Clozapine: Balancing Safety with Superior Antipsychotic Efficacy

Comprehensive Reviews
Clozapine: Balancing Safety with
Superior Antipsychotic Efficacy
Herbert Y. Meltzer 1
Abstract
Clozapine is often referred to as the gold standard for the treatment of schizophrenia and yet has also been described as
the most underutilized treatment for schizophrenia supported by solid evidence-based medicine. In 2008, it was used
to treat only 4.4% of patients with schizophrenia in the U.S., which is ~10–20% of those with approved indications for
clozapine for which there is no alternative of equal efficacy. Its use is much higher in Scandinavian countries and China.
The primary indications for clozapine are: 1) treatment-resistant schizophrenia or schizoaffective disorder, defined as
persistent moderate to severe delusions or hallucinations despite two or more clinical trials with other antipsychotic
drugs; and, 2) patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Concerns over
a number of safety considerations are responsible for much of the underutilization of clozapine: 1) agranulocytosis; 2)
metabolic side effects; and, 3) myocarditis. These side effects can be detected, prevented, minimized and treated, but
there will be a very small number of fatalities. Nevertheless, clozapine has been found in two large epidemiologic studies to have the lowest mortality of any antipsychotic drug, mainly due to its very large effect to reduce the risk for suicide. Other reasons for limited use of clozapine include the extra effort entailed in monitoring white blood cell counts
to detect granulocytopenia or agranulocytosis and, possibly, minimal efforts to market it now that it is largely generic.
Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent.
Key Words: Schizophrenia, Clozapine, Treatment Resistant, Suicide, Agranulocytosis,
Metabolic Side Effects, Myocarditis
Introduction
The primary aim of this article is to provide information
about the efficacy and safety of clozapine for the treatment
of schizophrenia to enable clinicians, patients, their families,
and other stakeholders to make informed decisions as to
Professor of Psychiatry and Behavioral Sciences,
Feinberg School of Medicine
1
Address for correspondence: Dr. Herbert Y. Meltzer, Professor of
Psychiatry and Behavioral Sciences, Northwestern Feinberg School of
Medicine, Ward Building-12-104, 303 East Chicago Avenue,
Chicago, IL 60611
Phone: 312-503-0309; Fax: 313-503-0486;
E-mail: h-meltzer@northwestern.edu
Submitted: June 28, 2011; Revised: June 12, 2012;
Accepted: June 16, 2012
134 •
when and how to use clozapine, a drug generally considered
the most effective, and at the same time, the most dangerous
treatment for schizophrenia and schizoaffective disorder.
Mainly because of perceived dangerousness, many clinicians
avoid prescribing clozapine even for those indications where
there is no good alternative for patients with schizophrenia
or schizoaffective disorder: 1) treatment resistance; 2) high
risk of suicide; and, 3) inability to tolerate other antipsychotic drugs because of motor side effects, including moderate–severe tardive dyskinesia. Thus, although conservative
estimates of the percentages of patients with schizophrenia
who are treatment resistant (~30%) and who have survived a
serious suicide attempt (~10%) suggest that at least 35–40%
(as the two groups partially overlap) should be treated with
clozapine, the latest available data in the U.S. (2008) show
Clinical Schizophrenia & Related Psychoses October 2012
Herbert Y. Meltzer
Clinical Implications
Despite the risk of agranulocytosis, metabolic side effects, and a variety of cardiovascular problems, including myocarditis, the specific advantages of clozapine with regard to efficacy can still make it a prudent choice for as many as 30–40%
of patients with schizophrenia or schizoaffective disorder. The following advantages are well established: 1) superiority
for positive symptoms in treatment-resistant patients; 2) lower risk for suicide; 3) lower risk for tardive dyskinesia and
suppression of established tardive dyskinesia; 4) improvement in cognition contributing to better work and social function; 5) higher quality of life and longer time to discontinuation; and, 6) decreased relapse. On the other hand, there are
serious risks: 1) agranulocytosis; 2) insulin resistance with increased risk of type II diabetes, weight gain, and various
vascular complications; and, 3) myocarditis. There are also other unpleasant side effects, such as hypersalivation and
increased risk of seizures. The results from the U.S. (47) and Finnish (50, 67) epidemiologic studies suggest that none of
the potentially life threatening risks, as managed in the “real world,” have enough of an impact to negate the advantages
which come from clozapine. Whether this will remain true after even longer term use of clozapine cannot be known for
sure. However, clozapine has been available for twenty years in the U.S. now, and there is no evidence that mortality in
the clozapine patients who have been taking it for this extended period is increasing. The success of clozapine in terms of
time to discontinuation and fewer relapses than almost any other drug suggests that once patients get started on clozapine, their subjective experience is sufficiently favorable that they prefer it to other treatments.
that clozapine has a 4.4% market share (IMS, 2010). The U.S.
lags behind many other countries in the use of clozapine,
especially Scandinavian and other European countries, and
China. This state of affairs has been singled out as the preeminent example of the lack of use of evidence-based medicine in the treatment of schizophrenia. Horvitz-Lennon et
al. noted that the FDA issuance of the indication for clozapine for use in patients deemed at high risk for suicide had no
impact on the prescription of clozapine, despite the intensive marketing efforts made by Novartis, the company who
funded the key research on clozapine and suicide, to educate
providers and facilitate access to management tools to prescribe clozapine for this new indication (1).
Clozapine: A Brief History
A brief historical review is useful to understand the reasons for this low utilization of clozapine and to point the way
to a possible increase in its use. There have been two seminal and transformational discoveries in the pharmacologic
treatment of schizophrenia. The first was the discovery of
chlorpromazine, serendipitously, in 1952 in Paris by Laborit,
Delay and Deniker, who were the first to observe that this
compound, which had been expected to be no more than a
highly sedative antihistamine to relieve agitation, controlled
delusions and hallucinations, and was, thus, the first antipsychotic drug (2). Little matter then, at least initially, that
during ongoing treatment, many of the patients manifested
a variety of motor side effects, including parkinsonism, dystonias, opisthotonus, akathisia, most likely a few cases of
neuroleptic malignant syndrome (NMS) which were probably misdiagnosed as “lethal catatonia,” and eventually many
cases of tardive dyskinesia or tardive dystonia. This would
be especially true in elderly and post-menopausal patients.
Other pharmaceutical companies sought to find other drugs
which were equally effective as antipsychotics but more tolerable. Numerous drugs with a similar mechanism of action,
which was quickly discovered to be a blockade of dopamine
D2 receptors, were identified but, like chlorpromazine, they
too produced motor side effects. This led to the expectation
that the “typical” antipsychotic drug should produce motor
side effects at clinically effective doses. The motor side effects gave these drugs a class name, neuroleptics, but they
are also referred to as typical or first-generation antipsychotics. The prior concern with tardive dyskinesia as a result of
neuroleptic treatment is diminished to some extent now that
it is so rarely seen because of the introduction of, and near
ubiquitous use of, atypical antipsychotic drugs. This may
be one reason why clozapine use is not as prevalent as it
should be.
However, in 1956, only a few years after the discovery of
chlorpromazine, a drug was synthesized and characterized
by Hunziker, Schmutz and Stille from the Wander Laboratories in Berne, Switzerland, which showed that antipsychotic
efficacy and motor side effects could be dissociated. That
drug was clozapine. In animal models, it did not cause catalepsy, an immobilized state which was shown to predict motor side effects with chlorpromazine and its congeners. Clozapine produced no motor side effects at doses in which it
was effective. Indeed, it was eventually found to be tolerable
in patients with Lewy Body Dementia and the L-DOPA-induced psychosis of Parkinson’s disease, who became totally
immobilized when even the smallest doses of a neuroleptic
able to control psychotic symptoms was administered. Thus,
clozapine was atypical and, like chlorpromazine, became the
progenitor of, and eventually the clue to, discovering the
pharmacologic properties needed to produce other atypical
antipsychotic drugs. This article will refer to these two types
of antipsychotic drugs as typical and atypical antipsychotic
Clinical Schizophrenia & Related Psychoses October 2012
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Clozapine: Balancing Safety
drugs. Since clozapine does not cause catalepsy, it is incorrect to call it a neuroleptic.
Clozapine usage spread throughout Europe and, interestingly, to China, where it became almost the only antipsychotic drug used once China substituted western antipsychotic drugs for traditional medicines (3). Clozapine testing
in the U.S. was just beginning when a cluster of elderly and
infirm patients in Finland developed agranulocytosis, leading to eight deaths in a small geographic region (4, 5). No
such clustering of deaths has been reported since, in Finland or anywhere else. The ensuing investigation rejected the
conclusion that clozapine was the cause of these deaths, at
least through an agranulocytosis mechanism (6). Nevertheless, these deaths led to its withdrawal from general use in all
countries where it had been marketed. Subsequently, many
patients who had been stabilized on clozapine relapsed severely shortly after its abrupt withdrawal (7). It was reintroduced on a very restricted basis with weekly monitoring of
the white blood count so as to detect agranulocytosis within
days of its emergence.
Clozapine would probably not have been reintroduced
were it not for observations that it appeared to be more effective to control the symptoms of severe tardive dyskinesia
and to improve psychotic symptoms in patients with tardive
dyskinesia than other antipsychotic drugs (8-10). The potential of clozapine to treat schizophrenia with minimal risk of
causing tardive dyskinesia was the main motivation for the
willingness of Sandoz (now Novartis) and the U.S. FDA to
permit a trial in patients who had failed to respond to other
antipsychotic drugs or who had intolerable motor side effects, including tardive dyskinesia. Thus, the issue that is the
subject of this article, balancing risk and benefit, is the main
reason why clozapine was given any chance for approval in
the U.S. The result was the U.S. Clozaril® study, intended to
determine if clozapine was more effective in patients who
had failed to respond to at least three other antipsychotic
drugs. The clear superiority of clozapine over chlorpromazine in a six-week trial, in the relatively small sample of 268
patients who were treatment resistant by history and failed
to respond to haloperidol at doses ≥60 mg/day for up to six
weeks, led to the approval of clozapine for use in treatmentresistant and neuroleptic-intolerant patients with weekly
monitoring of the white blood cell count on an indefinite
basis (11). Approval by the FDA led to its eventual approval
in all Western countries, but it was not until 2009 that it was
approved in Japan. Worldwide experience since its U.S. approval has confirmed the greater efficacy of clozapine over
not only typical but also other atypical antipsychotic drugs,
at least at conventional doses in treatment-resistant patients (12, 13). Clozapine is the recommended treatment for
treatment-resistant schizophrenia by the Texas Medical Algorithm Project (14), the web-based International Psycho-
136 •
pharmacology Algorithm (IPAP, www.IPAP.org), and the
Schizophrenia Patient Outcomes Research Team (PORT)
(15). With the exception of supplemental ECT and, as will be
discussed, high doses of other atypical antipsychotic drugs,
there is little disagreement that clozapine is the treatment of
choice once a patient with schizophrenia or schizoaffective
disorder has failed two trials of adequate duration and dosage of other antipsychotic drugs. About 10% of first-episode
patients fulfill this definition after a year of treatment (16),
while another ~20% do so after years of responding adequately to other antipsychotic drugs (17, 18).
With the exception of supplemental ECT and, as
will be discussed, high doses of other atypical
antipsychotic drugs, there is little disagreement
that clozapine is the treatment of choice once a
patient with schizophrenia or schizoaffective
disorder has failed two trials of adequate
duration and dosage of other
antipsychotic drugs.
Other benefits for clozapine that have to be considered to evaluate its benefit-to-risk ratio for specific patients
include, in order of importance and identifying the initial
reports of efficacy: 1) reducing the risk for suicide (19); 2)
improvement in some domains of cognition (20); and, 3)
blocking L-DOPA-induced psychosis in patients with Parkinson’s disease without worsening motor symptoms (21).
On the other hand, the early safety issues with clozapine,
which included major motor seizures, pulmonary embolism, and tachycardia, have been expanded as evidence for
metabolic side effects, including type II diabetes mellitus
and major weight gain for some patients (22, 23), myocarditis, cardiomyopathy and sudden death (24, 25) has accumulated.
Evaluating the Benefits of Clozapine
Efficacy in Treatment-Resistant
Schizophrenia
As mentioned in the Introduction, the first indication of
the superiority of clozapine over other antipsychotic drugs
in patients with schizophrenia was the advantages for positive and negative symptoms in treatment-resistant patients
who participated in the six-week, double-blind, randomized
U.S. Clozaril trial (11). Three issues that need to be clearly
delineated to make the decision to recommend clozapine
over other treatments, including other atypical antipsychotic
Clinical Schizophrenia & Related Psychoses October 2012
Herbert Y. Meltzer
drugs such as olanzapine and risperidone, for treatment-resistant patients are: 1) the definition of treatment resistance,
which includes which symptoms of schizophrenia are to be
targeted; 2) the dose of clozapine to be used during a trial;
and, 3) duration of the trial.
The definition of treatment-resistant schizophrenia
which is appropriate for consideration whether or not to begin a clozapine trial is: the subgroup of poor (or functionally
impaired) outcome schizophrenia which has persistent positive symptoms of at least moderate severity after two or more
trials of other antipsychotic drugs, typical or atypical. Approximately 30% of patients with schizophrenia meet these
criteria for treatment resistance (12, 26). There is no evidence that this percentage has diminished since the substitution of atypical for typical antipsychotic drugs as first-line
treatment, as these two classes of drugs are equal in efficacy
for the treatment of positive symptoms in nontreatmentresistant patients and, at ordinary doses, the atypicals are no
better than typical antipsychotic drugs in treatment-resistant
patients (27, 28; see Meltzer [29] for further discussion). Not
all schizophrenia patients with poor outcome have severe
positive symptoms, and those that do not are not as likely
to have a superior response to clozapine as those who do
(have persistent positive symptoms). The proportion with
poor outcome is estimated to be upwards of 50% (30). The
causes of poor outcome in those with minimal to moderate
positive symptoms, assuming they have been compliant with
treatment, may be severe, persistent negative symptoms,
cognitive impairment, substance abuse, inadequate psychosocial treatment and economic support, both of which
may be exacerbated in difficult economic conditions such as
those affecting the U.S. and other countries since 2008 (12).
While clozapine may be more effective for negative symptoms than other treatments, especially to the extent that the
negative symptoms are secondary to positive symptoms and
those positive symptoms respond to clozapine, the benefits
to be expected in such patients and, hence, the efficacy-tosafety ratio, may be less than those with moderate-to-severe
positive symptoms (11, 12, 31). Clozapine has been shown
to have advantages over other atypical antipsychotic drugs
for overall psychopathology, including general symptoms, in
poor-outcome patients (32), but this effect is weaker than
that for positive symptoms. Thus, it is the subset of poor
outcome patients who have persistent moderate-to-severe
positive symptoms, along with those who are highly suicidal,
whether or not they have moderate-to-severe positive symptoms, for which a trial of clozapine is most clearly justified.
Dosage of clozapine in treatment-resistant patients with
schizophrenia is usually between 300–600 mg/day (11, 12).
Both lower and higher doses may be sufficient or necessary
to achieve efficacy and tolerability. Nontreatment-resistant
patients usually respond at doses of 150–400 mg/day (see
[29] for discussion). The latter corresponds to doses of risperidone of 4–6 mg/day and olanzapine 10–20 mg/day.
There is some evidence that at higher doses of olanzapine
(e.g., 25–45 mg/day or higher) positive symptoms in treatment-resistant patients with schizophrenia or schizoaffective disorder will respond as well as to higher doses of
clozapine. At six months, both high-dose olanzapine and
clozapine improved multiple measures of psychopathology
with no significant difference between them, but the improvement in Global Assessment of Functioning score was
significantly greater with clozapine (p=0.01). There were no
significant differences in motor side effects, but weight gain
was significantly greater with high-dose olanzapine (p=0.05;
[33]). There are few trials with higher doses of other atypical
antipsychotic drugs to compare with clozapine in the higher
dose range. We are currently engaged in a trial of long-acting
risperidone at a dose of 100 mg/day in comparison with a
50 mg dose of the injectable risperidone. More such trials
are needed with other atypical antipsychotic drugs to investigate the possibility that clozapine is more effective than
other atypicals because its low motor side effect profile persists throughout a very wide dose range. There is no question
that high dosages of typical antipsychotic drugs do not improve their efficacy for treatment-resistant patients. A recent
report showing that ziprasidone, at ordinary doses, showed
comparable efficacy to clozapine in treatment-resistant patients requires independent replication (34).
Partly because the U.S. Clozaril trial (11) was of short
duration—six weeks—and was sufficient to show advantage
for clozapine over chlorpromazine, it has been assumed by
some that this is a sufficient duration for all trials with clozapine. Other comparative studies have produced similar
results (31, 35-38). However, there is considerable evidence
that improvement in positive symptoms with clozapine for
individual patients may require up to six months of treatment, and that some patients will show no advantage to clozapine during the first three months of treatment, or even
longer, and yet have a marked response. Clozapine differs
from typical antipsychotic drugs in this regard. The evidence
for this comes from open trials (39, 40), retrospective studies
(41), and the double-blind trial which compared clozapine
and high-dose olanzapine previously mentioned (33). Significant improvement in measures such as relapse and social
function, even after more prolonged treatment with clozapine, has been reported by Joffe et al. (41). A longer time
period of a trial with clozapine does increase the risk for
agranulocytosis, which peaks within the first six months, but
given the limited treatment options for treatment-resistant
patients it would appear that it is prudent to recommend
the longer trial rather than failing to identify all or nearly all
Clinical Schizophrenia & Related Psychoses October 2012
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Clozapine: Balancing Safety
patients who are responders. However, others have suggested that trials of clozapine should last no more than 3–4
months (42, 43).
It can be estimated from the effects of
clozapine on suicide attempts and the
proportion of attempters who complete
suicide that at least one-third of the
approximately 5,000 patients per year with
schizophrenia or schizoaffective disorder
who commit suicide in the U.S. would
not do so had they been
treated with clozapine.
Suicide Reduction with Clozapine:
Impact on Overall Mortality
Suicide is the major contributor to premature death
among patients with schizophrenia (44). Overall, approximately 30–50% of patients with schizophrenia attempt suicide, while 5% actually die from suicide, a fivefold greater
rate than the lifetime risk for suicide in the general population of the U.S. (45, 46). There is now extensive evidence
of various types that clozapine markedly reduces suicidal
behavior in patients with schizophrenia and schizoaffective
disorder, regardless of treatment-resistance status. The first
evidence for this effect of clozapine was a two-year mirror
image study of 88 patients with treatment-resistant schizophrenia which showed an 85% decrease in attempts following switching to clozapine (19). An epidemiologic study of
67,000 cases of clozapine-treated patients in the U.S. between
1989 and 1996, adjusted for age, sex, and race, found that
all-cause mortality was lower during the period of clozapine use than during nonuse. The longevity-enhancing effect
of clozapine was mainly the result of a dramatic decrease in
suicide in clozapine users (47). This was confirmed in a subsequent mirror image study from Europe (48). These studies
could not rule out the possibility that more frequent clinic
visits during clozapine treatment may have accounted for
the advantage. To address this issue, a multicenter, randomized, international, two-year follow-up study—the International Suicide Prevention Trial (InterSePT)—was conducted
to compare the risk for suicidal behavior in patients at high
risk for suicide who were randomized to clozapine or olanzapine (49). Patients randomized to clozapine attempted
suicide significantly less than those in the olanzapine group
(p=0.03). This led to clozapine being approved by the FDA
138 •
for the indication of suicide reduction but, as noted in the
Introduction, this had no discernable impact on the use of
clozapine for this purpose. Clearly, some knowledgeable
physicians are making their patients aware of this treatment
option, but many fewer than need to.
A second major epidemiologic study confirmed that
clozapine markedly reduces all-cause mortality compared
to all other antipsychotic drugs and that a major contributing factor is the reduction in death by suicide (50). Using
national record-based data on medication prescription and
deaths in 66,881 patients with a schizophrenia-related diagnosis from 1996 to 2006, it was found that the lowest risk
for overall mortality was present in patients treated with clozapine. Compared to the reference treatment, perphenazine,
the risk was reduced 26% (relative risk=0.74, confidence
interval=0.60 to 0.91, p=0.0045). Clozapine was superior to
all other antipsychotic drugs in reducing death due to suicide as well (p<0.0001). The risk of death from suicide on
clozapine, adjusted for risk factors, was 0.34, compared to
1.0 for perphenazine and 1.58 for quetiapine. No other drug
had a lower risk for suicide than any other. As will be discussed, there was no offsetting increase in mortality due to
ischemic heart disease with clozapine. Tiihonen et al. (50)
recommended a reconsideration of clozapine as a first-line
treatment based upon their data and other available data
supporting the efficacy of clozapine for reducing suicide.
This conclusion was challenged by De Hert et al. (51) but
none of the issues raised could possibly change the overall
findings. For example, they raise the possibility that because
the lower mortality rate was highly likely to be driven by the
ability to reduce the risk for suicide, a conclusion they accept, that there is a survivor bias in the overall mortality rate,
on the assumption that patients early in their course made a
suicide attempt and were prescribed clozapine and remained
on it, noting that discontinuation from clozapine is less frequent than other drugs. However, there are no data available
which indicate the proportion of patients who are treated
with clozapine in Finland which is due to a prior suicide attempt. Treatment resistance would be much more common
as a reason for prescribing clozapine.
It can be estimated from the effects of clozapine on suicide attempts and the proportion of attempters who complete suicide that at least one-third of the approximately
5,000 patients per year with schizophrenia or schizoaffective
disorder who commit suicide in the U.S. would not do so
had they been treated with clozapine. This requires treating survivors of serious previous suicide attempts with clozapine, and initiating clozapine treatment in those patients
whose well known other risk factors indicate a high risk for
suicide (e.g., hopelessness, substance abuse, family history of
suicide and insight) (44).
Clinical Schizophrenia & Related Psychoses October 2012
Herbert Y. Meltzer
Clozapine Advantages in Cognition
and Broad Outcome Measures
Improvement in positive and negative symptoms, general psychopathology, cognition, suicidality/mood, and fewer extrapyramidal side effects (EPS) contribute to clozapine
having broader advantages that most probably represent the
integrated sum of these effects. These include improvement
in work and social function, quality of life, lower relapse rate
and rehospitalization. Much of this depends upon improvement in cognitive function. Clozapine has been reliably
shown to improve some domains of cognition in schizophrenia. These include verbal fluency, declarative memory,
attention, and speeded mental functions (20, 52-54).
Some have claimed that this is simply a practice effect (55) or that typical antipsychotic drugs are as effective
(56). We have found that verbal fluency in 25% of patients
treated with clozapine improved at least one standard deviation, which is unlikely to be a practice effect. Improvement
of this magnitude was not observed in patients treated with
typical antipsychotic drugs (Meltzer and Sumiyoshi, to be
submitted). As with improvement in positive symptoms, it
may take up to six months for improvement in cognition
to become evident and maximal (20). There is abundant
evidence for the failure of typical antipsychotic drugs to improve cognition (see Meltzer and McGurk [22] for review).
The reasons for these discrepancies in views on clozapine
and other atypicals on cognition go beyond the scope of this
article to discuss in detail. It is important to note that preclinical studies of the effects of typical and atypical drugs on
certain models of cognitive impairment, such as impaired
novel object recognition due to subchronic phencyclidine
(PCP) administration in rodents, have demonstrated that
atypicals can reverse the deficit due to PCP while typical
antipsychotics are ineffective (57). The importance of cognitive improvement to functional outcome in schizophrenia is
sufficiently well established to warrant utilizing the possible
benefits conveyed by clozapine over typical antipsychotic
drugs in the consideration of whether or not to treat a patient with it.
Improvement in measures of quality of life also reflects
advantages of clozapine over typical antipsychotic drugs
(58, 59). In the European Schizophrenia Outpatients Health
Outcomes (EU-SOHO) study, a three-year observational
study of outcomes associated with antipsychotic treatment
for schizophrenia in an outpatient setting involving a total
of 9,340 patients, olanzapine and clozapine were associated
with important health-related quality of life benefits at endpoint, most of which occurred during the first six months
(60). Other broad outcome measures of clinical and pharmacoeconomic importance in which clozapine is advanta-
geous include time to discontinuation and fewer hospitalizations (38, 58, 61).
Improvement in cognition and psychopathology in
treatment-resistant patients after more prolonged treatment with clozapine can lead to functional improvement
in 30–50% of patients, which is a component of quality of
life measures (41, 62-65). Functional improvement, which
includes return to employment and continuing education
at an appropriate premorbid level, has been related more to
improvement in cognition than to improvement in positive
symptoms (64, 65) and requires longer periods of time and
psychosocial support. Short-term trials with clozapine are
generally insufficient in duration to achieve significant functional improvement (66). Clozapine can facilitate improvement in social function of patients with treatment-resistant
schizophrenia, particularly when combined with appropriate support from clinicians who can facilitate finding and
keeping jobs or returning to school (62, 63).
Relapse requiring rehospitalization is another highly
relevant clinical outcome in schizophrenia where clozapine
has been found to be superior to other treatments. Relapse
prevention is easily shown to translate into cost effectiveness, reduced burden on relatives, and functional benefits
to patients. A nationwide cohort of 2,230 consecutive adults
hospitalized in Finland for the first time because of schizophrenia or schizoaffective disorder between 1995 and 2001
found that initial use of clozapine (adjusted relative risk
0.17, 95% confidence interval 0.10 to 0.29), perphenazine
depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71)
were associated with the lowest rates of discontinuation
for any reason when compared with oral haloperidol (67).
During an average follow-up of 3.6 years, 4,640 cases of
rehospitalization were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to
0.71), and clozapine (0.64, 0.48 to 0.85) were associated with
the lowest risk of rehospitalization (67). A Cochrane metaanalysis of clozapine found fewer relapses in patients treated
with clozapine than those treated with typical antipsychotic
drugs (n=1,303, relative risk 0.62, confidence interval 0.5 to
0.8 [31]). We have reported an 89.6% reduction in relapse
in a one-year mirror image study in 57 treatment-resistant
schizophrenia patients in the U.S. (63). Similar benefits were
observed over a five-year period of clozapine treatment in a
large Korean cohort (68). Lower relapse was also noted in a
head-to-head comparison of risperidone and clozapine (69).
In summary, the advantages of clozapine which have
emerged from controlled clinical trials have been borne out
in clinical practice and in the often remarkable improvement
noted in patients who have failed previous attempts at treatment.
Clinical Schizophrenia & Related Psychoses October 2012 • 139
Clozapine: Balancing Safety
Between 4–8% of African Americans and
people of Middle Eastern origin have
chronically low white blood cell counts
(e.g., 2,500–3,500), with absolute neutrophil
counts of 1,300–1,700 (72). These
individuals are not at any greater risk for
agranulocytosis than are those with typical
white cell counts of 4,500–8,000.
Evaluating the Risk of Clozapine
Agranulocytosis
The risk of developing granulocytopenia or agranulocytosis during clozapine treatment is between 0.7–1.0% (70).
Most cases occur between six weeks and six months. The
chance in the second six months of treatment is 0.70/1,000
patient-years and, after the first year, 0.39/1,000 patientyears (71). Mandatory monitoring of white blood cells or
neutrophils permits early detection of granulocytopenia and
cessation of clozapine before full agranulocytosis occurs.
As a result, very few cases of full agranulocytosis occur any
more. Data from the U.S. clozapine registry covering the first
five years of use showed that, with monitoring, there were
382 cases of agranulocytosis in 99,502 patients (0.38%) and
12 deaths (0.01%). If agranulocytosis occurs, treatment with
granulocyte colony-stimulating factor is effective to restore
normal white blood cell levels in most cases, before infections develop. Treatment with antibiotics is usually effective
in those cases, so the mortality due to agranulocytosis is in
the range of 1/10,000. Given the mortality from other causes
of patients with clozapine, and the limited choices open to
patients who are treatment resistant or highly suicidal, it
would seem to be a relatively easy decision to balance the
benefits from clozapine against this small risk of fatality.
According to Schulte, even with no monitoring of clozapine after six months, the mortality due to agranulocytosis is
comparable to other drugs with no monitoring (e.g., mianserin or phenylbutazone) and with life in general. While it is
a real risk, it is not so great a risk that it overrides the benefit
for those patients who respond poorly to other antipsychotic
drugs. With appropriate monitoring, the rate of fatal agranulocytosis should be in the range of 1 per 10,000 patients. This
has to be compared with the reduced risk of suicide. Both
the epidemiologic studies noted above demonstrate that
mortality in schizophrenia is significantly less with clozap-
140 •
ine than any other antipsychotic drug. Between 4–8% of African Americans and people of Middle Eastern origin have
chronically low white blood cell counts (e.g., 2,500–3,500),
with absolute neutrophil counts of 1,300–1,700 (72). These
individuals are not at any greater risk for agranulocytosis
than are those with typical white cell counts of 4,500–8,000.
It is important not to deny such patients a trial of clozapine
or to stop clozapine when it might be chanced upon by another clinician.
Metabolic Side Effects of Clozapine
Clozapine and olanzapine are comparable to one another in risk of causing marked weight gain, glucose dysregulation leading in some cases to type II diabetes mellitus and
diabetic ketoacidosis, and lipid increases (23, 73, 74). These
metabolic changes result from insulin resistance (75). African Americans and Hispanic people may be at greater risk
than Caucasians (22). Both olanzapine and clozapine are
more likely to produce these changes than any other atypical or typical antipsychotic drug and, for this reason, would
be avoided compared to those which are atypical but which
produce infrequent and mild insulin resistance (e.g., ziprasidone and aripiprazole) (74). However, it is important to recall that factors such as life style, including diet, and intrinsic
vulnerability to metabolic problems present in schizophrenia
may minimize the differences between clozapine and other
antipsychotic treatments with regard to adverse metabolic
consequences (76). For some patients who develop type II
diabetes, it will be a particularly difficult decision to continue clozapine as long-term renal, peripheral vascular, and
ocular side effects may be such that patients will prefer not to
risk their development. Those patients with the most adverse
metabolic effects of clozapine should be counseled about the
need for diet and exercise. However, an interesting feature
of weight gain with clozapine is that weight gain with clozapine predicts clinical response (77, 78). Thus, because of
increased efficacy, the decision to stop clozapine treatment
may be more complicated. In addition, relapse following
termination of clozapine treatment may be rapid and severe
(79). Therefore, treatments to counteract the metabolic side
effects of clozapine may be of particular interest. Metformin
treatment has been found to be useful to reduce a wide range
of the adverse metabolic effects of clozapine (80). There is
extensive investigation of genetic markers for the risk for
developing metabolic syndrome. It is possible that these
will become sufficiently sensitive to allow identification of
those patients most like to develop metabolic effects (81),
and enable consideration of the value of the trial relative to
this added risk or permitting some preventive actions such
as diet and exercise.
Clinical Schizophrenia & Related Psychoses October 2012
Herbert Y. Meltzer
Motor Side Effects and
Tardive Dyskinesia
The difference between clozapine and neuroleptic drugs
such as haloperidol and perphenazine with regard to motor
side effects in rodents and humans was the basis for the second stage in the evolution of antipsychotic drug treatment
discussed in the Introduction. As noted in the Introduction,
the high prevalence of tardive dyskinesia in the U.S. in the
1980s (26), clearly the result of neuroleptic drug treatment,
led to the revival of clozapine after it had been banned due
to its risk for agranulocytosis. According to Kane et al. (26),
tardive dyskinesia developed in about 5% of patients with
each year of cumulative neuroleptic exposure. The incidence
in older individuals is markedly higher. While this high rate
may have been due to the high doses that were common in
that era, there is no indication that lower doses of neuroleptics when given for prolonged periods produce rates comparable to the atypical antipsychotic drugs (82). Clozapine
clearly has a lower likelihood to cause tardive dyskinesia
than typical neuroleptics and is among the least likely of the
atypicals to cause tardive dyskinesia (82). Thus, clozapine
should be considered for patients with severe tardive dyskinesia and given extra consideration as a treatment in patients who show signs of developing tardive dyskinesia and
who require continuing antipsychotic drug treatment. The
lower mortality rate with clozapine (50) plus the emerging
tardive dyskinesia provides more rationale for using clozapine even in nontreatment resistant and nonsuicidal patients.
The motor side effects of neuroleptics are an established
factor in noncompliance with antipsychotic drug treatment and relapse (83). The near complete absence of motor side effects contributes to the low rate of discontinuation with clozapine. The desire to find other antipsychotic
drugs which were as free of motor side effects as clozapine
but did not cause agranulocytosis or have some of the other
side effects specific to clozapine, such as hypersalivation and
major motor seizure, stimulated the development of risperidone, olanzapine, quetiapine, and subsequent atypical antipsychotic drugs. Because some patients with clozapine have
special vulnerability to develop motor side effects, very rare
cases of tardive dyskinesia and NMS have been reported.
Long-term clozapine usage as the primary, if not only, antipsychotic drug is needed to evaluate its risk for causing tardive dyskinesia. A study from China of 101 patients who received clozapine as a primary antipsychotic drug since their
first episode, with a mean follow up of 12±6 years, showed a
prevalence of tardive dyskinesia of 3.96%. The tardive dyskinesia was mild and orolingual in nature (84).
Clozapine is tolerable in patients who have had NMS
from prior antipsychotic drugs but can also rarely be a precipitating factor, usually in patients with concurrent treat-
ment with mood stabilizers or with a history of NMS from
other drugs (85). The greater tolerability of clozapine in
patients with Parkinson’s disease who require antipsychotic
drug treatment because of the development of psychosis following L-DOPA compared to all other antipsychotics, with
the exception of quetiapine, provides strong evidence that it
and quetiapine have the least likelihood of causing tardive
dyskinesia of all antipsychotic drugs (86). It also can suppress tardive dyskinesia (9, 87). Other atypical antipsychotics can do so as well, but clozapine may be more effective in
some patients (82). Thus, for patients who experience motor
side effects sufficiently on other antipsychotic drugs that it
is a factor in their adherence to treatment or leads to motor
side effects such as dystonias or NMS, clozapine’s benefits
would justify the increased risk of agranulocytosis.
Thus, clozapine should be considered for
patients with severe tardive dyskinesia and
given extra consideration as a treatment in
patients who show signs of developing
tardive dyskinesia and who require
continuing antipsychotic drug treatment.
Clozapine and Cardiovascular Risk
Clozapine is associated with a low (0.015% to 0.188%)
risk of potentially fatal myocarditis or cardiomyopathy (88).
A higher rate of suspected myocarditis (0.7% and 1.2%)
was identified in Australia. The condition developed within
a median 17 days (mean 171.7 days, ±530.9 days) and 12
(10.3%) died. The outcome was unknown in the rest. Clozapine is not associated with prolongation of the QTc interval or sudden death due to torsades de pointes (89).
Optimizing the Benefits of Clozapine
A few considerations on how best to administer clozapine will be mentioned here. The importance of initial
titration, dosage and adequate duration of treatment, and
avoidance of additional add-on antipsychotic drugs until
monotherapy has been tried are important general principles. It is critical at the outset of treatment with clozapine to
educate patients and significant others as to why a trial with
clozapine has been suggested, whether it be for treatment
resistance or suicide risk reduction, how evidence has accumulated that for the right patient benefits outweigh risks,
how the risk will be minimized with white blood cell monitoring, what will happen if the white count falls below the
thresholds for granulocytopenia and agranulocytosis, and
the wide range of annoying side effects, including sedation,
Clinical Schizophrenia & Related Psychoses October 2012 • 141
Clozapine: Balancing Safety
hypersalivation, tachycardia, weight gain, lipid changes,
myoclonic jerks and seizures. This group of side effects can
generally be effectively managed, although the weight gain
less so. They should rarely be the cause for discontinuation
in patients who require clozapine because of treatment resistance or suicide. A discussion of reduction in any current
extrapyramidal side effects and reduced risk of tardive dyskinesia, the necessity for compliance and not stopping the
medication in order to avoid a relapse, should also be part of
this discussion.
Achieving adequate plasma levels of clozapine (≥350
ng/ml), which may require periodic measurement at the
early phase of treatment and utilization of doses up to 900
mg/day, will enhance the benefit-to-risk ratio. If the patient is on another antipsychotic drug when clozapine is
initiated, it should be discontinued shortly after adequate
dosage has been achieved. Monotherapy trials should last
for six months whenever possible. As discussed above, for
some patients a second antipsychotic drug may sometimes
be effective. There is controversy about the value of adding
risperidone (90, 91). Some selective serotonin reuptake inhibitors, including paroxetine and fluoxetine (but especially
fluvoxamine), impair the metabolism of clozapine so that
reducing the dose of clozapine is usually appropriate. Sertraline and citalopram do not interfere with the metabolism of
clozapine (92). Valproic acid may also increase plasma levels
of clozapine, warranting reducing the dosage (92). Smoking
leads to induction of cytochrome P450 CYP1A2 which will
lead to lower plasma clozapine levels. Conversely, smoking
cessation may markedly elevate clozapine plasma levels (93).
Plasma levels of clozapine should be monitored for at least
3–6 months after smoking cessation and dosage adjustments
made as needed. Patients receiving clozapine will need psychosocial treatment to maximize the benefits from the improvement in psychosis, negative symptoms and cognitive
impairment which may emerge in the months after starting
clozapine. Family and group therapy, cognitive behavioral
treatment, supportive employment, and activity therapy
have all been used with considerable success to enhance improvement with clozapine.
sia; 4) improvement in cognition contributing to better work
and social function; 5) higher quality of life and longer time
to discontinuation; and, 6) decreased relapse. On the other
hand, there are serious risks: 1) agranulocytosis; 2) insulin
resistance with increased risk of type II diabetes, weight
gain, and various vascular complications; and, 3) myocarditis. There are also other unpleasant side effects, such as
hypersalivation and increased risk of seizures. The results
from the U.S. (47) and Finnish (50, 67) epidemiologic studies suggest that none of the potentially life threatening risks,
as managed in the “real world,” have enough of an impact to
negate the advantages which come from clozapine. Whether
this will remain true after even longer term use of clozapine cannot be known for sure. However, clozapine has been
available for twenty years in the U.S. now, and there is no evidence that mortality in the clozapine patients who have been
taking it for this extended period is increasing. The success
of clozapine in terms of time to discontinuation and fewer
relapses than almost any other drug suggests that once patients get started on clozapine, their subjective experience is
sufficiently favorable that they prefer it to other treatments.
Disclosures
HY Meltzer has been a consultant or grantee of Sandoz,
Novartis, Azur, Teva, ACADIA, BioLineRx, BioVail, Cephalon, Dainippon Sumitomo, Eli Lilly, EnVivo, Janssen, Merck,
Pfizer, Roche, and Schering-Plough.
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