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Journal of Psychopharmacology
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DOI: 10.1177/0269881112440513
 published online 30 March 2012J Psychopharmacol
Megan Sherwood, Allen E Thornton and William Honer
clozapine
A quantitative review of the profile and time course of symptom change in schizophrenia treated with
 
 
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DOI: 10.1177/0269881112440513
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Introduction
Reformulating the time course of antipsychotic treatment response 
in schizophrenia to an ‘early response’ model has important clinical 
implications (Agid et al., 2003; Honer et al., 2009). These include 
understanding the mechanism of action of antipsychotics (Li et al., 
2007), strategies for analysis of clinical trial data (van den Oord 
et al., 2009), and developing approaches to predict longer-term out-
come for individual patients depending on the extent of early 
response (Chen et al., 2009; Correll et al., 2003; Kinon et al., 2008, 
2010; Leucht et al., 2007). The early response model is supported 
by meta-analyses including typical (or first generation) and atypical 
(or second generation) antipsychotics (Agid et al., 2003; Leucht 
et al., 2005), and by increasing numbers of reports of specific dru-
gresponse profiles, including olanzapine (Kapur et al., 2005), risp-
eridone (Emsley et al., 2006; Glick et al., 2006; Raedler et al., 
2007), quetiapine (Small et al., 2004), and ziprasidone (Agid et al., 
2008). Notably absent from these meta-analyses, and from indi-
vidual agent studies, is an assessment of clozapine.
Clozapine is the only antipsychotic with proven efficacy in treat-
ment refractory patients (Chakos et al., 2001; Kane et al., 1988; 
McEvoy et al., 2006). The broad range of receptor interactions of 
clozapine may contribute to this unique property, including greater 
D1 and 5HT2A, and lower D2 receptor occupancy than many other 
antipsychotics (Farde et al., 1992; Kapur et al., 1999; Meltzer et al., 
1989b; Tauscher et al., 2004). Clinicians are familiar with a subset 
of patients with a delayed response to clozapine, slowly improving 
over weeks or months (Meltzer et al., 1989a). This could reflect 
different neurological pathways in refractory patients, or a cascade 
of non-linear effects over weeks. However, this ‘delayed response’ 
model was the conventional wisdom for all antipsychotics until 
recently. An apparent delayed response might occur based on inad-
equate clozapine serum concentration, slow titration of dose, or an 
average of early and non-persistent placebo effect balanced by late 
and persistent true clozapine effect (Conley et al., 1997). Clozapine 
appears equally effective as other antipsychotics in acute or first-
episode schizophrenia (Claghorn et al., 1987; Lieberman et al., 
2003; Woerner et al., 2003), and there is no reason to believe the 
action of clozapine is delayed in these patient populations which 
have made up the majority of studies contributing to meta-analyses 
of the time course of response to other antipsychotics (Agid et al., 
2003; Leucht et al., 2005). As well, withdrawal of clozapine is noted 
to be associated with rapid worsening of psychosis, perhaps repre-
senting a mirror image of an initial response (Moncrieff, 2006).
A quantitative review of the profile and 
time course of symptom change in 
schizophrenia treated with clozapine
Megan Sherwood1,2,3, Allen E Thornton2,4 and William G Honer1,2
Abstract
Contemporary analyses demonstrate an early response to antipsychotic treatment in non-refractory schizophrenia. The profile of response to clozapine 
is unknown. We used meta-analytic and statistical procedures to examine the response profile to clozapine. We identified 19 unique, randomized, 
double-blind controlled clinical trials with suitable time course data, representing 1745 subjects. Individual subject data were available for 419 
subjects, obtained from two industry-sponsored trials. Symptom severity scores from the BPRS or the PANSS were entered into regression analyses to 
estimate linear and quadratic coefficients of the rate of change of symptom severity over 4 weeks. Both linear and quadratic regression coefficients 
for clozapine, and for comparator antipsychotics differed significantly from zero (p ≤ 0.001), indicating early response profiles. Compared with other 
antipsychotic arms, for clozapine the treatment response was greater (d = -0.578, p = 0.021), and the linear coefficient was steeper (d = -0.502, 
p = 0.042); the quadratic coefficients indicating attenuation did not differ. Analyses of 6-week data and individual subject data from non-refractory 
and refractory trials were consistent with the primary findings. Somewhat surprisingly, clozapine shows an early response profile, similar in pattern 
but somewhat larger in magnitude than other antipsychotic drugs.
Keywords
Clozapine, antipsychotic, schizophrenia, BPRS, PANSS
1 Department of Psychiatry, University of British Columbia, Vancouver, 
BC, Canada 
2 Centre for Complex Disorders, BC Mental Health and Addictions 
Research Institute, Vancouver, BC, Canada 
3 Department of Psychiatry, Vancouver General Hospital, Vancouver, BC, Canada 
4 Department of Psychology, Simon Fraser University, Burnaby, BC, Canada
Corresponding author:
WG Honer, Centre for Complex Disorders, BC Mental Health and 
Addictions Research Institute, A3-127 938 West 28th Avenue, 
Vancouver, BC, V5Z 4H4, Canada 
Email: honer@mail.ubc.ca
Portions of the paper were presented at the 12th International Congress 
of Schizophrenia Research, San Diego, CA, April, 2009.
440513 JOP0010.1177/0269881112440513Honer et al.Journal of Psychopharmacology
2012
Original Paper
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2 Journal of Psychopharmacology 0(0)
A quantitative review of the time course of response to clozap-
ine would allow comparison with other studies of non-clozapine 
antipsychotics. The initial meta-analyses of antipsychotic treat-
ment response used week-to-week percentage change in symptom 
scores relative to baseline (Agid et al., 2003; Leucht et al., 2005). 
This approach was followed by a complementary strategy based 
on graphical analysis of response curves over time, asking whether 
the curves were linear, convex or concave (Sherwood et al., 2005). 
The latter two profiles are indicated by the presence of quadratic 
components to the equations describing the curves, and represent 
an early response (concave or hockey stick shape) or a delayed 
response (convex or outward bowing shape). A similar strategy 
was used earlier to model response in a study of first-episode 
schizophrenia (Lieberman et al., 2003).
In order to evaluate the time course of treatment response to 
clozapine compared with other antipsychotics, we carried out a 
quantitative review using aggregate data from trials that provided 
evaluations of 4–6 weeks of treatment. The outcome measures 
included change scores from baseline, as well as linear and quad-
ratic components of the profileof decrease in global psychopa-
thology. As a complementary strategy, we also applied the same 
approach to individual patient data from one treatment-refractory 
(Kane et al., 1988) and one non-refractory (Claghorn et al., 1987) 
study using the same comparator agent. Our hypothesis was that 
the profile of the time course of response to clozapine would be 
different from other antipsychotic agents. We also hypothesized 
that individual patient data would support the aggregate data anal-
ysis, and allow extension of the findings to positive symptoms.
Methods
The study was carried out in two parts. Aggregate data from stud-
ies of clozapine were used to perform a quantitative analysis of 
the symptom response profile over time in patients treated with 
clozapine and with comparator antipsychotic drugs. Second, we 
examined individual patient profiles of change in total and in posi-
tive symptom severity over time from two trials of clozapine com-
pared with chlorpromazine.
Aggregate data sources
Electronic searches included MEDLINE on OVID from 1950 to 
12 January 2011, EMBASE on OVID from 1980 to Week 1, 2011, 
Cochrane Central Register of Controlled Trials to 4th Quarter 
2010, LILACS on line (www.bireme.br) to January 2011, 
CINAHL from 1982 to January 2011 and PsychINFO to January 
2011.
Aggregate data selection
For the MEDLINE search, key words and phrases used were 
‘schizophrenia’, ‘psychiatric status rating scales’, and ‘clozapine’. 
These words were exploded. Results were limited in the searching 
process to ‘randomized controlled trial’, ‘human’, and ‘English 
language’. All abstracts were reviewed, and methods and results 
from the full text articles were reviewed as necessary. Where the 
abstract but not full text was available in English, and inclusion 
could not be determined from the abstract, translation was 
obtained. References from included studies from the Cochrane 
schizophrenia group systematic reviews of clozapine were simi-
larly reviewed. With the remainder of the databases, modifica-
tions included also using ‘rating scales’, ‘brief psychiatric rating 
scale’, ‘BPRS’, ‘positive and negative syndrome scale’, and/or 
‘PANSS’. ‘Randomized control trials’ was used as a key word, or 
‘clinical trial’ was used as a limit and results were searched by 
hand for the double-blind, randomized controlled trials.
The inclusion criteria were:
(1) Diagnoses of schizophrenia, schizoaffective disorder, or 
schizophreniform disorder.
(2) Medications were clozapine and a non-clozapine antipsy-
chotic comparator.
(3) Brief Psychiatric Rating Scale (BPRS) or Positive And 
Negative Syndrome Scale (PANSS) total scores were 
reported for at least three data-points, including baseline, 
2 and 4 weeks.
(4) Double-blind, randomized controlled trial.
(5) English language abstract or results of hand search of 
references.
The exclusion criteria were:
(1) Subjects with a primary mood disorder, or a diagnosti-
cally heterogeneous group of subjects.
(2) The primary study goal was treatment of negative or defi-
cit symptoms.
(3) Subjects received more than one primary trial medication 
or cross-over medication.
(4) Patients under the age of 15 years or mean age over 65 
years.
(5) Route of administration other than oral.
(6) Repeat publication.
There was no restriction on publication date or sample size. 
After review of published materials and method, and any related 
publications, the first author was contacted for trials where BPRS 
or PANSS data were collected but not reported at multiple time 
points, and publication was within the last 10 years. Database 
entries were screened (MS), and decisions concerning final selec-
tion of studies for analysis were made by consensus (MS, AET, 
WGH).
Description of individual patient data trials
The FDA was contacted but had no data available. Novartis pro-
vided individual patient trial data from previously reported 
Clozapine Studies 16 and 30 (Claghorn et al., 1987; Kane et al., 
1988). Clozapine Study 16 was a double-blind, randomized, 
multi-centre US trial with 151 patients. Subjects were diagnosed 
with schizophrenia by DSM-II with a 295 code, with moderate 
severity of illness and a minimum score of 4 on three of six pre-set 
BPRS items. There was no mention of treatment refractory status, 
and hospitalization was for less than 6 months. The median length 
of the episode was 72 days. Tardive dyskinesia was present in 
17% of subjects randomized to clozapine and in 24% of subjects 
randomized to chlorpromazine. The study included a baseline pla-
cebo phase of as long as 2 weeks, followed by dosage increase 
during 1 week, and flexible dosing (150–900 mg clozapine or 
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Sherwood et al. 3
300–1800 mg chlorpromazine) for 3 weeks. The outcome meas-
ure for symptom severity was the BPRS.
Clozapine Study 30 was the pivotal, double-blind, randomized, 
multi-center US trial with 268 patients. Subjects were diagnosed 
with schizophrenia by DSM-III, and were refractory defined by: 
three periods of treatment in 5 years with antipsychotics from at 
least two drug classes, for at least 6 weeks per trial, at dosages 
equivalent to 1000 mg CPZ, without ‘significant symptomatic 
relief’, and no period of good functioning within the preceding 5 
years. Subjects also were required to have a BPRS total score of at 
least 45 and a minimum CGI score of 4, as well as a score of 4 on 
two of four specified BPRS items. The median length of present 
hospitalization was 2 years, with a mean of seven prior hospitali-
zations by study entry. The study included a baseline placebo 
phase of 2 weeks, followed by a trial of haloperidol for 6 weeks. 
Patients with 20% improvement on the BPRS plus either a Clinical 
Global Impression (CGI) score of 3 or less, or a BPRS total score 
of less than 35 were excluded from subsequent phases. The halo-
peridol phase was followed by 1 week of placebo, then 6 weeks of 
trial medication. Clozapine up to 900 mg daily was compared 
with chlorpromazine up to 1800 mg daily administered with ben-
ztropine. The first 2 weeks of trial medication were fixed dose, if 
tolerated, followed by flexible dosing. A priori specified outcome 
measures were the total BPRS score, a cluster of four positive 
symptom BPRS items, and the CGI.
Data extraction and standardization
For both aggregate and individual patient data, PANSS and BPRS 
total scores were converted to a per-item score with a range of 
0–6. A PANSS per-item score was calculated as (baseline – 
30)/30. BPRS scores were assumed to be scored 1–7 on an 
18-item scale, unless otherwise specified, and the per-item calcu-
lated as (baseline–18)/18. Where BPRS or PANSS data were 
available in graphic form, these were enlarged then extracted by 
paper-and-ruler method by one of us (MS). Jadad scores grading 
the quality of each trial were obtained from the Cochrane system-
atic reviews (n = 12), or scored according to the published criteria 
(n = 7) (Jadad et al., 1996). Type of comparator antipsychotic and 
drug dosages were recorded. We based the analysis on clozapine 
versus active comparator treatment, as placebo comparison was 
not available. Each study arm was treated as a distinct ‘subject’, 
but within the same study, arms with different doses of the same 
medication were combined.
Trajectory estimates and analysis
For descriptive purposes, we first analyzed change in mean symp-
tom score at weeks 4 and 6 relative to baseline. The baseline 
scores in patients assigned to the clozapine and comparator arms 
were highly correlated across studies (r = 0.92). Therefore, paired 
t-test analyses were used to compare change over time between 
the arms of the studies.
To define the overall response profile, we modeled the treat-
ment responseas a quadratic function of time:
Expected BPRS Item Score = ß0 + ß1 * W + ß2 * W2
where W is the week number (0,..., 6), and ß0, ß1, and ß2 are 
coefficients produced by the regression analysis (Sherwood et al., 
2005). We were interested in the unstandardized coefficients. The 
constant (ß0) is the expected baseline level of symptoms. The lin-
ear coefficient (ß1) is the slope of the initial response curve from 
baseline (Week 0), with a negative value indicating the expected 
decline in symptom severity over time, and a positive value indi-
cating a rise. The quadratic coefficient (ß2) represents subsequent 
change in the slope over time, with a positive value indicating a 
subsequent increase in the slope, and a negative value indicating a 
decrease. An early response profile would be indicated by a large 
negative value for the linear coefficient ß1, and a positive value 
for the quadratic coefficient ß2 (concave shape with a steep initial 
response and attenuation over time). In contrast, a delayed 
response profile would be indicated by a smaller negative value 
for ß1, as well as a negative value for ß2 (convex response with a 
shallow initial response and acceleration over time).
We first considered whether linear and quadratic coefficients 
for clozapine, and for comparator, differed statistically from zero 
by using a one sample t-test. Then, the linear coefficients were 
compared between clozapine and comparator arms using a paired 
t-test. For all clozapine versus comparator analysis, effect sizes 
for non-independent samples (such as a paired t-test) are reported 
(Rosenthal and Rosnow, 1991). These estimates are based on the 
difference between the means of per-item score for the treatment 
arms divided by the standard deviation of the differences. 
Although the effect sizes calculated in this way are expressed in a 
similar manner to the more familiar Cohen’s d as small (≤ .3), 
medium (.4–.7) or large (≥ .8) (Cohen, 1988), caution should 
be applied in direct comparisons of effect sizes between non- 
independent and independent samples.
Studies used for the aggregate data analysis specified refractory 
patients (n = 7) or were likely a heterogeneous mix of non-refractory 
and refractory patients (n = 12). Rather than split the aggregate 
data into subgroups of studies with reduced power due to small 
sample size, we explored the effects of ‘non-refractory’ and refrac-
tory status by examining the individual patient data from Studies 
16 (n = 96, including non-refractory patients) and Study 30 (n = 
254, limited to refractory patients). Similar calculations were car-
ried out for the individual patient data as described above for the 
aggregate data. Independent sample t-tests were used to compare 
response profile coefficients of clozapine versus chlorpromazine 
treated patients within each study. Conventional effect estimates 
(d) for independent samples are reported (Rosenthal and Rosnow, 
1991). These estimates are based on the difference between the 
means of per-item scores for the treatment arms divided by the 
pooled standard deviations of the arms (Hedges’ formula).
Results
From the electronic databases, a total of 411 entries were identi-
fied (MEDLINE n = 94, EMBASE n = 246, CCRCT n = 125, 
LILACS n = 2, CINAHL n = 4, and PsychINFO n = 51). Following 
application of inclusion and exclusion criteria, 26 double-blind, 
randomized controlled trials remained. Of these, with the addition 
of hand-searches of references, 19 trials with 38 separate con-
densed arms had sufficient data points to be included in the analy-
sis, representing 1745 subjects (Table 1). Three data arms were 
eliminated: two comparator drugs were given simultaneously 
(Potter et al., 1989), a placebo arm was terminated prematurely 
(Shopsin et al., 1979), and an arm of an alternate comparator was 
a subsequently withdrawn antipsychotic (remoxipride) (Klieser 
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4 Journal of Psychopharmacology 0(0)
et al., 1994). Two studies were included after responses from 
authors to queries (Bondolfi et al., 1998; Kluge et al., 2007).
Study characteristics appear in Tables 1 and 2. The studies 
ranged in duration from 4–18 weeks; the most consistently avail-
able data were for 4- and 6-week durations. The mean number of 
data points contributing to analysis of the 4-week coefficients for 
each study was 4.6, with modal value 5. For the 6-week coeffi-
cients, the values were mean 6.5 data points, modal value 7.
By the end of the first week of treatment, both clozapine and 
comparator drugs had reached a mean value of 73% of the week 4 
final dose, suggesting titration schedules were similar (Figure 1). 
The mean final doses of clozapine, 337 mg/day at week 4, and 297 
mg/day for the week 6 studies, were at the lower limit of 300 mg/
day suggested in the product monograph. At the end of week 4, 
5/16 studies reported dosages < 275 mg/day; at the end of week 6, 
4/10 studies reported dosages < 275 mg/day. Regarding titration 
of clozapine, 7/17 studies initiated treatment with a dose of clo-
zapine greater than 25 mg/day. At the end of week 1, 5/16 studies 
were below a mean dose of 162.5 mg/day as recommended in the 
product monograph for a slow titration schedule, and 2/16 were 
above the dose of 325 mg/day recommended for the maximum. 
By the end of week 2, 6/16 studies were below a mean dose of 300 
mg/day as recommended in the product monograph for a slow 
titration schedule, and 0/16 were above the dose of 450 mg/day 
recommended for the maximum.
Meta-analysis of aggregate data
Baseline, per-item scores and the decline in these scores appear 
in Table 2, with statistical comparisons in Table 3. For all 
studies, declines of symptom scores from baseline to 4 weeks of 
treatment were present for both the clozapine and comparator 
arms; these were associated with a high degree of statistical sig-
nificance and large effect sizes. The clozapine treatment arms 
showed statistically significant greater declines in the per-item 
scores compared with the comparator arms; the effect size for 
the difference between drugs was moderate. This magnitude of 
effect size indicates that the median decline for the clozapine 
arms was greater than the decline observed in 72% of the com-
parator arms. The response profiles at 4 weeks were assessed by 
the associated linear and quadratic coefficients (Table 3, and 
Figure 2). The linear and quadratic coefficients were different 
from zero for both clozapine and comparator drugs, indicating 
early response profiles in both. However, the linear coefficients 
indicated a more precipitous decline for clozapine arms; the dif-
ference relative to the comparator was statistically significant 
and corresponded to a moderate effect (Table 3, the median lin-
ear coefficient of the clozapine arms suggested an initial 
response to clozapine that exceeded the initial response in 70% 
of comparator arms).
The 6-week data showed an advantage for clozapine versus 
comparator arms in symptom reduction, now associated with a 
large effect size. Similar to the 4-week data, both clozapine and 
comparator arms showed early response profiles, with negative 
linear and positive quadratic regression coefficients that differed 
from zero. Again similar to the 4-week data, the linear coefficient 
for clozapine was greater than for comparator arms, indicating a 
more precipitous decline in per-item symptom severity in the clo-
zapine arms, now associated with a moderate-to-large effect size 
(Table 3).
Table 1. Characteristics of included studies.
Study Type Year Age (yr) Age at first 
diagnosis (yr)
Male 
(percent)
Completion 
rate (percent)
Jadad 
score
Data points 
(wk)
Singer and Law (1974) NR 1974 31.9 29.4 47.4 95.0 3 01246
Fischer-Cornelssen and Ferner(1976) NR 1976 34.0 UNK 69.8 90.2 4 0123456
Gelenberg and Doller (1979) NR 1979 29.6 UNK 53.3 53.3 3 01234
Shopsin et al. (1979) NR 1979 UNK UNK UNK 45.2 4 01234
Honigfeld et al. (1984) NR 1984 UNK UNK UNK 70.9 2 0123456
Claghorn et al. (1987) NR 1987 30.0 UNK 60.9 58.3 4 01234
Kane et al. (1988) R 1988 35.7 20.4 80.0 87.5 5 0123456
Potter et al. (1989) NR 1989 32.5 27.1 56.8 UNK 2 024
Stein et al. (1989) R 1989 UNK UNK UNK 95.5 2 0123456
Heinrich et al. (1994) NR 1994 33.2 UNK 52.5 52.5 3 01234
Klieser et al. (1994) NR 1994 32.4 27.4 38.3 94.4 2 01234
Bondolfi et al. (1998) R 1998 37.3 23.0 70.9 79.1 4 012346
Kane et al. (2001) R 2001 40.5 21.0 70.5 47.9 3 012345
Tollefson et al. (2001) R 2001 38.6 22.8 63.9 59.5 3 012346
Li et al. (2002) NR 2002 29.0 28.4 49.2 100.0 2 024
Wang et al. (2002) NR 2002 27.9 23.8 47.5 93.8 2 024
Bitter et al. (2004) R 2004 37.6 UNK 59.9 58.0 3 0123456
Sacchetti et al. (2009) R 2006 40.0 26.2 69.2 61.6 3 0123456
Kluge et al. (2007) NR 2007 34.8 29.0 40.0 86.7 3 0123456
Mean 34.1 25.3 58.1 73.8 3 
SD 3.9 3.2 12.1 19.2 0.9 
NR, non-refractory; R, refractory; SD, standard deviation; UNK, unknown.
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Sherwood et al. 5
In summary, the 4- and 6-week response profiles of both clo-
zapine and the comparator antipsychotic drugs were early and 
subsequently attenuated. Notably, clozapine arms showed steeper 
linear coefficients of symptom decline than the comparator arms, 
indicating a greater initial response to clozapine.
Analysis of Study 16 individual subject data
To further elucidate the clozapine response profile, linear and 
quadratic coefficients were compared for 47 individual partici-
pants randomized to clozapine and 49 participants randomized to 
Table 2. Treatment and symptoms in included studies. Symptoms are the mean per-item score on the BPRS or PANSS, using a 0–6 scaling.
Study Type Clozapine Symptoms Comparator Symptoms
 n
Highest 
dose (mg/d) Baseline
Change 
at wk 4
Change 
at wk 6 Drug n
Highest 
dose (mg/d) Baseline
Change 
at wk 4
Change 
at wk 6
Singer and Law (1974) NR 20 155 1.67 -1.43 -1.53 CPZ 20 196 1.63 -1.23 -1.39
Fischer-Cornelssen and 
Ferner (1976)
NR 110 312 2.52 -1.48 -1.76 CPZ 113 378 2.35 -1.13 -1.25
Gelenberg and Doller 
(1979)
NR 7 279 1.50 -1.00 CPZ 8 606 1.61 -0.44 
Shopsin et al. (1979) NR 16 800 2.62 -1.48 CPZ 15 1333 2.52 -1.09 
Honigfeld et al. (1984) NR 39 397 2.49 -0.82 -0.92 HAL 40 8 2.53 -0.47 -0.61
Claghorn et al. (1987) NR 75 417 2.23 -1.36 CPZ 76 795 2.05 -1.09 
Kane et al. (1988) R 126 592 2.39 -0.73 -0.88 CPZ 142 908 2.39 -0.31 -0.29
Potter et al. (1989) NR 17 UNK 1.26 -0.44 CPZ 20 UNK 1.58 -0.92 
Stein et al. (1989) R 11 400 2.95 -1.56 -1.95 HAL 11 20 2.50 -0.68 -1.06
Heinrich et al. (1994) NR 20 400 2.19 -1.37 RISP 39 6 2.01 -1.27 
Klieser et al. (1994) NR 18 350 2.06 -1.06 HAL 18 16 2.22 -1.17 
Bondolfi et al. (1998) R 43 293 2.35 -0.55 -0.67 RISP 43 6 2.54 -0.79 -0.87
Kane et al. (2001) R 37 433 1.63 -0.39 -0.49 HAL 34 10 1.49 -0.06 0.00
Tollefson et al. (2001) R 90 231 2.49 -0.61 -0.84 OLANZ 90 17 2.61 -0.58 -0.75
Li et al. (2002) NR 31 148 1.86 -0.95 QUET 32 252 1.89 -0.92 
Wang et al. (2002) NR 31 UNK 2.04 -1.29 OLANZ 30 UNK 1.98 -1.31 
Bitter et al. (2004) R 72 170 2.50 -0.80 -1.01 OLANZ 75 12 2.63 -0.79 -1.03
Sacchetti et al. (2009) R 73 312 2.56 -0.43 -0.54 ZIP 73 123 2.63 -0.48 -0.51
Kluge et al. (2007) NR 15 267 2.03 -1.15 -1.39 OLANZ 15 21 2.04 -0.80 -1.10
Mean 44.8 350 2.17 -0.99 -1.09 47.1 2.17 -0.82 -0.80
SD 35.6 163 0.44 0.40 0.49 37.6 0.39 0.36 0.43
NR, non-refractory; R, refractory; UNK, unknown; CPZ, chlorpromazine; HAL, haloperidol; RISP, risperidone; OLANZ, olanzapine; QUET, quetiapine; ZIP, ziprasidone.
Figure 1. Dosing of clozapine in study arms included in the aggregate analysis. In the left panel, for both clozapine and comparator dose on a 
week-by-week basis was calculated as a percentage of the final dose at week 4. In the right panel, actual mean doses of clozapine obtained on a 
week-by-week basis are illustrated. Data were available for n = 16/19 clozapine study arms, and n = 16/19 comparator arms.
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6 Journal of Psychopharmacology 0(0)
Table 3. Changes in symptom severity, and response profiles (linear and quadratic coefficients) for clozapine and comparator antipsychotic 
drugs in aggregate analyses. For clozapine and comparator columns, effect sizes and p-values for change in symptom severity refer to differences 
from baseline, and for coefficients refer to differences from zero. Linear coefficients different from zero indicate a significant slope of change in 
symptoms over time, and quadratic coefficients greater than zero indicate attenuation of the response over time. For Clozapine versus comparator 
column, effect sizes and p-values refer to comparisons between clozapine and comparator arms.
Clozapine Comparator Clozapine versus comparator
 K Mean SD d p-value Mean SD d p-value Mean Diff. SD Diff. d p-value
0–4 week data
 Change in 
symptom severity 
(per item score)
19 -0.995 0.398 -2.500 <0.001 -0.816 0.357 -2.286 < 0.001 -0.1788 0.3096 -0.578 0.021
 Linear coefficients 19 -0.409 0.228 -1.794 <0.001 -0.311 0.165 -1.885 < 0.001 -0.0982 0.1957 -0.502 0.042
 Quadratic 
coefficients
19 0.040 0.037 1.081 <0.001 0.028 0.029 0.966 0.001 0.0120 0.0352 0.341 0.155
0–6 week data
 Change in 
symptom severity
11 -1.090 0.493 -2.211 <0.001 -0.803 0.429 -1.872 < 0.001 -0.2867 0.3188 -0.899 0.014
 Linear coefficients 11 -0.330 0.168 -1.964 <0.001 -0.240 0.129 -1.860 < 0.001 -0.0898 0.1166 -0.770 0.029
 Quadratic 
coefficients
11 0.025 0.017 1.471 0.001 0.018 0.013 1.385 0.001 0.0069 0.0126 0.548 0.098
K, number of included study arms; SD, standard deviation; d, effect size.
Figure 2. Change in symptom severity in clozapine and in chlorpromazine study arms over time (0–4 weeks left panels, 0–6 weeks right panels). 
Each profile illustrated with a thin line represents data from one treatment arm; mean data for all arms appear in the heavy line. Number of arms 
included was: n = 19 for 0–4 week analysis, and n = 11 for 0–6 week analysis. Symptom severity scores are per-item, from the BPRS or PANSS, 
converted to a 0–6 scale.
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Sherwood et al. 7
chlorpromazine from Study 16. This study was not restricted to 
refractory patients, nor do refractory patients appear to have been 
excluded. Attrition of 25 clozapine and 26 chlorpromazine treated 
participants from the published data set was principally due to loss 
of subjects with less than the minimum of three BPRS ratings nec-
essary to estimate quadratic functions. In addition, four extreme 
outlying coefficients were identified during data screening and the 
associated cases (n = 3 from the clozapine group and n = 1 from 
the chlorpromazine group) were deleted from the analyses. The 
total, and the positive symptom scores derived from the BPRS 
were investigated through 4 weeks of treatment (Figure 3). Both 
clozapine and chlorpromazine dosages were increased rapidly to a 
plateau during this trial (Table 4).
Analysis of this subset of the Study 16 data indicated improve-
ment in symptom severity over 4 weeks in both the clozapine and 
chlorpromazine groups (Table 5). Clozapine had a statistically 
significant advantage over chlorpromazine, associated with a 
medium effect size. This result is consistent with the original 
report of the complete data set (Claghorn et al., 1987). Concerning 
the response profile, the negative value linear coefficients dif-
fered from zero for both the clozapine and the chlorpromazine 
arms. Testing of the quadratic coefficients for clozapine andfor 
chlorpromazine indicated that the responses attenuated. Both clo-
zapine and chlorpromazine showed an early response profile; 
comparison of the linear and quadratic coefficients between 
groups showed no statistically significant differences.
Positive symptom scores were examined; again, improve-
ments over 4 weeks were observed for both drugs, with an advan-
tage for clozapine, associated with a medium effect size. 
Consistent with the findings for the response profiles for overall 
symptom severity, for positive symptoms both drugs showed an 
early response profile. There were no statistically significant dif-
ferences in the linear or quadratic coefficients between drugs.
Figure 3. Change in symptom severity in clozapine and in chlorpromazine study arms over time from a study of non-refractory schizophrenia (Study 
16, (Claghorn et al., 1987) NR, left panels) and a study of refractory schizophrenia (Study 30, (Kane et al., 1988) R, right panels). Each profile 
illustrated with a thin line represents data from a single subject; mean data for all subjects appear in the heavy line. Number of subjects illustrated: 
n = 50 for clozapine – NR, and n=50 for chlorpromazine – NR; and n = 123 for clozapine – R, and n = 138 for chlorpromazine – R.
Table 4. Doses of clozapine and chlorpromazine on a weekly basis in 
studies 16 and 30.
Week
 1 2 3 4 5 6
Study 16
 Clozapine mg/d 255 377 415 417 
 Chlorpromazine mg/d 516 858 783 795 
Study 30
 Clozapine mg/d 288 325 538 571 592 442
 Chlorpromazine mg/d 571 679 1075 1154 1183 908
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8 Journal of Psychopharmacology 0(0)
To summarize, the findings from Study 16 for overall and for 
positive symptom severity show an early response profile for both 
clozapine and chlorpromazine treatments.
Analysis of Study 30 individual subject data
Study 30 is well known as the pivotal trial of clozapine limited to 
treatment refractory patients. We analyzed data for 123 partici-
pants randomized to clozapine and 138 participants randomized to 
chlorpromazine, through 6 weeks of treatment. Seven extreme 
outlying coefficients (n = 3 clozapine and n = 4 chlorpromazine) 
were deleted from estimates. As with Study 16, the clozapine and 
chlorpromazine doses were increased rapidly, and in parallel dur-
ing Study 30 (Table 4).
Improvement in symptom severity from baseline was observed 
for both clozapine and chlorpromazine arms; clozapine had an 
advantage over chlorpromazine associated with a large effect size 
(Table 5, Figure 3). Concerning the response profiles, at 6 weeks, 
the negative value linear coefficients for clozapine and for chlor-
promazine differed from zero. In addition, the decline in symptom 
severity was steeper for clozapine, associated with a small-to-
medium effect size compared with chlorpromazine. The response 
to clozapine attenuated over 6 weeks; the quadratic coefficient of 
the response profile was positive and different from zero. 
In contrast, the response profile for chlorpromazine did not show 
statistically significant attenuation, although the overall treatment 
response was not as favorable as that observed for clozapine.
Clinical response was also analyzed on the basis of an eight-
item BPRS positive symptom scale (Kane et al., 1988). The find-
ings related to difference in change of positive symptom severity 
were similar to those for overall symptoms. Similarly, for positive 
symptoms clozapine showed an early response profile, with a 
steeper linear coefficient than chlorpromazine.
To summarize the findings from Study 30, a clear early 
response profile was observed for clozapine, for both total and 
positive symptoms. Both linear and quadratic coefficients were 
different from zero. The linear response of both total and 
positive symptoms was greater for clozapine compared with 
chlorpromazine.
Discussion
The findings of the aggregate analyses and the individual studies 
demonstrated that clozapine and antipsychotic comparators show 
an early response profile through 6 weeks of treatment. Our 
hypothesis of difference between clozapine and other antipsy-
chotic agents was supported with respect to the steeper linear pat-
tern of symptom improvement for clozapine. However, the overall 
Table 5. Studies 16 (0–4 weeks) and 30 (0–6 weeks). Changes in symptom severity, and response profiles (linear and quadratic coefficients) for 
clozapine and chlorpromazine using individual subject data. For clozapine and chlorpromazine columns, effect sizes and p-values for change in 
symptom severity refer to differences from baseline, and for coefficients refer to differences from zero. Linear coefficients different from zero 
indicate a significant slope of change in symptoms over time, and quadratic coefficients greater than zero indicate attenuation of the response over 
time. For Clozapine versus chlorpromazine column, effect sizes and p-values refer to comparisons between clozapine and chlorpromazine arms
Clozapine Chlorpromazine
Clozapine versus 
chlorpromazine
 n Mean SD d p-value Mean SD d p-value d p-value
Study 16
 Total symptoms
 Change in symptom 
 severity (per item score)
 96 -1.325 0.671 -1.975 <0.001 -0.873 0.707 -1.235 <0.001 -0.656 0.002
 Linear coefficients 96 -0.695 0.598 -1.162 <0.001 -0.558 0.727 -0.768 <0.001 -0.204 0.319
 Quadratic coefficients 96 0.084 0.146 0.575 <0.001 0.082 0.206 0.398 0.007 0.011 0.957
 Positive symptoms
 Change in symptom 
 severity (per item score)
 96 -1.676 0.811 -2.067 <0.001 -1.166 0.925 -1.261 <0.001 -0.585 0.005
 Linear coefficients 96 -0.856 0.668 -1.281 <0.001 -0.754 0.939 -0.803 <0.001 -0.125 0.541
 Quadratic coefficients 96 0.094 0.184 0.511 0.001 0.114 0.276 0.413 0.006 -0.085 0.679
Study 30
 Total symptoms
 Change in symptom 
 severity (per item score)
254 -0.916 0.815 -1.124 <0.001 -0.297 0.702 -0.423 <0.001 -0.817 <0.001
 Linear coefficients 254 -0.270 0.360 -0.750 <0.001 -0.104 0.342 -0.304 0.001 -0.474 <0.001
 Quadratic coefficients 254 0.020 0.058 0.345 <0.001 0.006 0.060 0.100 0.234 0.241 0.056
 Positive symptoms
 Change in symptom 
 severity (per item score)
254 -1.119 0.982 -1.140 <0.001 -0.434 0.883 -0.492 <0.001 -0.734 <0.001
 Linear coefficients 254 -0.355 0.429 -0.828 <0.001 -0.154 0.495 -0.311 <0.001 -0.433 0.001
 Quadratic coefficients 254 0.029 0.073 0.397 <0.001 0.010 0.090 0.111 0.223 0.236 0.061
SD, standard deviation; d, effect size
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Sherwood et al. 9
profile for clozapine of a steep, early linear response with subse-
quent attenuation was similar to other atypical and typical antip-
sychotics. Analysis of individual data from Study 16 with broad 
inclusion criteria and from Study 30 of refractory patients sup-
ported these conclusions, and indicated the response profiles for 
positive symptoms were similar to symptoms overall.
The clozapine literature has a number of limitations, which 
include the absence of placebo-controlled trials, possible inade-
quate dosing of clozapine, mixed use of Last-Observation-Carried-
Forward (LOCF) methodology and observed case analyses, lack 
of publication of negative data, failure to include weekly data, 
concomitant medication use, and a heterogeneous trial population 
as study enrollment practices changed with time. Possible effects 
of LOCF reporting were not analyzed here, as this correlated with 
year of publication and refractory study status. However, reporting 
LOCF could have resulted in flattening of the response curve, and 
has variably been a confounder in previous antipsychotic meta-
analyses (Agid et al., 2003; Leucht et al., 2005; Sherwood et al., 
2005). With respect to the trial population, many clozapine trials 
are now several decades old. Early trials usedDSM-II criteria for 
schizophrenia and subjects without previous atypical antipsy-
chotic exposure. The efficacy of drug versus placebo appears to 
have decreased over the last several decades (Leucht et al., 2008), 
thus relevance of older clinical trials to current patients may be 
variable. Under-dosing or slow titration of clozapine is less likely 
at the study level, as the positive quadratic effect or attenuation of 
response seen in the meta-analysis indicates an early, robust clo-
zapine response even when doses were below maximal. Figure 1 
shows that the dosing strategy used in these studies was consistent 
with the current product monograph. In the studies considered 
here, over 70% of the week 4 dose was achieved by week 1, and 
the mean endpoint dose was above 300 mg/day. The possibility of 
a small number of under-dosed studies remains.
Surprisingly, clozapine may be the prototypical antipsychotic 
drug showing an early response profile. The early response may be 
initiated as soon as occupancy of dopamine D2 receptors by clozap-
ine reaches 50–65%, predicted to occur at the mean dose of 236 
mg/day obtained during the first week of the aggregate studies 
(Kapur et al., 1999). Since refractory patients have already been 
exposed to this amount (and likely much greater) of dopamine 
receptor occupancy with other drugs, the early response effects of 
clozapine may not be reduced to only D2 occupancy, at least in 
refractory patients. From a clinical practice perspective, the results 
suggest some symptom reduction with clozapine would be 
expected within the first few weeks in most cases. However, the 
present analysis does not predict time to remission, or the adequate 
length of a clozapine trial. Studies with longer durations and fre-
quent reporting of symptom severity are few, limiting our ability to 
perform a quantitative analysis to address these questions. Further 
investigation into trial length beyond 6 weeks is needed to inform 
both research and clinical practice. More detailed information on 
patterns of response of individual symptoms would also be of inter-
est, as delusions appear to respond more slowly than hallucinations 
in first-episode patients (Gunduz-Bruce et al., 2005). As well, 
recent reports indicate that dividing groups of patients according to 
initial response profile may help predict longer-term outcome 
(Chen et al., 2009; Correll et al., 2003; Kinon et al., 2008, 2010; 
Leucht et al., 2007). The majority of data available to us were col-
lected after 4–6 weeks, limiting our ability to carry out such analy-
ses or to study the phenomena of late response to clozapine.
In summary, based on analysis of 19 studies in the literature, 
and individual subject data from two clinical trials, we confirmed 
the superiority of clozapine versus comparator antipsychotic 
drugs in reducing symptom severity in schizophrenia. Somewhat 
surprisingly, like other antipsychotic drugs, clozapine showed an 
early response profile, with a steep initial response and attenua-
tion apparent after 4–6 weeks of treatment. The linear component 
of this response profile was steeper for clozapine than comparator 
drugs. These observations may apply only to the dose titration and 
dosages of clozapine used in these clinical trials, and longer dura-
tion studies may yield different results. However, the findings of 
an early response profile for clozapine, even in refractory patients, 
support the importance of research into the time course of treat-
ment response as a component of studies of the mechanism of 
action of antipsychotic drugs.
Acknowledgments
We would like to thank Dr Raymond F Koopman for statistical consulta-
tion on this paper. Profs Peter Falkai and Eric Chen helped with transla-
tions. We also thank researchers who responded to our queries: Drs Robert 
Buchanan, Nina Schooler, John Kane, Jan Volavka, Jean-Michel Azorin, 
Pierre Baumann, Robert Rosenheck, Deanna Kelly, Les Citrome, Eckhard 
Klieser, Michael Kluge, and Philip Harvey. Novartis, Pfizer, and Eli Lilly 
also responded to inquiries concerning studies. All authors had access to 
all of the data for the study, and all participated in writing the manuscript. 
Funding
British Columbia Mental Health and Addictions Services provided support.
Conflict of interest 
Drs Megan Sherwood and Allen Thornton declare that, except for income 
received from their primary employers, no financial support or compensa-
tion was received from any individual or corporate entity over the past 
three years for research or professional service and there are no personal 
financial holdings that could be perceived as constituting a potential con-
flict of interest. Dr William Honer reports receiving consulting fees or 
sitting on paid advisory boards for: Janssen, Novartis, Roche and the 
Canadian Agency for Drugs and Technologies in Health.
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