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Clozapine and Haloperidol in Moderately Refractory Schizophrenia
A 6-Month Randomized and Double-blind Comparison
John M. Kane, MD;
Stephen R. Marder, MD;
Nina R. Schooler, PhD;
William C. Wirshing, MD;
Daniel Umbricht, MD;
Robert W. Baker, MD;
Donna A. Wirshing, MD;
Allan Safferman, MD;
Rohan Ganguli, MD;
Marjorie McMeniman, PhD;
Michael Borenstein, PhD
Arch Gen Psychiatry. 2001;58:965-972.
ABSTRACT
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Background Despite the demonstrated efficacy of clozapine in severely refractory
schizophrenia, questions remain regarding its efficacy for primary negative
symptoms, comparison with a moderate dose of a first-generation antipsychotic,
and adverse effects during a longer-term trial. This study examined its efficacy
in partially responsive, community-based patients, compared clozapine with
moderate-dose haloperidol, and extended treatment to 6 months.
Methods Randomized, double-blind, 29-week trial comparing clozapine (n = 37)
with haloperidol (n = 34). Subjects with schizophrenia who were being treated
in community settings at 3 collaborating clinical facilities were enrolled.
Results Subjects treated with haloperidol were significantly more likely to
discontinue treatment for lack of efficacy (51%) than were those treated with
clozapine (12%). A higher proportion of clozapine-treated subjects met an
a priori criterion of improvement (57%) compared with haloperidol-treated
subjects (25%). Significantly greater improvement was seen in symptoms of
psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance,
and total score measured on the Brief Psychiatric Rating Scale. No differences
were detected in negative symptoms using the Brief Psychiatric Rating Scale
or the Schedule for Assessment of Negative Symptoms. Subjects treated with
clozapine experienced more excess salivation, dizziness, and sweating and
less dry mouth and decreased appetite than those treated with haloperidol.
Conclusions Compared with a first-generation antipsychotic given in a moderate dose,
clozapine offers substantial clinical benefits to treatment-refractory subjects
who can be treated in the community. Advantages are seen in a broad range
of symptoms but do not extend to negative symptoms.
INTRODUCTION
DESPITE ADVANCES in treatment of schizophrenia, more than 10% of totally
disabled individuals in the United States have this disease, although it affects
only 1% of the population.1, 2 The
introduction of chlorpromazine hydrochloride and other conventional antipsychotic
agents revolutionized the care of schizophrenia. These medications provide
dramatic improvement in psychotic symptoms and reduce risk for relapse, but
recent estimates of patients with partial or poor response exceed 40%.3, 4
Clozapine was the first medication to produce significantly greater
improvement than conventional antipsychotics in carefully selected, treatment-refractory
patients.5 Subsequent studies confirmed clozapine's
effectiveness.6, 7, 8, 9, 10
Controlled trials that showed greatest symptom improvement with clozapine
were relatively brief (ie, 6-10 weeks).6, 7, 8
Longer randomized trials found significant reduction in rehospitalization
rather than symptoms.9, 10
Questions remain about the efficacy of clozapine for primary negative
symptoms.11, 12, 13 Kane
et al5 studied subjects withdrawn from high-dose
haloperidol therapy (mean dosage, 60 mg/d) and compared clozapine with high-dose
chlorpromazine plus benztropine mesylate (mean maximum dosage, 1200 mg/d).5 They reported significantly greater improvement in
the Brief Psychiatric Rating Scale (BPRS) anergia factor, which could be attributed
to reduction in extrapyramidal adverse effects.14
The time course of clozapine response also remains in question.
Open and uncontrolled reports suggest that clozapine improves social
and cognitive functioning15 and overall quality
of life.16 Rosenheck et al17
report that clozapine facilitates psychosocial treatment participation, enhancing
effects on quality of life and long-term symptom outcome.
The present trial was designed to address several questions regarding
clozapine's effects. First, community-dwelling and hospitalized patients were
included. Second, we compared clozapine with haloperidol decanoate given in
moderate doses and used a gradual titration schedule to assess whether clozapine's
efficacy for negative symptoms was a function of reduction of extrapyramidal
adverse effects. Third, this study extended double-blind observation to 29
weeks to assess long-term response. Three to 6 months is considered adequate
to assess clozapine's usefulness in routine clinical care.9, 10
A trial duration of 6 months may also allow discrimination of negative symptoms
from akinesia. Since clozapine is the only medication specifically labeled
for treatment of refractory schizophrenia and is associated with high cost
and increased risk for agranulocytosis, such information is sorely needed
to inform clinical practice.
SUBJECTS AND METHODS
We conducted a 6-month, double-blind, prospective, random-assignment
trial comparing clozapine (target dosage, 500 mg/d) with haloperidol (target
dosage, 10 mg/d). Identical protocol and procedures were followed at 3 centers,
including the West Los Angeles Veterans Affairs and University of California–Los
Angeles (UCLA) Medical Centers; Hillside Hospital, North Shore–Long
Island Jewish Health System, Glen Oaks, NY; and the Western Psychiatric Institute
and Clinic and Mayview State Hospital, Pittsburgh, Pa. The study was approved
by the institutional review boards at Long Island Jewish Medical Center, the
University of Pittsburgh, UCLA, Mayview State Hospital, and the West Los Angeles
Veterans Affairs Medical Center. Seventy-one subjects provided informed consent
and were randomized to treatment. Computer-generated randomization schedules
(blocked by site) were provided to each site; sealed envelopes with treatment
assignment were available to clinical personnel if needed to break the blind.
SUBJECTS
Inclusion criteria consisted of DSM-III-R18 diagnosis of schizophrenia or schizoaffective disorder
by one of the authors using a diagnostic checklist, 20 to 55 years of age,
and living in the community or judged clinically treatable in the community
despite psychotic symptoms. Partial or poor response was defined by documented
treatment failure in 2 trials of conventional antipsychotics at dosages equivalent
to or greater than chlorpromazine hydrochloride, 600 mg/d, for at least 6
weeks (high-dose qualification) and 1 trial of a conventional agent at dosages
equivalent to chlorpromazine hydrochloride, 250 to 500 mg/d, for the same
length of time (low-dose qualification). Patients for whom a low-dose trial
could not be documented received prospective dose reduction for 4 weeks or
less if clinical worsening was seen. Only patients who met symptom criteria
for inclusion after such treatment (a rating of at least moderate on 1 of
the following 4 BPRS items19, 20:
conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual
thought content) entered the trial.
Exclusion criteria consisted of receipt of psychotropic medication therapy
other than antipsychotics (eg, antidepressants or mood stabilizers) that could
not be discontinued, documented history of intolerance to haloperidol at dosages
of 4 mg/d or more because of disabling extrapyramidal adverse effects, diagnosis
of neuroleptic malignant syndrome with recurrence on rechallenge, evidence
that refractoriness was related to medication noncompliance, organic brain
disease (eg, epilepsy or brain tumor), mental retardation that precluded understanding
study participation or assessment procedures, chronic medical illness that
made study participation inappropriate, DSM-III-R
diagnosis of substance abuse or dependence18
within 6 months, current treatment with medication(s) for other medical conditions
that may have psychotropic effects or agranulocytosis risk or may interfere
with drug absorption or metabolism, total white blood cell count below 3.5
x 103/µL (3500/mm3), and pregnancy.
Subject recruitment strategies varied. At Hillside Hospital, inpatient
admissions were reviewed daily, and patient rosters at Queens Day Treatment
Center, Jamaica, NY, a facility that serves patients with chronic illness,
were reviewed quarterly. At the University of Pittsburgh, patient rosters
in the Schizophrenia Treatment and Research Center (outpatient clinic and
day hospital) were reviewed with primary clinicians quarterly. At Mayview
State Hospital, a satellite facility of the University of Pittsburgh, admission
service rosters were reviewed weekly and continuing care service rosters were
reviewed quarterly. Recruitment at UCLA took place in the Mental Health Clinic
and Inpatient Service of the West Los Angeles Veterans Affairs Medical Center
and the Aftercare Clinic of the UCLA Neuropsychiatric Hospital. Clinicians
in each setting were asked by recruiters to refer refractory individuals.
If patients met study criteria and provided informed consent, their treatment
was transferred to the research clinic.
All subjects were competent to give informed consent. Competency was
assessed by asking the patients to describe in their own words the essential
elements of the informed consent document. Potential subjects who were unable
to appreciate risks, benefits, or discomforts of the study were considered
ineligible.
Subjects receiving fluphenazine decanoate or haloperidol decanoate received
oral haloperidol or fluphenazine for 2 injection intervals before beginning
double-blind dosage titration.
TREATMENT IMPLEMENTATION
Dosage Titration
Medication was administered under double-blind conditions. Clozapine
therapy was begun at a test dosage of 12.5 mg/d on day 1. Haloperidol therapy
was begun at a dosage of 5 mg/d. Identical capsules contained haloperidol
or clozapine in a 1:50 ratio with a range of 200 to 800 mg of clozapine or
4 to 16 mg of haloperidol. Dosage was gradually increased to a target dosage
of 500 mg/d for clozapine or 10 mg/d for haloperidol within 5 weeks. Simultaneously,
current antipsychotic and all other psychotropic medication therapies were
gradually decreased. Haloperidol-treated subjects received benztropine mesylate,
2 mg twice daily. Clozapine-treated subjects received matching placebo. To
maintain the blind, all subjects had a weekly blood draw. Titration could
be slowed or stopped below the target dose if subjects could not tolerate
the standard titration schedule because of adverse effects. At the Hillside
Hospital and UCLA sites, outpatients were hospitalized for initial dosage
titration. At the University of Pittsburgh, subjects recruited as outpatients
had initial dosage titration in the community and were seen by research personnel
at least 3 times a week for the first 4 weeks of dosage titration.
Double-blind treatment continued for up to 29 weeks. Dosage could be
increased beyond the target dosage to 800 mg/d for clozapine or 16 mg/d for
haloperidol if symptoms did not improve or if initially controlled symptoms
reemerged. Dosage could be reduced to 200 mg/d for clozapine or 4 mg/d for
haloperidol in response to adverse effects. The only other psychotropic medication
allowed was lorazepam after the first week. Medication was dispensed labeled
with day of the week and morning (AM) or afternoon (PM). Patients returned
remaining medication supplies at weekly visits, and pills were counted. Most
outpatients in the study lived in supervised settings where medication taking
was observed by staff. Family members were questioned about compliance by
telephone, if patients lived with them.
Ancillary Clinical Services
Clinical programs at the centers differed, but all shared a common treatment
philosophy, ie, provision of services tailored to patient needs determined
by a treatment team. Subjects were seen at least weekly by a research treatment
team including a psychiatrist, nurse, and ancillary clinical personnel. Progress
and problems were discussed in weekly research team meetings that reviewed
recommendations for clinical services and developed strategies for enhancing
patient engagement and compliance. Decisions regarding subjects' continued
study participation were also made at these meetings. If subjects had clinical
treatment teams, they continued to receive services through those teams, and
such services were coordinated with the research team.
OUTCOME MEASURES
Psychopathology was assessed using the BPRS,19, 20
the Schedule for Assessment of Negative Symptoms (SANS),21
and Clinical Global Impressions Scale (CGI).22
Adverse effects were monitored using the Simpson Angus Scale for Extrapyramidal
Side Effects–Hillside Version,23 Barnes
Akathisia Scale,24 a checklist of adverse effects,
and the Abnormal Involuntary Movements Scale.25
Full assessments were completed at baseline and weeks 5, 11, 17, and 29. The
BPRS and CGI were also completed at weeks 1, 2, 3, and 4 and then biweekly
throughout the trial. Research psychiatrists who completed psychopathology
assessments received initial joint training for administration of the BPRS
and SANS at the Hillside Clinical Research Center. Subsequently, cross-site
reliability was monitored through ongoing conference calls. Assessment cores
of National Institute of Mental Health research centers monitored within-site
reliability.
DATA ANALYSIS
We used analysis of variance (ANOVA) for continuous variables and logistic
or multinomial regression for categorical variables, including terms for treatment,
site, and site x treatment interaction, to evaluate demographic and
psychiatric history characteristics.
Time to treatment discontinuation for lack of efficacy was based on
a clinical judgment made by the research treatment team. This criterion and
time to 20% improvement in the 4 psychotic symptoms used to qualify subjects
for study inclusion were the primary outcome measures. Survival analysis was
used to evaluate the following outcomes: time to discontinuation of study
medication for any reason; time to discontinuation for lack of clinical efficacy;
time to 2 consecutive ratings of 20% improvement in BPRS psychotic symptoms;
and time to remission, defined by 20% improvement and no psychotic symptom
rated worse than mild. In the survival analyses of time to discontinuation
for any reason and for lack of efficacy, other reasons (eg, adverse effects,
subject decision to withdraw) were treated as "withdrawn alive" at time of
discontinuation. Computation of rate differences and confidence intervals
followed the method outlined by Borenstein.26
Psychopathology (BPRS factors thought disturbance, hostility-suspiciousness,
activation, anergia, and anxiety-depression and SANS affective flattening,
alogia, avolition-apathy, and anhedonia-asociality global ratings) were evaluated
for all subjects (n = 71) at the last available time point. Ratings of adverse
effects at 5 weeks or the last available time point before that were drawn
from the Simpson Angus Scale, the Barnes Akathisia Scale, and the checklist
of adverse effects. Each measure of psychopathology and adverse effects was
included as the dependent variable in an ANOVA that tested the effects of
treatment, site, and site x treatment. The  level in all analyses
was .05 (2-tailed).
RESULTS
SAMPLE CHARACTERISTICS
Table 1 displays demographic
and psychiatric characteristics by treatment. Subjects were comparable to
those in other studies of refractory schizophrenia. The mean ages were 40
and 41 years for the haldoperidol and clozapine treatment groups, respectively.
Most subjects were male and had never been married. Mean age at first hospitalization
was 23 years in the haloperidol group and 24 years in the clozapine group.
Slight differences were found between groups for mean number of hospitalizations
(9 vs 11) and mean number of months in the hospital in the 17 years since
illness onset (17 vs 27). Both groups had received neuroleptic medication
for approximately 16 years.
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Table 1. Demographic and Psychiatric History Characteristics of Trial
Participants*
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Subjects had a history of relatively good premorbid functioning; more
than half had at least some college education and were characterized by appropriate
functioning to 19 years of age in the the haloperidol group and 21 years in
the clozapine group. During the premorbid period, more than two thirds of
all subjects were characterized as having functioned at least moderately well.
Their longest period of sustained employment was less than 3 years.
DOSAGE
Dosages of clozapine and haloperidol were calculated for subjects still
in treatment at given times. Dosage was protocol driven during the first 5
weeks. The mean dosage of haloperidol was 5 mg/d at week 1 and 10 mg/d (SD,
1.3 mg/d) at week 5 (n = 29); the mean dosage of clozapine was 141 mg/d (SD,
28 mg/d) at week 1 and 433 mg/d (SD, 122 mg/d) at week 5 (n = 29). Subsequently,
clinical response influenced dosage. For haloperidol, dosage increased to
14.3 mg/d (SD, 6.4 mg/d) at week 11 (n = 22), 15.7 mg/d (SD, 6.5 mg/d) at
week 17 (n = 14), and 18.9 mg/d (SD, 7.0 mg/d) at week 29 (n = 9). For clozapine,
dosage remained relatively constant, ie, 491 mg/d (SD, 127 mg/d) at week 11
(n = 28), 506 mg/d (SD, 174 mg/d) at week 17 (n = 25), and 523 mg/d (SD, 171
mg/d) at week 29 (n = 25).
DURATION OF STUDY PARTICIPATION
Subjects randomized to clozapine were significantly more likely to complete
29 weeks of receiving study medication than were subjects assigned to haloperidol.
By week 29, 22 (66.7%) of the haloperidol-treated patients were discontinued
from the study compared with 13 (35.1%) of the clozapine-treated patients,
a 32% difference (Wilcoxon  21, 4.59; P = .03). Three haloperidol- and 2 clozapine-treated patients were
discontinued from the study due to adverse effects.
Figure 1 shows the cumulative
proportions of subjects discontinued from the study specifically for lack
of efficacy; by 29 weeks, 50.5% of haloperidol-treated subjects discontinued
for lack of efficacy compared with 11.6% of clozapine-treated subjects, a
39% difference (Wilcoxon 21, 5.58; P = .02).
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Figure 1. Time to discontinuation of study
medication specifically for lack of clinical response. The clozapine group
included 37 subjects; the haloperidol group, 34 (Wilcoxon 21, 5.58; P = .02).
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PSYCHOTIC SYMPTOMS
A second major criterion for response was 20% improvement on the 4-item
BPRS psychosis cluster, as shown in Figure
2. A subject was classified as improved
if this score decreased 20% from baseline for at least 2 consecutive assessments
and was classified as not improved otherwise. (The 20% improvement is based
on BPRS ratings scaled from 1 to 7.) Subjects who discontinued treatment for
lack of efficacy—improved or not—were excluded from the at-risk
sample at discontinuation.
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Figure 2. Time to first of 2 consecutive
ratings of 20% improvement on the Brief Psychiatric Rating Scale psychosis
subscale. The clozapine group included 37 subjects; the haloperidol group,
34 (Wilcoxon 21, 5.88; P = .02).
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Separation between groups was seen by week 4, when 39% of clozapine-treated
subjects and 19% of haloperidol-treated subjects met this criterion. By 29
weeks, the proportions classified as improved were 56.6% for the clozapine
group compared with 24.8% for the haloperidol group, a 32% difference (Wilcoxon 21, 5.88; P = .02).
These criteria for improvement are based on change from baseline and
do not require that the subject meet an absolute threshold of symptom absence.
For this reason, the outcome represents improvement rather than remission.
In fact, in this population of patients with chronic illness, 1 (3%) of the
haloperidol-treated patients and 7 (19%) of the clozapine-treated patients
would have been rated as in remission at study conclusion if remission is defined by the 20% improvement criterion and no symptom
in the BPRS psychosis cluster rated greater than mild (Fisher exact test, P = .06; 1 df).
Table 2 presents means and
SDs over time by treatment group for symptom factors of the BPRS, global ratings
of the SANS, and psychiatrists' ratings of severity and improvement for observed
cases.
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Table 2. Symptom Ratings of Psychopathology by Time and Treatment*
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Changes in psychopathology from baseline to last rating indicate improvement
at end point for each subject. Figure 3
shows change from baseline to final rating for the BPRS total score and all
BPRS subscales. For comparison, scores were converted to the 7-point severity
scale by dividing by the number of items. For the psychosis subscale, the
haloperidol-treated group showed a decrease of 0.2 point, whereas the clozapine-treated
group showed an improvement of 0.8 point, an overall difference of 1 scale
point. The mean rating at final evaluation was 3.2 for the clozapine group,
closer to mild than moderate, compared with 4.2 for the haloperidol group.
Mean improvement between groups at end point (including the baseline measure,
site, and site x treatment in the analysis) had a 95% confidence interval
(CI) of 0.5 to 1.5 (treatment effect, F1 = 18.37; P<.001).
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Figure 3. Scale score improvement from baseline
to final rating for Brief Psychiatric Rating Scale subscales and total score
for all randomized subjects. The clozapine group included 37 subjects (n =
36 for thought disturbance); the haloperidol group, 34. All subscales are
displayed using change based on a 7-point scale to allow meaningful comparisons.
Asterisk indicates P<.001; dagger, P<.05;
and double dagger, P<.01.
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OTHER PSYCHOPATHOLOGY SYMPTOMS
Figure 3 shows that the advantage
of clozapine to haloperidol is 0.8 scale point for thought disturbance. A
difference of 0.6 scale point in anxiety-depression reflects improvement in
the clozapine group and deterioration in the haloperidol group. A smaller
effect (closer to 0.5 scale point) is evident for the BPRS total score and
the hostile-suspiciousness factor. A significant effect was not evident for
the anergia or activation factors.
The CGI ratings show a similar pattern of treatment effects. Severity
of illness is rated on a 7-point scale; 4 indicates moderately ill and 5,
markedly ill. The mean rating at final evaluation was 4.0 for clozapine compared
with 5.0 for haloperidol, a difference of 1.0 scale point in favor of clozapine.
Mean improvement between the groups at end point (including the baseline measure,
site, and site x treatment in the analysis) had a 95% CI of 0.4 to 1.4
(treatment effect, F1 = 14.77; P<.001).
The CGI improvement scale is a 7-point scale; 3 indicates minimally improved
and 4, no change. The mean final rating for clozapine-treated subjects was
3.0 compared with 4.2 for the haloperidol-treated subjects, a difference of
1.2 points. Mean improvement between the groups at end point (including site
and site x treatment in the analysis) had a 95% CI of 0.7 to 1.9 (treatment
effect, F1 = 19.30; P<.001).
NEGATIVE SYMPTOMS
There were no treatment differences on the SANS global composite (sum
of the 4 global ratings). Means for the haloperidol group changed from 9.8
to 10.4 at final rating, whereas means for the clozapine group changed from
10.3 to 9.7 at final rating. Mean improvement between the groups on the 20-point
scale (including the baseline measure, site, and site x treatment in
the analysis) had a 95% CI of -0.7 to 2.3 (treatment effect, F1 = 1.12; P = .29).
We considered the possibility that our failure to identify a treatment
effect in negative symptoms might be the result of the relatively low baseline
level of negative symptoms, and we repeated the analysis with subjects whose
baseline negative symptoms fell in the top 50%. Even in this subgroup, the
initial level of negative symptoms was modest and no treatment effect was
identified.
ADVERSE EFFECTS
The ANOVAs used to evaluate adverse effects used ratings completed at
5 weeks or last available observation if that occurred before 5 weeks. Clozapine-treated
subjects experienced more salivation, sweating, and dizziness; haloperidol-treated
subjects experienced more dry mouth and decreased appetite (Table 3). No other adverse effects were significantly different
between treatment groups. Since adverse effects may break the blind, the correlation
of adverse effects and responder/nonresponder status was examined. None of
these correlations was significant, although the correlation for dry mouth
approached significance (r = 0.22; P = .07).
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Table 3. Treatment-Emergent Adverse Effects by Treatment at Week 5
Observation*
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COMMENT
These findings extend our understanding of clozapine's efficacy in comparison
with first-generation antipsychotics. Benefits are seen for subjects who can
be treated in the community despite poor or partial response to conventional
antipsychotics. These advantages occur in subjects who had not responded previously
to either high or low dosages of conventional medication. This study is the
first to consider the possibility of an improved response to low doses of
antipsychotics in patients who have failed to respond to high doses. Some
patients who no longer met symptom criteria after dose reduction were excluded
from the trial. We used a moderate dose of haloperidol coupled with benztropine
to address the possibility that the advantage for clozapine resulted primarily
from reduction of adverse effects in contrast to the comparator group. In
fact, our findings regarding dosage suggest that clinicians were not satisfied
with the response of some haloperidol-treated subjects who remained in the
study. Haloperidol dosage was increased in more responsive patients, since
less responsive patients had discontinued the therapy.
Benefit increased rapidly during the 29-week trial, suggesting that
treatment exposure to clozapine produced rapid response. Had the trial been
4 weeks long, about 39% of subjects would have met the relatively modest 20%
improvement criterion that was attained by 57% in the trial. At 11 weeks,
54% had met this criterion.
How do these findings fit with results of other randomized trials comparing
clozapine with conventional antipsychotics? Kane et al5
compared clozapine with high-dose chlorpromazine in a 6-week trial. Response
was defined as a reduction in BPRS total score of greater than 20% from baseline
plus a posttreatment CGI score of mild or less or a posttreatment BPRS total
score of 35 or lower. Response rates were 30% for clozapine compared with
3.5% for chlorpromazine, a difference of 27% (95% CI, 18%-31%).
The Maryland study6, 8 compared
clozapine with haloperidol given in a moderate dosage in a 10-week trial.
Response was defined as a 20% or greater decrease in BPRS positive symptom
scores and a BPRS positive symptom score of less than 8. Response rates were
44% for clozapine compared with 5.5% for haloperidol, a difference of 39%
(95% CI, 5%-49%).
Rosenheck et al9 compared clozapine and
haloperidol in a 1-year trial. Excluding crossovers, the proportions of patients
improving 20% or more on the total Positive and Negative Syndrome Scale in
the clozapine group were 30% at 6 weeks, 30% at 6 months, and 42% at 1 year.
Improvement rates for the haloperidol group were 14%, 14%, and 31%, respectively.
Differences in results of comparisons at 6 weeks and 6 months were significant,
but the difference of 11% at 1 year was not.
In a randomized but nonblind effectiveness study using the same response
criteria as the study by Kane et al5 (excluding
crossovers), Essock et al10 reported that 62%
of the clozapine-treated patients had responded at 24 months compared with
49% of the usual-care subjects (a nonsignificant difference).
In the present trial, we found a 57% improvement with clozapine after
29 weeks. In the 3 double-blind efficacy studies, improvement rates increased
(30% at 6 weeks, 44% after 10 weeks, and 57% after 29 weeks) as trial length
increased, suggesting an advantage to longer treatment with clozapine, qualified
by differences in definition of improvement.
Our findings, as well as those of other recent studies, suggest that
the clozapine advantage is not just a function of comparison with a high dose
of a conventional antipsychotic. However, these studies underscore that improvement
is not always remission. We used a liberal definition of remission in our
trial (20% improvement in psychotic symptoms and no psychosis item rated above
mild). Only 3% of haloperidol- and 19% of clozapine-treated subjects met this
criterion. Perhaps less severely ill patients or those with a shorter duration
of illness (our subjects had been ill for a mean of 17 years) would be more
likely to experience remission.
Findings are most consistent for positive signs and symptoms. We saw
effects for a range of symptoms, including psychosis, anxiety/depression,
thought disturbance, and hostility, with the notable exception of negative
signs. Our inability to detect differences between clozapine and haloperidol
on negative symptoms may result in part from the low levels of negative symptoms
in our subjects. However, even when we restricted analysis to the smaller
group of subjects who manifested some negative symptoms, we did not see an
effect. Given the small differences we found, it is unlikely that a larger
study would have been more informative. In contrast to effects on positive
symptoms that are seen even in comparisons with low-dose conventional agents,
effects on negative symptoms might be, to some extent, a function of the high
dose of a comparator agent. Another possibility is that the exclusion of patients
who responded to low doses of conventional antipsychotics eliminated subjects
who showed negative symptom response in other trials.
The next generation of studies regarding clozapine needs to compare
it with the next generation of antipsychotics. The sparse existing literature
comparing clozapine and risperidone is inconclusive because of the small number
of subjects involved (<100 in total) and because of methodological questions.27, 28 Recently published guidelines for the
treatment of schizophrenia uniformly recommend at least 1 trial with a second-generation
antipsychotic before proceeding to clozapine.29, 30
However, these recommendations are based on expert opinion rather than experimental
studies.
On balance, clozapine provides substantial clinical advantages for patients
who experience persistent psychotic symptoms. It is a difficult medication
to use, with potentially severe adverse effects and the need for continued
monitoring of the white blood cell count, which is mandatory in the United
States. That mandate has been reduced by the Food and Drug Administration
from weekly to biweekly after 6 months, but any ongoing monitoring requirement
is infrequent among psychotropic medications. The positive findings of this
study, added to others in the literature, should encourage psychiatrists to
try clozapine for patients who continue to have residual symptoms and to use
it long enough to see maximal benefit.
AUTHOR INFORMATION
Accepted for publication March 22, 2001.
This study was supported by grants MH46672 (Dr Schooler), MH46613 (Dr
Kane), and MH46484 (Dr Marder) from the National Institute of Mental Health,
Rockville, Md. We also acknowledge financial support to aid in clozapine-required
monitoring and medication supplies from Novartis.
Joan Bezner, RN, Joanne McKenzie, RN, and Linda Porto, RN, provided
ongoing clinical support and assessment for study subjects as the nurse clinicians
on the treatment teams.
From the Department of Psychiatry, Hillside Hospital, North Shore–Long
Island Jewish Health System, Glen Oaks, NY (Drs Kane, Umbricht, Safferman,
McMeniman, and Borenstein); the Department of Psychiatry, West Los Angeles
Veterans Affairs Medical Center, Los Angeles, Calif (Drs Marder, W. C. Wirshing,
and D. A. Wirshing); and the Western Psychiatric Institute and Clinic, Department
of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pa
(Drs Schooler, Baker, and Ganguli). Dr Schooler is now with the Department
of Psychiatry, Hillside Hospital; Dr Umbricht, the Department of Psychiatry,
Psychiatric University Hospital, Zurich, Switzerland; Dr Baker, Eli Lilly
and Company, Indianapolis, Ind; and Dr Safferman, Pfizer Pharmaceuticals,
New York, NY.
Corresponding author and reprints: John M. Kane, MD, Hillside Hospital,
Glen Oaks, NY 11004.
REFERENCES
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1. Rupp A, Keith SJ. The costs of schizophrenia. Psychiatr Clin North Am. 1993;16:413-423.
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