to accidents, suicide, or violence was significantly higher in patients with reduced lipid levels (P =
0.004).
The overall impact of clozapine—and of virtually all other antipsychotic medications—on lipids,
glucose, and obesity may result in an increase in the prevalence of the metabolic syndrome. The
term metabolic syndrome describes a set of risk factors for diabetes, heart disease, and
cerebrovascular disease. According to the National Cholesterol Education Program and American
Diabetes Association criteria (Lamberti et al. 2006; Meyer et al. 2006), metabolic syndrome is
defined as the presence of three or more of the following:
Waist circumference >102 cm for men and >88 cm for women
Fasting blood triglyceride level ≥150 mg/dL
HDL cholesterol level <40 mg/dL for men and <50 mg/dL for women
Blood pressure ≥130 mm Hg systolic or ≥85 mm Hg diastolic
Fasting blood glucose level ≥100 mg/dL
To examine whether the medical consequences of obesity may offset the lifesaving benefits gained
from clozapine’s potentially decreased suicide rate, Fontaine et al. (2001), using mathematical
modeling, estimated that 492 suicide deaths per 100,000 schizophrenia patients would be
prevented over 10 years with the use of clozapine. This was compared with an estimated 416
additional deaths due to antipsychotic-induced weight gain. Although this estimate is
mathematically based and somewhat controversial, these investigators suggest that the lives saved
by clozapine may essentially be offset by the deaths associated with weight gain. Thus, it behooves
physicians prescribing clozapine to monitor weight, glucose, and lipids—we recommend obtaining
measurements at the onset of therapy and every 6 months thereafter—to assist in minimizing the
increased risks for coronary artery disease to which our patients are already predisposed.
In 2004, in response to growing concern that the majority of antipsychotic medications may be
associated with weight gain and other metabolic changes, the American Diabetes Association and
other groups published a set of guidelines for monitoring weight, glucose, and lipids (American
Diabetes Association et al. 2004). Also in 2004, a very comprehensive literature review was
conducted by Marder et al. (2004) to provide guidance to clinicians regarding monitoring of weight,
glucose, lipids, and other parameters of physical health in patients with schizophrenia. Labeling
changes were made for all antipsychotic medications, including clozapine, regarding these
metabolic risk factors.
Seizures
A well-known risk of clozapine treatment is the risk for seizures, which are thought to occur in
5%–10% of patients treated with this medication (Welch et al. 1994). The cause of seizures is
unclear, but it is generally thought that rapid escalations in dosage and possibly high plasma levels
of clozapine may account for the development of seizures (Klimke and Klieser 1995).
Clozapine-associated seizures occur most often at dosages greater than 600 mg/day. ThePrint: Chapter 28. Clozapine
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relationship between clozapine plasma levels and seizures is somewhat inconsistent in the
literature (Simpson and Cooper 1978; Vailleau et al. 1996). Some speculations as to whether the
therapeutic efficacy of clozapine lies in its ability to induce subcortical seizure-like activity have
been put forth by Stevens and colleagues (Stevens 1995; Stevens et al. 1996), who proposed that
the amino acid neurotransmitter system might include naturally occurring anticonvulsants that
suppress signal transduction and ultimately lead to information-processing deficits. According to
this hypothesis, the emergence of electroencephalogram (EEG) abnormalities would correspond to
an increase in signal transduction and improved information processing.
In addition to seizure risk, several researchers have observed that EEG abnormalities, such as
slowing, occur in the majority of patients treated with clozapine (Welch et al. 1994). Slowing may
be attributable to the anticholinergic activity of this medication. Because patients with
schizophrenia often have EEG abnormalities (some estimated rates are 25%), it is unclear whether
a baseline EEG would predict whether a particular patient would develop seizures when given
clozapine. On the basis of their experience with clozapine in treating patients with refractory
illness, Welch et al. (1994) proposed guidelines that recommend increased monitoring for patients
with abnormal baseline EEGs. Our own experience leads us to recommend obtaining a baseline EEG
when initiating clozapine treatment in patients who have a history of possible head injury, loss of
consciousness, or other risk factors for seizures. In cases where EEG abnormalities are found, we
still believe that clozapine treatment is warranted, but it would be best if treatment were initiated
with prophylactic anticonvulsant medication.
The anticonvulsant agents sodium valproate, gabapentin, and topiramate have been used
successfully to treat clozapine-induced seizures (Navarro et al. 2001; Toth and Frankenburg 1994;
Usiskin et al. 2000). Topiramate has an advantage over sodium valproate in that it is associated
with very little weight gain. In cases in our clinic where patients have developed seizures while
taking clozapine, we institute rapid loading with anticonvulsant medication and temporarily
discontinue the clozapine treatment. We then slowly reintroduce and retitrate the clozapine once
the patient is taking an adequate dose of anticonvulsant medication.
Constipation
A truly problematic consequence of clozapine’s anticholinergic activity is its propensity to cause
significant constipation. This can be a difficult side effect to manage in severely mentally ill
individuals, who may not complain about the problem until a medical emergency, such as acute
bowel obstruction, occurs. In institutional settings and in prisons, where patients may have little
access to exercise and where monitoring of patients’ fluid intake is not performed, constipation
from clozapine can be serious or even fatal (Drew and Herdson 1997; Hayes and Gibler 1995; Levin
et al. 2002). Typically, constipation can be avoided by proactive modifications in patients’ diets and
education about adequate fluid intake and exercise. The medical treatment that we favor is
prophylactic therapy with sorbitol. We are less inclined to recommend treatments involving bulking
agents, particularly in the setting of poor fluid intake. High-fiber diets can also be beneficial.
Other Side Effects
Sedation is one of the most difficult and common side effects of clozapine to manage. Patients often
do not want their doses increased in the setting of increased sedation and will complain of sedation
as one of the most annoying consequences of clozapine treatment (Angermeyer et al. 2001). In our
experience, sedation is usually the limiting factor controlling both the rate at which the dosage of
clozapine can be increased and the maximum dosage the patient can tolerate. However, no rigorous
studies have been published.
There have been several reports of respiratory arrest or depression during the early stages of
treatment with clozapine (Novartis 2002). Two of the patients who experienced respiratory arrest
were concomitantly taking benzodiazepines.
Sialorrhea is a commonly reported side effect of clozapine (occurring in over 50% of patients) that
can be problematic for patients. The etiology of sialorrhea is unclear, but the condition does notPrint: Chapter 28. Clozapine
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seem to be caused by the dopamine blockade. It may be mediated through -adrenergic receptor
blockade. Case series and small pilot studies indicate that treating sialorrhea with antiadrenergic
agents, such as the clonidine patch, or anticholinergic agents, such as benztropine and intranasal
ipratropium bromide, may be successful (Calderon et al. 2000). We generally recommend that
patients sleep with a towel on their pillow, as this side effect seems to be most bothersome during
the night. Unfortunately, the use of concomitant antiadrenergic or anticholinergic agents adds to
the potential side-effect burdens of hypotension and constipation, respectively.
Neuroleptic malignant syndrome (NMS), a syndrome of unknown etiology that includes
hyperthermia, autonomic instability, and severe rigidity, has been reported in several patients
treated with clozapine (Anderson and Powers 1991). The etiology of NMS that occurs in the context
of clozapine use, as well as that occurring with use of conventional antipsychotics, remains unclear.
Hepatotoxicity has been reported with clozapine, especially in the setting of polypharmacy
(Macfarlane et al. 1997; W. Wirshing et al. 1997). Asymptomatic elevation of transaminase levels
was observed most commonly, affecting between 30% and 50% of patients treated with clozapine.
Icteric hepatitis was uncommonly seen in Macfarlane et al.’s (1997) review of clozapine-related
hepatotoxicity and was noted in 84 of 136,000 patients (0.06%). Fatal acute fulminant hepatitis
has been documented in 2 patients (0.001%). Although serious toxicity is rare, prescribers of
clozapine should be aware of its hepatotoxic potential.
Sexual side effects, including priapism and impotence, have been reported with clozapine. Urinary
retention and bladder dysfunction can also result from clozapine. In a study surveying patients’
sexual side effects, we found that clozapine-treated patients actually had fewer sexual complaints
than patients on other antipsychotic medications (prolixin and risperidone) (D. A. Wirshing et al.
2002b).
Although this daunting array of side effects—along with the management of the risk of
agranulocytosis—makes the treatment of patients with clozapine complex, it is common for patients
to report a sense of relief from the dysphoric moods they experienced while taking conventional
drugs. Additionally, the freedom from EPS may account for the enhanced sense of well-being in
patients treated with clozapine.
DRUG–DRUG INTERACTIONS
As previously mentioned, clozapine is predominately metabolized by cytochrome P450 (CYP) 1A2,
although CYP2D6 and CYP3A3 also contribute to its metabolism (Buur-Rasmussen and Brosen
1999). Smoking, which induces CYP1A2, lowers clozapine plasma levels. Fluvoxamine, a potent
inhibitor of CYP1A2, dramatically increases plasma levels of clozapine (Heeringa et al. 1999), and
on occasion, adverse effects are seen (Koponen et al. 1996). This phenomenon can lead to
clozapine intoxication in patients receiving high doses of fluvoxamine. Other reports suggest that
inhibitors of CYP2D6, including paroxetine and fluoxetine, can elevate clozapine levels (Joos et al.
1997; Spina et al. 1998).
CONCLUSION
Clozapine maintains an important place in the treatment of severe psychosis. Side effects, including
agranulocytosis, seizures, sedation, and weight gain, make it the most difficult antipsychotic to
prescribe. As a result, clozapine should be reserved for patients who have failed to respond to other
SGAs. The difficulty in administering clozapine has led many patients and their clinicians to resist
its use. This is unfortunate, because patients should never be deemed “treatment refractory” or
“partial responders” until they have received an adequate trial of clozapine.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved
Course Content
Introduction to Clozapine: History and Mechanism of Action
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The Evolution of Clozapine: A Historical Perspective
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Understanding Clozapine’s Mechanism of Action
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Clozapine’s Role in Modern Psychiatry
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Quiz: Historical Milestones and Mechanisms of Clozapine
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The Discovery and Clinical Use of Clozapine
Patient Selection and Initiation: Guidelines and Best Practices
Monitoring and Management of Side Effects: Ensuring Patient Safety
Advanced Case Studies: Complex Scenarios and Solutions
Future Directions and Innovations: The Evolving Landscape of Clozapine Therapy
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