Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue1.2001:
Double-Blind Comparison of Olanzapine versus
Clozapine in Schizophrenic Patients Clinically Eligible
for Treatment with Clozapine
Gary D. Tollefson, Martin A. Birkett, Gerilyn M. Kiesler, Andrew J. Wood, and
The Lilly Resistant Schizophrenia Study Group
Background: The treatment of schizophrenic patients
who fail to respond to adequate trials of neuroleptic drugs
is a major challenge. Clozapine has been one treatment
option; however, it is not universally effective and is
limited in its use by safety concerns. With the introduction
of newer agents, their performance relative to clozapine is
of great clinical interest.
Methods: The primary objective of this study was to
evaluate the efficacy and safety of olanzapine versus
clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to
demonstrate the “noninferiority” of olanzapine compared
to clozapine after 18 weeks of double-blind treatment.
Conclusions were based on the one-sided lower 95%
confidence limit about the treatment effect observed from
the primary efficacy variable (Positive and Negative
Syndrome Scale [PANSS] Total).
Results: Mean changes from baseline to end point in
PANSS Total score, using a last observation carried
forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the “noninferiority” of olanzapine when compared to clozapine. Overall, significantly fewer
olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p 5 .022). Among spontaneously reported adverse
events, increased salivation, constipation, dizziness, and
nausea were reported significantly more often among
clozapine-treated patients, whereas only dry mouth was
reported more often among olanzapine-treated patients.
Conclusions: Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant
From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
(GDT, GMK), Eli Lilly and Company Limited, Lilly Research Centre,
Windlesham, United Kingdom (MAB), and Lilly Development Centre, MontSaint Guibert, Belgium (AJW).
Address reprint requests to Gary D. Tollefson, M.D., Ph.D., Lilly Research
Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2033,
Indianapolis IN 46285.
Received September 8, 1999; revised March 13, 2000; revised August 1, 2000;
accepted August 4, 2000.
© 2001 Society of Biological Psychiatry
schizophrenic patients clinically eligible for treatment
with clozapine. Biol Psychiatry 2001;49:52– 63 © 2001
Society of Biological Psychiatry
Key Words: Olanzapine, clozapine, treatment resistant,
schizophrenia, clinical trial
Introduction
T
he treatment of schizophrenic patients who fail to
respond to or tolerate adequate trials of neuroleptics is
a major challenge (Ciompi 1980; Kane 1996). It has been
repeatedly demonstrated that many schizophrenic patients
either do not respond or only partially respond to conventional dopamine-D2 antagonist antipsychotic agents; estimates vary between 40% and 80%. Even among patients
who respond in terms of core psychotic symptoms, other
disease manifestations, including negative, affective, and
anxious symptoms, may go unimproved. These features
contribute significantly to individual patient disability.
Furthermore, a number of adverse events characterize the
currently available conventional antipsychotic agents
(Kane 1989). The severity of these adverse events in a
considerable number of schizophrenic patients contributes
to poor compliance (Corrigan et al 1990; Weiden et al
1986). These adverse events include extrapyramidal syndromes (EPS; Chouinard et al 1988), such as drug-induced
parkinsonism, acute dystonic reactions, akathisia, tardive
dyskinesia, and tardive dystonia. Other reasons for drug
intolerance include sexual dysfunction, cognitive dulling,
seizure, or galactorrhea and gynecomastia attributable to
hyperprolactinemia.
Novel antipsychotic compounds that minimize such
adverse events and/or improve the breadth and depth of
clinical response offer the chance to improve overall
patient outcomes (Kinon and Lieberman 1996; Meltzer
1991). Although such benefits have been demonstrated in
standard subject populations, a greater challenge is pre0006-3223/01/$20.00
PII S0006-3223(00)01026-X
Olanzapine vs. Clozapine in Schizophrenia
sented by an intolerant or resistant schizophrenic patient
group. Subjects who have failed to benefit with conventional antipsychotic drugs constitute a particular and significant public health concern, by virtue of their significant
morbidity, mortality, and societal cost (Malhotra et al
1996).
Clozapine, an atypical antipsychotic drug, with pharmacologic features that distinguishes it from conventional
neuroleptic agents, represents one such novel alternative
(Carlsson 1988; Coward 1992; Meltzer 1989,1992). In
several multicenter clinical trials clozapine has been
shown to be effective in the treatment of DSM-III schizophrenic patients who have failed to respond to a variety of
conventional neuroleptics (Conley et al 1988; Hirsch and
Puri 1993; Kane et al 1988). These treatment benefits may
include improvement in positive and/or negative symptoms in schizophrenic patients (Naber and Hippius 1990).
Resultingly, clozapine has been approved specifically for
patients with schizophrenia who have proved intolerant of
and/or nonresponsive to conventional neuroleptic agents.
Olanzapine represents another novel alternative. Although exhibiting a similar in vitro profile to clozapine,
unique differences are evident (Bymaster et al 1996).
Clinical studies have shown that olanzapine is effective in
the control of psychotic symptomatology, including both
positive and negative symptoms among both acute and
chronic schizophrenic populations. Moreover, the rate of
early discontinuations attributable to adverse events is
significantly less than that seen with haloperidol (Beasley
et al 1996; Tollefson and Sanger 1997). Given these
apparent safety advantages, olanzapine may also be well
suited for the treatment of treatment-resistant schizophrenic patients (Miller et al 1994).
This study was designed to evaluate the efficacy and
safety of olanzapine compared with clozapine in schizophrenic patients who have been classified as having
treatment-resistant psychopathology eligible for treatment
with clozapine.
Methods and Materials
Study Design
The study was designed a priori as a “noninferiority” study, or
therapeutic equivalence study (Garbe et al 1993; Rohmel 1998). The
design is becoming more commonly used in studies where the
comparator is an established reference drug in clinical practice.
Trials to demonstrate the superiority of one treatment to another are
common, but in the case of an active controlled trial the demonstration of superiority for the investigational drug is considered unlikely
or would require too many patients to be practically and financially
feasible. Failure to demonstrate a statistical difference in favor of the
investigational drug cannot, of course, be used as proof of equivalence to the active control, hence the study must be designed with
the specific hypothesis of “noninferiority” in mind.
BIOL PSYCHIATRY
2001;49:52– 63
53
Interpretation of data from “noninferiority” trials is made on
the basis of confidence intervals. In such trials, the upper limit of
the confidence interval (in this case how much better the
investigational drug might be compared to the active control) is
of little interest, because we only want to try and reject the null
hypothesis that the investigational drug has less efficacy than the
control, for which we utilize the lower limit of the confidence
interval. Once rejected we can conclude that the investigational
drug is not inferior to the active control, meaning that we have
not ruled out the potential superiority compared to the active
control, a question that cannot be answered in the present study,
because it was not designed for this purpose.
The conclusions are based on interpretation of the one-sided
lower 95% confidence limit about the treatment effect observed
from the primary efficacy variable, and whether this confidence
limit lies in the correct half space compared to D (all values
larger than D), which marks the limit for differences that are
considered clinically acceptable. D was selected a priori to avoid
accusations of setting the clinically acceptable limit in a biased
manner based on observed data; however, there are no generally
accepted guidelines on how this clinically acceptable limit
should be chosen.
The study was conducted by 41 investigators in 14 countries
(Belgium, Denmark, Finland, France, Germany, Italy, Norway,
Portugal, South Africa, Spain, Sweden, Switzerland, Great Britain, and Ireland). All investigators and raters were English
speaking. The study protocol was approved by local ethical
review boards, and a signed informed consent was obtained from
all eligible patients after the procedures and possible side effects
were explained.
The study consisted of three periods: 1) a washout period from
previous antipsychotic drugs (2–9 days for oral antipsychotic
drugs; at least one injection cycle for depot antipsychotics); 2) an
18-week double-blind therapy period in which patients were
randomly allocated in a 1:1 ratio to treatment with olanzapine
15–25 mg/day or clozapine 200 – 600 mg/day; and 3) an optional
open-label extension period of up to 3 years or until olanzapine
became available in the relevant country (for olanzapine-treated
patients only). To ensure uninterrupted availability of the appropriate treatment at the end of the double-blind study period,
patients were unblinded after 18 weeks of therapy.
Randomized patients started olanzapine at 15 mg/day once
daily, or clozapine at a fixed dose escalation from 25 mg to 200
mg/day during the first 8 days of therapy. Flexible dosing, across
a range of 15–25 mg daily for olanzapine and 200 – 600 mg daily
for clozapine was permitted after the first 2 weeks of doubleblind treatment. With either drug, blinded titration was permitted
to optimize an individual patient’s outcome. Investigators had the
opportunity to increase or decrease the dosage by either 2.5 or 5
mg of olanzapine, or by 50 or 100 mg of clozapine per visit
interval (as per manufacturer’s instructions). Concomitant psychotropic medications were not allowed during the study with the
exception of a benzodiazepine (up to 40 mg/day diazepam
equivalent or 8 mg lorazepam equivalent) for agitation, chloral
hydrate for insomnia, and biperiden or benztropine mesylate (up
to 4 mg/day) for treatment-emergent EPS. Prophylactic use of
anticholinergic medications was prohibited.
54
G.D. Tollefson et al
BIOL PSYCHIATRY
2001;49:52– 63
Sample Size
The study was designed to be able to evaluate the “noninferiority” of olanzapine versus clozapine based on the one-sided lower
95% confidence limit of the difference between treatments in
change in Positive and Negative Syndrome Scale (PANSS) Total
scores.
A sample size of 220 patients (110 per treatment group) was
planned, assuming an expected treatment effect of 4 units (in
favor of olanzapine), with a common SD of 22 units, 85% power,
and a one-sided significance level of .05. The clinically acceptable limit (D) of 24 units for the treatment effect was selected
and denoted a priori in the protocol for the basis of declaring the
“noninferiority” of olanzapine compared to clozapine. The lower
limit was chosen to be 25% of what we estimated the overall
treatment benefit (i.e., change from baseline to end point in
PANSS Total score) would be; in this case we assumed 16 units.
Patient Population
Patients were men or women between the ages of 18 and 70 years
who met with a clinical diagnosis of DSM-IV criteria for
schizophrenia and who had a minimum score on the Brief
Psychiatric Rating Scale (BPRS1–7), extracted from the PANSS
(Kay et al 1987), of at least 45 and a score of 4 or more on at least
2 items of the PANSS Positive symptom subscale (items 1–7).
Patients who had previously been treated with olanzapine or
who were olanzapine or clozapine nonresponders were specifically excluded from this study. All study participants were
required to have a documented history that they were clinically
resistant to previous antipsychotic treatments. Resistance was
defined as a lack of satisfactory clinical response to at least 2
previous oral neuroleptic treatments, each of a different chemical
class, given for a duration of at least 6 weeks at an appropriate
daily dosage equivalent to at least 500 mg chlorpromazine, or to
the maximum daily dosage when intolerable side effects had
been documented. Patients known to be intolerant to either
clozapine or olanzapine were not included.
Patients could begin the study as inpatients or outpatients, and
changes in hospitalization status during the protocol were permitted. All patients who commenced the study as inpatients were
returned to outpatient status within 2 weeks of randomization to
double-blind treatment. Pregnant or lactating women, or patients
with serious medical illnesses in which pharmacotherapy posed a
substantial clinical risk or confounded diagnosis, were excluded.
Assessments
Clinical assessments were carried out at the screening visit and
again at the baseline assessment. Postrandomization assessments
were conducted weekly up to 18 weeks, throughout the study for
safety. For efficacy, assessments were performed weekly for the
first month, every 2 weeks for the next 6 weeks and finally every
4 weeks for the remainder of the study.
At the screening visit a standard history, physical examination,
and laboratory profile were obtained. Hematology tests were
performed at baseline as well as weekly during the 18-week
treatment period. Serum prolactin was measured at baseline and
at end point.
The efficacy measures included the PANSS Total score
(primary efficacy measure) and its subscales (positive and
negative); the 18-item BPRS1–7 total extracted from the PANSS
and the Clinical Global Impression Severity of Illness Scale
(CGI-Severity).
Adverse events were detected by clinical evaluation and
spontaneous report at each visit and mapped, classified, and
recorded using a system based on the U.S. Food and Drug
Administration Coding Symbols and Thesaurus for Adverse
Reaction Terms (COSTART; U.S. Food and Drug Administration 1990). In addition, adverse events were solicited by the
investigator using the 40-item Association for Methodology and
Documentation in Psychiatry (AMDP-5) adverse event questionnaire (Association for Methodology and Documentation in Psychiatry [Arbeltsgemeinschaft fur methodik und dokumentation in
der psychiatrie] 1981; Guy and Ban 1982).
Extrapyramidal symptoms, akathisia, and dyskinesia were
further assessed with the Simpson–Angus Scale (Simpson and
Angus 1970), the Barnes Akathisia Scale (Barnes 1989), and the
Abnormal Involuntary Movement Scale (AIMS; Guy 1976).
The modal daily dose was defined as the most frequently
administered daily dosage of study drug for each individual
patient during the 18-week double-blind therapy period; the
maximum daily dose was defined as the highest dose given to a
patient even if only for one day. The average daily dose is
calculated for each patient by deriving the cumulative dosage
received during the study divided by the number of days of
therapy.
All investigators attended a formal and standardized start-up
meeting, country by country, during which they were trained on
how to complete the different scales. No formal inter-rater
reliability was performed.
Statistical Methods
The primary intent of this study was to evaluate the effectiveness
and safety of olanzapine versus clozapine during double-blind
therapy. All end point analyses used a last observation carried
forward (LOCF) algorithm (the last available visit, from visit 3
onwards, served as an end point). For analyses of baseline
efficacy and safety measures and changes from baseline to end
point, only patients with a baseline (visit 2) and at least one
postbaseline measure were included. In the computation of total
scores on any individual scale, the total score was treated as
missing if any of the individual items were missing.
A one-sided lower 95% confidence limit for the difference in
LOCF mean change in PANSS Total score for clozapine minus
olanzapine was used in the primary efficacy analysis to demonstrate the “noninferiority” of olanzapine compared to clozapine.
The inference was based on the lower limit of the confidence
interval. A lower limit of .0 would indicate that olanzapine was
statistically significantly superior to clozapine. A lower limit of
$24 and #0 would indicate there was no difference between the
two treatments, and “noninferiority” could be concluded,
whereas a lower limit of ,24 would indicate that no conclusion
could be drawn regarding the “noninferiority” or superiority of
olanzapine compared with clozapine. One-sided lower 95%
confidence limits were also calculated for the secondary efficacy
Olanzapine vs. Clozapine in Schizophrenia
variables, although no predefined criteria for determining “noninferiority” were stated.
An analysis of variance (ANOVA) model with terms for
treatment, geographic region, and treatment-by-geographic region interaction was used to evaluate continuous efficacy data. If
the interaction was not significant (p . .10) then it was removed
and a model with terms for treatment and geographic region was
used. One-sided lower 95% confidence limits based on the
“absolute” difference in means were evaluated. In addition, the
difference in least squares means were also evaluated and used to
calculate the “adjusted” one-sided lower 95% confidence limit.
Both observed cases (OC) and LOCF visitwise summary
statistics were calculated. Significance tests for visitwise analyses were not performed since the primary outcome was to be
evaluated based on the change from baseline to end point.
Response rates were primarily calculated using the BPRS1–7
total score and CGI-Severity score using an LOCF technique. A
responder was defined a priori as any patient who achieved at
least a 20% reduction in BPRS1–7 total score from baseline to
end point, plus either an end point CGI-Severity scale score of
#3 or an end point BPRS1–7 total score of #35, as defined and
used by Kane et al (Kane et al 1988). Response rates (LOCF)
were also evaluated for patients who achieved reductions in
PANSS Total score of 20%, 30%, 40%, and 50% from baseline
to end point.
All statistical analyses for safety parameters are presented
based on two-sided hypothesis tests. Categorical data (demographic variables, reasons for study discontinuation, treatmentemergent adverse events, solicited adverse events, incidence of
EPS, and treatment-emergent abnormal laboratory analytes) were
evaluated using a Pearson x2 test. Kaplan–Meier survival curves
of time to discontinuation were compared between treatment
groups using the log-rank test.
The categorical incidence of EPS based on rating scale
definition was evaluated as follows. To assess treatment-associated psuedoparkinsonism, the proportion of patients with a
Simpson–Angus Scale total score of .3 at any postbaseline visit
was calculated among those with a total score of #3 at baseline.
To assess treatment-associated akathisia, the proportion of patients with a Barnes Akathisia Scale global score (item 4) $ 2 at
any postbaseline visit was calculated among those with a score of
,2 at baseline. To assess treatment-associated abnormal dyskinetic movements, the proportion of patients with a score of $3
on any one of the AIMS items 1 through 7 or a score of $2 on
any two of the AIMS items 1 through 7 at any postbaseline visit
was calculated among those without either of these criteria at
baseline. The latter definition is consistent with the crosssectional research diagnostic criteria suggested by Schooler and
Kane (1982). All these definitions were made a priori and used
in previous studies.
Results
Patient Characteristics
A total of 180 patients (olanzapine: n 5 90; clozapine: n 5
90) were assigned to receive double-blind therapy. The
BIOL PSYCHIATRY
2001;49:52– 63
55
Table 1. Patient Characteristics
Olanzapine
(n 5 90)
Male
Female
White
Other
Schizophrenia subtype
Catatonic
Disorganized
Paranoid
Undifferentiated
Residual
Schizophrenia course
Residual symptoms
No residual symptoms
Continuous
In partial remission
Other pattern
Clozapine
(n 5 90)
n
%
n
%
61
29
86
4
67.8
32.2
95.6
4.4
54
36
87
3
60.0
40.0
96.7
3.3
2
21
51
12
4
2.2
23.3
56.7
13.3
4.4
1
13
50
22
4
1.1
14.4
55.6
24.4
4.4
36
3
49
1
1
40.0
3.3
54.4
1.1
1.1
45
0
43
1
1
50.0
0
47.8
1.1
1.1
reduced sample size was declared before unblinding and
reflected a significant decline in recruitment once olanzapine had been approved for routine clinical use in Europe.
The 180 randomized subjects decreased the power to
declare “noninferiority” to 78% (instead of the planned
85%, based on 220 patients).
The treatment groups were comparable with respect to
baseline demographic and illness characteristics (Table 1).
The majority of the patients were male (63.9%), white
(96.1%), and 56.1% displayed a paranoid subtype of
schizophrenia. The courses of illness, according to DSMIV, were mainly continuous (51.1%) or episodic with
interepisode residual symptoms (45.0%), and 72.6% had
prominent residual negative symptomatology, based on
the DSM-IV classification of longitudinal course of the
disease.
The mean (SD) age of the patient population was 38.6
(10.6) years with a mean (SD) age of onset of illness of
22.8 (5.6) years. The median (range) length of patient’s
current episodes was 187 (6 –13,313) days, with 16
(17.8%) clozapine-treated patients and 9 (10.0%) olanzapine-treated patients having a current episode of less than
6 weeks duration. A large proportion of patients (43.4%)
had more than 10 previous schizophrenic episodes before
entry into the study. Patient’s baseline scores on the
PANSS and its subscales, the BPRS1–7, and the CGISeverity indicated that overall patients had severe and
mixed symptomatology (positive and negative; Table 2).
Patients also had a long history of illness and were
documented by the investigators as being resistant to other
antipsychotics.
56
G.D. Tollefson et al
BIOL PSYCHIATRY
2001;49:52– 63
Table 2. Mean Change in Efficacy Measures, Baseline to Endpoint (LOCF)
Measure
PANSS Total
PANSS Positive
PANSS Negative
CGI-Severity
BPRS1–7 Total
Therapy
n
Mean
(SD)
Mean
(SD)
Treatment
effecta
One-sided
lower 95%
confidence
limitb
Olanzapine
Clozapine
Olanzapine
Clozapine
Olanzapine
Clozapine
Olanzapine
Clozapine
Olanzapine
Clozapine
89
87
89
87
89
87
89
87
89
87
108.2 (15.7)
104.6 (20.0)
26.2 (5.8)
25.3 (6.4)
29.1 (6.3)
28.4 (6.9)
5.5 (0.8)
5.4 (0.9)
60.4 (9.5)
59.0 (11.3)
225.6 (25.5)
222.1 (23.1)
26.8 (7.6)
26.4 (7.2)
27.1 (7.4)
25.6 (6.9)
21.1 (1.2)
20.9 (1.1)
215.2 (15.3)
214.0 (13.3)
3.5
22.2
0.4
21.4
1.5
20.1
0.2
20.02
1.2
22.1
Baseline
Change
LOCF, last observation carried forward; N, number of patients with a baseline and at least one postbaseline measurement;
PANSS, Positive and Negative Syndrome Scale; CGI-Severity, Clinical Global Impressions Severity of Illness Scale; BPRS,
Brief Psychiatric Rating Scale.
a
Calculated as clozapine minus olanzapine.
b
Based on the “absolute” group mean change from baseline.
Patient Disposition
A total of 107 (59.4%) patients completed the 18-week,
double-blind treatment period (olanzapine: 60.0%; clozapine: 58.9%). Completion rates after 6 weeks and 12
weeks of therapy for olanzapine-treated patients were
85.6% and 70.0%, respectively, and for clozapine-treated
patients were 75.6% and 65.6%, respectively. Rates of
discontinuation from the study because of adverse events
were significantly lower for olanzapine compared to clozapine-treated patients [4.4% vs. 14.4%, x2(1) 5 5.26, p 5
.022]. There were no statistically significant differences
between the two treatment groups for any other reason of
discontinuation (lack of efficacy, 13.3% vs. 10.0%; patient
decision, 10.0% vs. 4.4%; lost to follow-up, 2.2% vs.
2.2%; other, 10.1% vs. 10.1%). More patients discontinued early in the double-blind therapy period in the clozapine treatment group [Kaplan–Meier survival estimates;
log-rank x2(1) 5 0.206, p 5 .650; mainly owing to
adverse events].
Dosage, Compliance, and Medication Use
Only patients who received therapy beyond the 1-week
titration period were included in the summary of exposure
and modal drug dose (olanzapine: n 5 88; clozapine: n 5
83). For these patients, there were a total of 8802 patientdays of exposure to olanzapine and 8074 patient-days of
exposure to clozapine. Table 3 shows the distribution of
patients maximum daily dose and modal daily dose for
each treatment group. A high incidence of clozapinetreated patients (44/83, 53.0%) received a maximum daily
dose of 400 – 600 mg, and the majority of olanzapinetreated patients (59/88, 67.0%) received a maximum daily
dose of 25 mg. The mean (SD) daily dose for olanzapine-
treated patients was 20.5 (2.8) mg/day (starting dosage of
15 mg/day) and for clozapine-treated patients was 303.6
(108.7) mg/day (starting dosage of 200 mg/day after
1-week titration period).
The numbers of patients using benzodiazepines at any
time during the study were similar for the two treatment
groups (olanzapine: 64.4%; clozapine: 53.3%). Investigation of benzodiazepine use during the washout period and
at the time of randomization indicated that a similarly
greater proportion of olanzapine patients were using benzodiazepines compared to clozapine (57.8% vs. 44.4%,
Table 3. Summary of Maximum and Modal Daily Dosage
During 18 Weeks Double-Blind Therapy for Patients Who
Received Study Drug after the Initial Titration Period
Maximum
daily dose
Dose level
Olanzapine (N 5 88)
15.0 mg
17.5 mg
20.0 mg
22.5 mg
25.0 mg
Clozapine (N 5 83)
200 mg
250 mg
300 mg
350 mg
400 mg
450 mg
500 mg
550 mg
600 mg
Modal daily
dose
n
%
n
%
8
7
11
3
59
9.1
8.0
12.5
3.4
67.0
14
6
10
4
54
15.9
6.8
11.4
4.5
61.4
19
8
8
4
10
8
7
5
14
22.9
9.6
9.6
4.8
12.0
9.6
8.4
6.0
16.9
27
7
8
5
8
7
7
3
11
32.5
8.4
9.6
6.0
9.6
8.4
8.4
3.6
13.3
N, number of patients who received study drug after the initial titration period;
n, frequency at each dose level.
Olanzapine vs. Clozapine in Schizophrenia
BIOL PSYCHIATRY
2001;49:52– 63
57
Table 4. Weekly Changes in PANSS Total Score Using LOCF and OC Techniques
LOCF
Week of therapy
1 week
2 weeks
3 weeks
4 weeks
6 weeks
8 weeks
10 weeks
14 weeks
18 weeks
OC
Olanzapine
(N 5 89)
Clozapine
(N 5 87)
Mean (SD)
Mean (SD)
n
Mean (SD)
n
Mean (SD)
24.2 (11.1)
29.4 (13.6)
214.6 (17.7)
217.1 (19.3)
220.7 (22.0)
220.8 (22.8)
223.0 (23.7)
224.0 (24.8)
225.6 (25.5)
22.9 (9.1)
29.2 (12.4)
213.5 (15.0)
215.4 (17.1)
220.5 (19.8)
220.5 (20.7)
221.0 (21.8)
221.5 (22.2)
222.1 (23.1)
88
85
84
84
81
69
66
57
55
24.2 (11.1)
29.8 (13.8)
214.8 (18.1)
217.3 (19.6)
222.4 (20.4)
224.0 (19.9)
227.4 (20.5)
231.5 (19.7)
234.2 (20.5)
86
82
75
72
69
65
61
58
53
22.9 (9.1)
210.3 (11.6)
215.9 (13.8)
218.2 (16.4)
225.2 (18.3)
226.8 (18.5)
228.1 (19.0)
229.5 (18.8)
230.6 (20.3)
Olanzapine
Clozapine
PANSS, Positive and Negative Syndrome Scale; LOCF, last observation carried forward; OC, Observed; N, Number of
patients with a baseline and at least one postbaseline measurement qualifying for LOCF analysis; n, number of patients with
measurements at each visit eligible for OC analysis.
respectively). Only seven olanzapine-treated patients and
eight clozapine-treated patients initiated use of benzodiazepines during the study, and one olanzapine-treated patient
used a benzodiazepine during the washout period but not
during the study. Few patients used an anticholinergic
agent (olanzapine: 4.4%; clozapine: 10.0%).
The mean (SD) daily benzodiazepine medication use,
expressed in lorazepam equivalents (mg/day), was not
clinically different in the two groups (olanzapine: 4.2 (3.0)
mg; clozapine: 3.2 (2.8) mg) nor was the mean (SD) daily
anticholinergic medication use, expressed in benztropine
equivalents (mg/day) (olanzapine: 1.3 (1.7) mg; clozapine:
1.8 (0.7) mg).
Efficacy
CHANGES IN EFFICACY MEASURES. There were no
statistically significant differences between treatment
groups on baseline efficacy measures, and although the
PANSS Total scores were numerically different, they were
not statistically significantly different (p 5 .888). Both
treatment groups showed significant within-group improvement (p , .001) from baseline to end point (LOCF)
in PANSS Total, PANSS Positive, PANSS Negative,
BPRS1–7 Total, and CGI-Severity scores (Table 2).
PANSS Total scores were used to test the primary hypothesis that olanzapine was not inferior to clozapine in this
study. Using the “absolute” observed group mean changes
from baseline, the difference in means was 3.5 units in
favor of olanzapine, and the one-sided lower 95% confidence limit was 22.2. Because this lower limit was $24
and #0, it indicated there was no clinical difference
between the two treatments and “noninferiority” could be
concluded. Using the “adjusted” group mean changes from
baseline (obtained using the least squares means from the
main effects model with terms for treatment and geo-
graphic region), the difference in means was 3.8 units in
favor of olanzapine, and the one-sided lower 95% confidence limit was 21.9, leading to the same conclusion.
Because of the apparent imbalance in baseline PANSS
Total scores between the two treatment groups, an analysis
of covariance was performed post hoc, where the covariate
was the baseline PANSS Total score and the end point
score was the dependent variable. The adjusted end point
least squares means from this analysis were 80.3 for
olanzapine and 83.4 for clozapine, with a one-sided 95%
confidence interval for the difference (3.1 units in favor of
olanzapine) being 23.7. Therefore, “noninferiority” could
still be concluded.
The visitwise mean change in PANSS Total score is
shown in Table 4 using both an LOCF and OC method.
The pattern of change over time was similar for the two
treatment groups. Examination of mean changes from
baseline for OC patients shows numerically greater
changes during weeks 2 through 10 for clozapine, but for
patients who receive treatment for 14 or 18 weeks there is
a similar treatment effect in favor of olanzapine as
calculated using the LOCF approach.
RESPONSE RATES. Among the secondary study objectives, a similar proportion of olanzapine- (38.2%) and
clozapine-treated patients (34.5%) achieved a response
based on the combined BPRS1–7 and CGI-Severity response definition (Table 5). Another definition of response, based on a 20%, 30%, 40%, and 50% change in
PANSS Total score, yielded similar proportions of responders across the two treatment groups. The one-sided
lower 95% confidence limits at the 30% and 40% criteria
are .0, providing evidence of a significantly greater
response with olanzapine.
The incidence of patients showing no improvement or
58
G.D. Tollefson et al
BIOL PSYCHIATRY
2001;49:52– 63
Table 5. Response Rates
Olanzapine
(N 5 89)
Response definition
BPRS1–7 1 CGI-Severityb
PANSS Total score
$20% improvement
$30% improvement
$40% improvement
$50% improvement
Clozapine
(N 5 87)
Treatment
effecta
One-sided lower
95% confidence
limit
n (%)
n (%)
34 (38.2)
30 (34.5)
3.7%
28.2%
53 (59.6)
41 (46.1)
24 (27.0)
9 (10.1)
47 (54.0)
28 (32.2)
14 (16.1)
9 (10.3)
5.6%
13.9%
10.9%
20.2%
26.7%
1.9%
0.8%
27.7%
N, number of patients with a baseline and at least one postbaseline measurement; n, number of responders based upon each
response definition; BPRS, Brief Psychiatric Rating Scale; CGI-Severity, Clinical Global Impressions Severity of Illness Scale;
PANSS, Positive and Negative Syndrome Scale.
a
Calculated as olanzapine minus clozapine.
b
Responder defined as a patient who achieved at least a 20% reduction in BPRS1–7 total score from baseline to end point,
plus either an end point CGI-Severity scale score of #3 or an end point BPRS1–7 total score of #35.
worsening of symptoms (defined as a percent change $0)
was 11/89 (12.4%) for olanzapine-treated patients and
14/87 (16.1%) for clozapine-treated patients. Analysis of
response rates controlling for gender and geographic
region showed no evidence of differing patterns of response between treatments.
Safety
SPONTANEOUSLY
REPORTED
TREATMENT-EMER-
Table 6 shows the spontaneously reported adverse events that were reported by at
least 5% of the patients in either treatment group or with
a statistically significant difference in the rate of reporting
(p , .05) between treatment groups. The most frequently
reported treatment-emergent adverse events in the olanzapine group were somnolence (13.3%), agitation (11.1%),
and headache (11.1%). The most frequently reported
treatment-emergent adverse events in the clozapine group
were increased salivation (28.9%), somnolence (24.4%),
constipation (18.9%), and nausea (11.1%). Throughout the
18 weeks of double-blind therapy, only one event (dry
mouth) was reported statistically significantly (p , .05)
more often among the olanzapine-treated patients, whereas
five events (increased salivation, constipation, nausea,
dizziness, and tooth disorder) were reported statistically
significantly more often among clozapine-treated patients.
Other adverse events showed numerical differences between the treatment groups, the most notable being leukopenia, somnolence, and agitation. Leukopenia was reported for six patients (clozapine: five; olanzapine: one).
The five clozapine-treated patients had leukocytes counts
ranging from 3.1 109/L to 4.5 109/L (lower limit of normal
range: 3.6 109/L), with only two out of five below the
lower limit, and neutrophil counts ranging from 1.3 109/L
to 2.1 109/L (lower limit of normal range: 1.79 109/L) with
three below the lower limit. The one olanzapine-treated
patient entered the trial with a low neutrophil count (1.82
GENT ADVERSE EVENTS.
109/L), which then normalized throughout the study, with
the exception of one value after 1 week (1.55 109/L)
considered as a laboratory error and consequently re-tested
(2.66 109/L). Some investigators discontinued patients
before they had reached the lower normal limit for these
analytes. For instance, of the two clozapine-treated patients who discontinued for leukopenia after 2 months of
treatment, only one had a neutrophil count below the
normal limit, and in the one olanzapine-treated patient
who discontinued after 5 weeks of therapy the neutrophil
count was within the normal range.
Table 6. Spontaneously Reported Treatment-Emergent
Adverse Events with an Incidence of $5% in Either Treatment
Group, or with a Statistically Significant Difference (p ,
.05) between Treatment Groups
Olanzapine
(N 5 90)
Clozapine
(N 5 90)
Event classification
n
%
n
%
p valuea
Somnolence
Agitation
Headache
Insomnia
Constipation
Weight gain
Anxiety
Rhinitis
Dry mouth
Vomiting
Flu syndrome
Asthenia
Increased salivation
Sweating
Dizziness
Fever
Leukopenia
Nausea
Tooth disorder
12
10
10
7
6
6
5
5
4
4
3
2
2
2
1
1
1
1
0
13.3
11.1
11.1
7.8
6.7
6.7
5.6
5.6
4.4
4.4
3.3
2.2
2.2
2.2
1.1
1.1
1.1
1.1
0
22
4
5
3
17
6
5
3
0
5
5
6
26
5
8
5
5
10
4
24.4
4.4
5.6
3.3
18.9
6.7
5.6
3.3
0
5.6
5.6
6.7
28.9
5.6
8.9
5.6
5.6
11.1
4.4
.057
.095
.178
.193
.014
1.00
1.00
.469
.043
.732
.469
.148
,.001
.247
.017
.097
.097
.005
.043
N, total number of patients randomized to each treatment group; n, number of
patients reporting each adverse event.
a
Frequencies are analyzed using a Pearson x2 test with one degree of freedom.
Olanzapine vs. Clozapine in Schizophrenia
Table 7. Solicited Adverse Events (AMDP-5) with a
Statistically Significant Difference (p , .05) in Incidence
Olanzapine
(N 5 89)
treated patients compared to clozapine-treated patients
[F(1,161) 5 7.90, p 5 .006].
Clozapine
(N 5 86)
WEIGHT AND ORTHOSTATIC BLOOD PRESSURE.
a
Event classification
n
%
n
%
p value
Drowsiness
Hypersalivation
Dry mouth
Dizziness
Increased perspiration
Hypotonia
Tardive dyskinesia
23
13
24
6
8
2
5
25.8
14.6
27.0
6.7
9.0
2.2
5.6
41
54
11
26
19
9
0
47.7
62.8
12.8
30.2
22.1
10.5
0
.003
,.001
.019
,.001
.016
.025
.026
AMDP-5, Association for Methodology and Documentation in Psychiatry; N,
number of randomly assigned patients with a postbaseline AMDP-5 assessment; n,
number of patients reporting each adverse event.
a
Frequencies are analyzed using a Pearson x2 test with one degree of freedom.
SOLICITED
59
BIOL PSYCHIATRY
2001;49:52– 63
TREATMENT-EMERGENT
ADVERSE
Based on the AMDP-5 solicited
adverse events scale, a statistically significantly greater
proportion of clozapine-treated patients (p , .05) experienced treatment-emergent drowsiness, hypersalivation,
dizziness, increased perspiration, and hypotonia, whereas
only the event terms of dry mouth and dyskinesia were
reported significantly more often in olanzapine-treated
patients (Table 7); however, of the five olanzapine-treated
patients reported on the AMDP-5 to exhibit dyskinesia,
only two patients met the criteria for treatment-emergent
tardive dyskinesia (Schooler and Kane 1982) on the AIMS
(one exhibited a probable withdrawal dyskinesia with
evidence of a moderate dyskinesia first appearing in the
first week, and the second experienced mild dyskinesia
between weeks 4 and 10, which resolved spontaneously
with continued treatment). The others only had transient
mild or moderate dyskinetic episodes lasting from 1 to 4
weeks. It is doubtful that such symptoms represented
tardive dyskinesia, as the usual duration criteria were not
fulfilled. Rather these cases appeared to represent “withdrawal” dyskinesias.
EVENTS (AMDP-5).
There was no significant difference between treatment
groups in the mean (SD) change from baseline to end point
(LOCF) of body weight [olanzapine: 1.8 (5.0) kg; clozapine: 2.3 (4.9) kg; F(1,163) 5 0.39, p 5 .534]. In the
olanzapine-treated group, patients had a mean (SD) decrease in orthostatic blood pressure of 0.5 mm Hg (14.5)
from baseline to end point, compared to 3.7 mm Hg (18.1)
in the clozapine-treated group [F(1,161) 5 1.64, p 5
.202).
CLINICAL LABORATORY EVALUATION. Monitoring
of leukocyte, neutrophil, and lymphocyte counts was
performed extensively during the study, as specified in the
clozapine monitoring requirements of the manufacturer.
Comparisons between treatment groups showed no statistically significant differences from baseline to end point in
leukocytes or neutrophils, although for lymphocytes there
was a significantly greater baseline to end point decrease
in clozapine-treated patients [F(1,159) 5 13.46, p , .001].
Baseline and end point prolactin levels were obtained
from 120 patients, 46 of whom (38.3%) had baseline
prolactin levels above the normal range. The mean change
from baseline to end point in prolactin levels [olanzapine:
0.18 nmol/L; clozapine: 20.14 nmol/L; F(1,109) 5 5.53,
p 5 .021] was significantly but not clinically different
between the two treatment groups with olanzapine-treated
patients demonstrating a greater increase compared to
clozapine-treated patients.
Five of the 17 discontinuations due to adverse events
were laboratory related. Two clozapine-treated patients
discontinued for “leukopenia,” after 8 and 10 weeks of
Table 8. Mean Change in EPS Rating Scales, Baseline to
Endpoint (LOCF)
Baseline
TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMP-
Categorical
analyses of the Simpson–Angus Scale, the Barnes Akathisia Scale, and the AIMS showed no statistically significant
or clinically relevant differences between olanzapine and
clozapine-treated patients in the incidence of treatmentemergent pseudoparkinsonism (7.5% vs. 10.5%), akathisia
(9.7% vs. 11.3%), and dyskinesia (5.0% vs. 4.0%),
respectively.
Changes from baseline to end point in the Simpson–
Angus total score, the AIMS Non-Global total score (items
1–7), and the Barnes Global score (item 4) are shown in
Table 8. There was a statistically significantly greater
decrease in the Simpson-Angus total score for olanzapine-
TOMS AS ASSESSED BY RATING SCALES.
Measure
Therapy
Simpson-Angus total
Olanzapine
Clozapine
AIMS Non-Global total
Olanzapine
Clozapine
Barnes Global score
Olanzapine
Clozapine
Change
n Mean (SD) Mean (SD) p valuea
.006
88
84
4.6 (5.6)
3.7 (5.1)
23.2 (4.8)
21.4 (3.3)
89
86
1.5 (3.0)
1.7 (3.2)
20.8 (2.2)
20.7 (2.5)
89
86
0.7 (1.0)
0.6 (1.0)
20.3 (0.9)
20.4 (1.0)
.630
.659
EPS, extrapyramidal symptoms; LOCF, last observation carried forward; n,
number of patients with a baseline and at least one postbaseline measurement;
AIMS, Abnormal Involuntary Movement Scale.
a
p value is treatment effect from the main effects model with terms for
treatment and geographic region using raw data.
60
BIOL PSYCHIATRY
2001;49:52– 63
treatment, although only one of the two had a neutrophil
count (1.65 109/L) below the lower normal limit of the
Lilly reference range (1.7 109/L). One olanzapine-treated
patient discontinued after 5 weeks for a similar reason,
despite a neutrophil count (1.87 109/L) above the lower
normal limit. One clozapine-treated patient discontinued
after 2 weeks for abnormal liver function test (ALT: 429
units/L; GGT: 798 units/L; alkaline phosphatase: 358
units/L) and one olanzapine-treated patient discontinued
after 2 weeks for jaundice (AST: 361 units/L; ALT: 2786
units/L; GGT: 202 units/L; alkaline phosphatase: 189
units/L).
Discussion
This study represents the first direct head-to-head comparison of olanzapine and clozapine in a nonresponsive
sample with schizophrenia. A significant strength was the
large scale, prospective, double-blind nature of the trial.
The study results confirmed that clozapine was effective in
a treatment-resistant cohort as originally described by
Kane et al (1988). Moreover, it demonstrated that olanzapine was at least as effective as clozapine in reducing the
severity of overall psychotic symptoms and better tolerated. Thus, the results support early consideration of
olanzapine in treatment-resistant schizophrenia based on a
favorable risk-benefit profile. The nature of the olanzapine
treatment effect, in such a sample, is concordant with the
open-label reports of Martin et al (1997) and Dossenbach
et al (in press), as well as interim results from a four-arm,
blinded comparison of olanzapine, clozapine, risperidone,
and haloperidol (personal communication, Jan Volavka);
however, a similar magnitude of effectiveness was not
apparent in a study by Conley et al (1998). In an effort to
model aspects of the Kane design (Kane et al 1988),
Conley followed 84 DMS-III schizophrenic patients who
had failed an open-label run-in with haloperidol (10 – 40
mg/day) and were subsequently randomized to an 8-week,
fixed-dose course of either olanzapine (25 mg/day) or
chlorpromazine (1200 mg/day). Neither study arm demonstrated a high rate of a therapeutic response, defined as
a 20% or greater reduction in BPRS and a posttreatment
CGI less than 3 or a posttreatment BPRS score less than 35
(olanzapine: 7%; chlorpromazine: 0%). Of note, though,
the results of Kane et al (1988) were clozapine 30% and
chlorpromazine 4%, a seven-fold difference. Thus, the
relative between-group comparisons may not be that
disparate.
This contrasting absolute response rate difference could
have been attributed to one or more of the following
design features: olanzapine dose, subject age, study design, severity of patient sample, completer’s only analysis,
or the length of the observational period.
G.D. Tollefson et al
For example, it may have been that study participants at
the Conley et al site represented an especially refractory
cohort, perhaps by nature of that research center. Of note,
only one of 103 subjects responded to haloperidol (10 – 40
mg) during the open 6-week qualifying phase. To that
possibility, subjects also could have been previously
treated with clozapine, since over half of those enrolled
had previously not responded to an atypical agent, risperidone (Conley et al 1998). Thus, their response rates may
not be directly comparable to either our study or that of
Kane et al (1988). Relative to the duration of treatment, it
is interesting to note that observed cases at weeks 7 and 8
began to diverge among the Conley sample favoring
olanzapine. Subsequently, Conley et al (1998) rolled these
double-blind subjects over to open-label olanzapine trial
and subsequently noted a higher response rate (personal
communication, Robert Conley). This may suggest that
even among severely ill patients, responses may be delayed relative to those less severely ill. Conversely, this
enhanced response rate may have only reflected the open
nature of the follow-up. Although the impact of comparative dose selections is speculative, the utility of doses of
olanzapine in excess of 25 mg has been suggested. Thus,
it is plausible that such higher doses might have been
associated with higher rates of response in the Conley
sample.
Last, it should be emphasized that the study methodologies across our study, Kane et al (1988), and Conley et al
(1998) differed in both design and primary objectives.
Most notably Conley et al (1998) did not include a
clozapine arm. Thus, conclusions about the treatment
responsivity of their cohort vis a vis another is limited.
Several features of our methodology merit discussion.
Our study was not intended to be a replicate of the Kane
study. The primary purpose of our study was not to
demonstrate that olanzapine was more effective than
clozapine, but to show that olanzapine was not inferior to
clozapine in treating refractory schizophrenic patients. To
achieve this goal, only the population for which the use of
clozapine was not restricted in Europe (i.e., resistant
patients) could be studied. The definition of resistance was
therefore based on clinical criteria obtained by history
(defined as a lack of satisfactory clinical response to at
least two previous oral neuroleptic treatments, each of a
different chemical class, given for a duration of at least 6
weeks at an appropriate daily dosage). To accommodate
ethical concerns in several Northern European countries,
the “appropriate daily dosage” had to be restricted to at
least 500 mg chlorpromazine equivalent. In addition, a
sentence referring to the maximum tolerated daily dosage
due to intolerable side effects had to be incorporated in the
protocol, and investigators were asked to document it.
Investigator sites were pooled within each country for
Olanzapine vs. Clozapine in Schizophrenia
statistical modeling purpose, leading to satisfactory numbers investigating the homogeneity of treatment effects
from a geographic region point of view. This is common
practice when many investigator sites have to be used to
recruit sufficient patient numbers in a reasonable amount
of time. Because our inclusion/exclusion criteria were
quite strict to try to obtain a true population of resistant
patients, enrollment had to take place across many centers.
The criteria for resistance did not specify whether it
needed to be within the current episode or was to be based
on the history of previously treated episodes, although the
data suggest the latter was used. The mean baseline BPRS
score of 60 for patients in this study is similar to the range
of mean scores of 51– 60 obtained from patients who
participated in previoius clinical trials of olanzapine;
however, patients with treatment-resistant schzophrenia
need not necessarily exhibit more severe symptoms, and
thus the baseline scores obtained are fully compatible with
treatment resistance.
Although there are no formal rules applicable to washout conditions, the wash-out period may have been considered as too short in this study. Again, ethics and
feasibility had to be taken into consideration. A longer
period of wash-out would have been highly criticized by
investigators and possibly rejected by Ethical Review
Committees. Such a resistant population had already been
treated with multiple conventional antipsychotic compounds. It is unlikely that 10 –15 additional “drug-free”
days would have changed the final outcome. After several
weeks of wash-out, patients would have likely been even
more severely ill and would have demonstrated a higher
PANSS score at baseline. Any possible carry-over effect
potentially operative at the beginning of the study would
have been equally distributed across the two study arms
and not contributory to the final results. All but one
adverse event (anxiety) causing discontinuation were not
present at baseline and therefore were not likely attributable to a carry-over effect from previous treatment.
The failure to complete rate, although high (around
40%), is consistent with that expected in clinical trials with
the population targeted in this study (exclusively resistant
schizophrenic patients).
Considering the known pharmacologic and clinical
profile of the two drugs (higher serotonin 2 than D2
activity, as well as the low activity of the two drugs for D2
receptors, with relatively low D2 occupancy levels found
in vitro and in vivo at clinical doses with positron emission
tomography methods (Pilowsky et al 1996), it was anticipated that only a few patients would report EPS (Tran et
al 1997). Earlier treatments with neuroleptics may also
have had an impact on the emergence of EPS. The
proportion of patients with emergent EPS was low in both
groups. On all EPS scales the categorical incidence of EPS
BIOL PSYCHIATRY
2001;49:52– 63
61
occurring at any point in time was numerically in favor of
olanzapine. The ob
Clozapine in Schizophrenic Patients Clinically Eligible
for Treatment with Clozapine
Gary D. Tollefson, Martin A. Birkett, Gerilyn M. Kiesler, Andrew J. Wood, and
The Lilly Resistant Schizophrenia Study Group
Background: The treatment of schizophrenic patients
who fail to respond to adequate trials of neuroleptic drugs
is a major challenge. Clozapine has been one treatment
option; however, it is not universally effective and is
limited in its use by safety concerns. With the introduction
of newer agents, their performance relative to clozapine is
of great clinical interest.
Methods: The primary objective of this study was to
evaluate the efficacy and safety of olanzapine versus
clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to
demonstrate the “noninferiority” of olanzapine compared
to clozapine after 18 weeks of double-blind treatment.
Conclusions were based on the one-sided lower 95%
confidence limit about the treatment effect observed from
the primary efficacy variable (Positive and Negative
Syndrome Scale [PANSS] Total).
Results: Mean changes from baseline to end point in
PANSS Total score, using a last observation carried
forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the “noninferiority” of olanzapine when compared to clozapine. Overall, significantly fewer
olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p 5 .022). Among spontaneously reported adverse
events, increased salivation, constipation, dizziness, and
nausea were reported significantly more often among
clozapine-treated patients, whereas only dry mouth was
reported more often among olanzapine-treated patients.
Conclusions: Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant
From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
(GDT, GMK), Eli Lilly and Company Limited, Lilly Research Centre,
Windlesham, United Kingdom (MAB), and Lilly Development Centre, MontSaint Guibert, Belgium (AJW).
Address reprint requests to Gary D. Tollefson, M.D., Ph.D., Lilly Research
Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2033,
Indianapolis IN 46285.
Received September 8, 1999; revised March 13, 2000; revised August 1, 2000;
accepted August 4, 2000.
© 2001 Society of Biological Psychiatry
schizophrenic patients clinically eligible for treatment
with clozapine. Biol Psychiatry 2001;49:52– 63 © 2001
Society of Biological Psychiatry
Key Words: Olanzapine, clozapine, treatment resistant,
schizophrenia, clinical trial
Introduction
T
he treatment of schizophrenic patients who fail to
respond to or tolerate adequate trials of neuroleptics is
a major challenge (Ciompi 1980; Kane 1996). It has been
repeatedly demonstrated that many schizophrenic patients
either do not respond or only partially respond to conventional dopamine-D2 antagonist antipsychotic agents; estimates vary between 40% and 80%. Even among patients
who respond in terms of core psychotic symptoms, other
disease manifestations, including negative, affective, and
anxious symptoms, may go unimproved. These features
contribute significantly to individual patient disability.
Furthermore, a number of adverse events characterize the
currently available conventional antipsychotic agents
(Kane 1989). The severity of these adverse events in a
considerable number of schizophrenic patients contributes
to poor compliance (Corrigan et al 1990; Weiden et al
1986). These adverse events include extrapyramidal syndromes (EPS; Chouinard et al 1988), such as drug-induced
parkinsonism, acute dystonic reactions, akathisia, tardive
dyskinesia, and tardive dystonia. Other reasons for drug
intolerance include sexual dysfunction, cognitive dulling,
seizure, or galactorrhea and gynecomastia attributable to
hyperprolactinemia.
Novel antipsychotic compounds that minimize such
adverse events and/or improve the breadth and depth of
clinical response offer the chance to improve overall
patient outcomes (Kinon and Lieberman 1996; Meltzer
1991). Although such benefits have been demonstrated in
standard subject populations, a greater challenge is pre0006-3223/01/$20.00
PII S0006-3223(00)01026-X
Olanzapine vs. Clozapine in Schizophrenia
sented by an intolerant or resistant schizophrenic patient
group. Subjects who have failed to benefit with conventional antipsychotic drugs constitute a particular and significant public health concern, by virtue of their significant
morbidity, mortality, and societal cost (Malhotra et al
1996).
Clozapine, an atypical antipsychotic drug, with pharmacologic features that distinguishes it from conventional
neuroleptic agents, represents one such novel alternative
(Carlsson 1988; Coward 1992; Meltzer 1989,1992). In
several multicenter clinical trials clozapine has been
shown to be effective in the treatment of DSM-III schizophrenic patients who have failed to respond to a variety of
conventional neuroleptics (Conley et al 1988; Hirsch and
Puri 1993; Kane et al 1988). These treatment benefits may
include improvement in positive and/or negative symptoms in schizophrenic patients (Naber and Hippius 1990).
Resultingly, clozapine has been approved specifically for
patients with schizophrenia who have proved intolerant of
and/or nonresponsive to conventional neuroleptic agents.
Olanzapine represents another novel alternative. Although exhibiting a similar in vitro profile to clozapine,
unique differences are evident (Bymaster et al 1996).
Clinical studies have shown that olanzapine is effective in
the control of psychotic symptomatology, including both
positive and negative symptoms among both acute and
chronic schizophrenic populations. Moreover, the rate of
early discontinuations attributable to adverse events is
significantly less than that seen with haloperidol (Beasley
et al 1996; Tollefson and Sanger 1997). Given these
apparent safety advantages, olanzapine may also be well
suited for the treatment of treatment-resistant schizophrenic patients (Miller et al 1994).
This study was designed to evaluate the efficacy and
safety of olanzapine compared with clozapine in schizophrenic patients who have been classified as having
treatment-resistant psychopathology eligible for treatment
with clozapine.
Methods and Materials
Study Design
The study was designed a priori as a “noninferiority” study, or
therapeutic equivalence study (Garbe et al 1993; Rohmel 1998). The
design is becoming more commonly used in studies where the
comparator is an established reference drug in clinical practice.
Trials to demonstrate the superiority of one treatment to another are
common, but in the case of an active controlled trial the demonstration of superiority for the investigational drug is considered unlikely
or would require too many patients to be practically and financially
feasible. Failure to demonstrate a statistical difference in favor of the
investigational drug cannot, of course, be used as proof of equivalence to the active control, hence the study must be designed with
the specific hypothesis of “noninferiority” in mind.
BIOL PSYCHIATRY
2001;49:52– 63
53
Interpretation of data from “noninferiority” trials is made on
the basis of confidence intervals. In such trials, the upper limit of
the confidence interval (in this case how much better the
investigational drug might be compared to the active control) is
of little interest, because we only want to try and reject the null
hypothesis that the investigational drug has less efficacy than the
control, for which we utilize the lower limit of the confidence
interval. Once rejected we can conclude that the investigational
drug is not inferior to the active control, meaning that we have
not ruled out the potential superiority compared to the active
control, a question that cannot be answered in the present study,
because it was not designed for this purpose.
The conclusions are based on interpretation of the one-sided
lower 95% confidence limit about the treatment effect observed
from the primary efficacy variable, and whether this confidence
limit lies in the correct half space compared to D (all values
larger than D), which marks the limit for differences that are
considered clinically acceptable. D was selected a priori to avoid
accusations of setting the clinically acceptable limit in a biased
manner based on observed data; however, there are no generally
accepted guidelines on how this clinically acceptable limit
should be chosen.
The study was conducted by 41 investigators in 14 countries
(Belgium, Denmark, Finland, France, Germany, Italy, Norway,
Portugal, South Africa, Spain, Sweden, Switzerland, Great Britain, and Ireland). All investigators and raters were English
speaking. The study protocol was approved by local ethical
review boards, and a signed informed consent was obtained from
all eligible patients after the procedures and possible side effects
were explained.
The study consisted of three periods: 1) a washout period from
previous antipsychotic drugs (2–9 days for oral antipsychotic
drugs; at least one injection cycle for depot antipsychotics); 2) an
18-week double-blind therapy period in which patients were
randomly allocated in a 1:1 ratio to treatment with olanzapine
15–25 mg/day or clozapine 200 – 600 mg/day; and 3) an optional
open-label extension period of up to 3 years or until olanzapine
became available in the relevant country (for olanzapine-treated
patients only). To ensure uninterrupted availability of the appropriate treatment at the end of the double-blind study period,
patients were unblinded after 18 weeks of therapy.
Randomized patients started olanzapine at 15 mg/day once
daily, or clozapine at a fixed dose escalation from 25 mg to 200
mg/day during the first 8 days of therapy. Flexible dosing, across
a range of 15–25 mg daily for olanzapine and 200 – 600 mg daily
for clozapine was permitted after the first 2 weeks of doubleblind treatment. With either drug, blinded titration was permitted
to optimize an individual patient’s outcome. Investigators had the
opportunity to increase or decrease the dosage by either 2.5 or 5
mg of olanzapine, or by 50 or 100 mg of clozapine per visit
interval (as per manufacturer’s instructions). Concomitant psychotropic medications were not allowed during the study with the
exception of a benzodiazepine (up to 40 mg/day diazepam
equivalent or 8 mg lorazepam equivalent) for agitation, chloral
hydrate for insomnia, and biperiden or benztropine mesylate (up
to 4 mg/day) for treatment-emergent EPS. Prophylactic use of
anticholinergic medications was prohibited.
54
G.D. Tollefson et al
BIOL PSYCHIATRY
2001;49:52– 63
Sample Size
The study was designed to be able to evaluate the “noninferiority” of olanzapine versus clozapine based on the one-sided lower
95% confidence limit of the difference between treatments in
change in Positive and Negative Syndrome Scale (PANSS) Total
scores.
A sample size of 220 patients (110 per treatment group) was
planned, assuming an expected treatment effect of 4 units (in
favor of olanzapine), with a common SD of 22 units, 85% power,
and a one-sided significance level of .05. The clinically acceptable limit (D) of 24 units for the treatment effect was selected
and denoted a priori in the protocol for the basis of declaring the
“noninferiority” of olanzapine compared to clozapine. The lower
limit was chosen to be 25% of what we estimated the overall
treatment benefit (i.e., change from baseline to end point in
PANSS Total score) would be; in this case we assumed 16 units.
Patient Population
Patients were men or women between the ages of 18 and 70 years
who met with a clinical diagnosis of DSM-IV criteria for
schizophrenia and who had a minimum score on the Brief
Psychiatric Rating Scale (BPRS1–7), extracted from the PANSS
(Kay et al 1987), of at least 45 and a score of 4 or more on at least
2 items of the PANSS Positive symptom subscale (items 1–7).
Patients who had previously been treated with olanzapine or
who were olanzapine or clozapine nonresponders were specifically excluded from this study. All study participants were
required to have a documented history that they were clinically
resistant to previous antipsychotic treatments. Resistance was
defined as a lack of satisfactory clinical response to at least 2
previous oral neuroleptic treatments, each of a different chemical
class, given for a duration of at least 6 weeks at an appropriate
daily dosage equivalent to at least 500 mg chlorpromazine, or to
the maximum daily dosage when intolerable side effects had
been documented. Patients known to be intolerant to either
clozapine or olanzapine were not included.
Patients could begin the study as inpatients or outpatients, and
changes in hospitalization status during the protocol were permitted. All patients who commenced the study as inpatients were
returned to outpatient status within 2 weeks of randomization to
double-blind treatment. Pregnant or lactating women, or patients
with serious medical illnesses in which pharmacotherapy posed a
substantial clinical risk or confounded diagnosis, were excluded.
Assessments
Clinical assessments were carried out at the screening visit and
again at the baseline assessment. Postrandomization assessments
were conducted weekly up to 18 weeks, throughout the study for
safety. For efficacy, assessments were performed weekly for the
first month, every 2 weeks for the next 6 weeks and finally every
4 weeks for the remainder of the study.
At the screening visit a standard history, physical examination,
and laboratory profile were obtained. Hematology tests were
performed at baseline as well as weekly during the 18-week
treatment period. Serum prolactin was measured at baseline and
at end point.
The efficacy measures included the PANSS Total score
(primary efficacy measure) and its subscales (positive and
negative); the 18-item BPRS1–7 total extracted from the PANSS
and the Clinical Global Impression Severity of Illness Scale
(CGI-Severity).
Adverse events were detected by clinical evaluation and
spontaneous report at each visit and mapped, classified, and
recorded using a system based on the U.S. Food and Drug
Administration Coding Symbols and Thesaurus for Adverse
Reaction Terms (COSTART; U.S. Food and Drug Administration 1990). In addition, adverse events were solicited by the
investigator using the 40-item Association for Methodology and
Documentation in Psychiatry (AMDP-5) adverse event questionnaire (Association for Methodology and Documentation in Psychiatry [Arbeltsgemeinschaft fur methodik und dokumentation in
der psychiatrie] 1981; Guy and Ban 1982).
Extrapyramidal symptoms, akathisia, and dyskinesia were
further assessed with the Simpson–Angus Scale (Simpson and
Angus 1970), the Barnes Akathisia Scale (Barnes 1989), and the
Abnormal Involuntary Movement Scale (AIMS; Guy 1976).
The modal daily dose was defined as the most frequently
administered daily dosage of study drug for each individual
patient during the 18-week double-blind therapy period; the
maximum daily dose was defined as the highest dose given to a
patient even if only for one day. The average daily dose is
calculated for each patient by deriving the cumulative dosage
received during the study divided by the number of days of
therapy.
All investigators attended a formal and standardized start-up
meeting, country by country, during which they were trained on
how to complete the different scales. No formal inter-rater
reliability was performed.
Statistical Methods
The primary intent of this study was to evaluate the effectiveness
and safety of olanzapine versus clozapine during double-blind
therapy. All end point analyses used a last observation carried
forward (LOCF) algorithm (the last available visit, from visit 3
onwards, served as an end point). For analyses of baseline
efficacy and safety measures and changes from baseline to end
point, only patients with a baseline (visit 2) and at least one
postbaseline measure were included. In the computation of total
scores on any individual scale, the total score was treated as
missing if any of the individual items were missing.
A one-sided lower 95% confidence limit for the difference in
LOCF mean change in PANSS Total score for clozapine minus
olanzapine was used in the primary efficacy analysis to demonstrate the “noninferiority” of olanzapine compared to clozapine.
The inference was based on the lower limit of the confidence
interval. A lower limit of .0 would indicate that olanzapine was
statistically significantly superior to clozapine. A lower limit of
$24 and #0 would indicate there was no difference between the
two treatments, and “noninferiority” could be concluded,
whereas a lower limit of ,24 would indicate that no conclusion
could be drawn regarding the “noninferiority” or superiority of
olanzapine compared with clozapine. One-sided lower 95%
confidence limits were also calculated for the secondary efficacy
Olanzapine vs. Clozapine in Schizophrenia
variables, although no predefined criteria for determining “noninferiority” were stated.
An analysis of variance (ANOVA) model with terms for
treatment, geographic region, and treatment-by-geographic region interaction was used to evaluate continuous efficacy data. If
the interaction was not significant (p . .10) then it was removed
and a model with terms for treatment and geographic region was
used. One-sided lower 95% confidence limits based on the
“absolute” difference in means were evaluated. In addition, the
difference in least squares means were also evaluated and used to
calculate the “adjusted” one-sided lower 95% confidence limit.
Both observed cases (OC) and LOCF visitwise summary
statistics were calculated. Significance tests for visitwise analyses were not performed since the primary outcome was to be
evaluated based on the change from baseline to end point.
Response rates were primarily calculated using the BPRS1–7
total score and CGI-Severity score using an LOCF technique. A
responder was defined a priori as any patient who achieved at
least a 20% reduction in BPRS1–7 total score from baseline to
end point, plus either an end point CGI-Severity scale score of
#3 or an end point BPRS1–7 total score of #35, as defined and
used by Kane et al (Kane et al 1988). Response rates (LOCF)
were also evaluated for patients who achieved reductions in
PANSS Total score of 20%, 30%, 40%, and 50% from baseline
to end point.
All statistical analyses for safety parameters are presented
based on two-sided hypothesis tests. Categorical data (demographic variables, reasons for study discontinuation, treatmentemergent adverse events, solicited adverse events, incidence of
EPS, and treatment-emergent abnormal laboratory analytes) were
evaluated using a Pearson x2 test. Kaplan–Meier survival curves
of time to discontinuation were compared between treatment
groups using the log-rank test.
The categorical incidence of EPS based on rating scale
definition was evaluated as follows. To assess treatment-associated psuedoparkinsonism, the proportion of patients with a
Simpson–Angus Scale total score of .3 at any postbaseline visit
was calculated among those with a total score of #3 at baseline.
To assess treatment-associated akathisia, the proportion of patients with a Barnes Akathisia Scale global score (item 4) $ 2 at
any postbaseline visit was calculated among those with a score of
,2 at baseline. To assess treatment-associated abnormal dyskinetic movements, the proportion of patients with a score of $3
on any one of the AIMS items 1 through 7 or a score of $2 on
any two of the AIMS items 1 through 7 at any postbaseline visit
was calculated among those without either of these criteria at
baseline. The latter definition is consistent with the crosssectional research diagnostic criteria suggested by Schooler and
Kane (1982). All these definitions were made a priori and used
in previous studies.
Results
Patient Characteristics
A total of 180 patients (olanzapine: n 5 90; clozapine: n 5
90) were assigned to receive double-blind therapy. The
BIOL PSYCHIATRY
2001;49:52– 63
55
Table 1. Patient Characteristics
Olanzapine
(n 5 90)
Male
Female
White
Other
Schizophrenia subtype
Catatonic
Disorganized
Paranoid
Undifferentiated
Residual
Schizophrenia course
Residual symptoms
No residual symptoms
Continuous
In partial remission
Other pattern
Clozapine
(n 5 90)
n
%
n
%
61
29
86
4
67.8
32.2
95.6
4.4
54
36
87
3
60.0
40.0
96.7
3.3
2
21
51
12
4
2.2
23.3
56.7
13.3
4.4
1
13
50
22
4
1.1
14.4
55.6
24.4
4.4
36
3
49
1
1
40.0
3.3
54.4
1.1
1.1
45
0
43
1
1
50.0
0
47.8
1.1
1.1
reduced sample size was declared before unblinding and
reflected a significant decline in recruitment once olanzapine had been approved for routine clinical use in Europe.
The 180 randomized subjects decreased the power to
declare “noninferiority” to 78% (instead of the planned
85%, based on 220 patients).
The treatment groups were comparable with respect to
baseline demographic and illness characteristics (Table 1).
The majority of the patients were male (63.9%), white
(96.1%), and 56.1% displayed a paranoid subtype of
schizophrenia. The courses of illness, according to DSMIV, were mainly continuous (51.1%) or episodic with
interepisode residual symptoms (45.0%), and 72.6% had
prominent residual negative symptomatology, based on
the DSM-IV classification of longitudinal course of the
disease.
The mean (SD) age of the patient population was 38.6
(10.6) years with a mean (SD) age of onset of illness of
22.8 (5.6) years. The median (range) length of patient’s
current episodes was 187 (6 –13,313) days, with 16
(17.8%) clozapine-treated patients and 9 (10.0%) olanzapine-treated patients having a current episode of less than
6 weeks duration. A large proportion of patients (43.4%)
had more than 10 previous schizophrenic episodes before
entry into the study. Patient’s baseline scores on the
PANSS and its subscales, the BPRS1–7, and the CGISeverity indicated that overall patients had severe and
mixed symptomatology (positive and negative; Table 2).
Patients also had a long history of illness and were
documented by the investigators as being resistant to other
antipsychotics.
56
G.D. Tollefson et al
BIOL PSYCHIATRY
2001;49:52– 63
Table 2. Mean Change in Efficacy Measures, Baseline to Endpoint (LOCF)
Measure
PANSS Total
PANSS Positive
PANSS Negative
CGI-Severity
BPRS1–7 Total
Therapy
n
Mean
(SD)
Mean
(SD)
Treatment
effecta
One-sided
lower 95%
confidence
limitb
Olanzapine
Clozapine
Olanzapine
Clozapine
Olanzapine
Clozapine
Olanzapine
Clozapine
Olanzapine
Clozapine
89
87
89
87
89
87
89
87
89
87
108.2 (15.7)
104.6 (20.0)
26.2 (5.8)
25.3 (6.4)
29.1 (6.3)
28.4 (6.9)
5.5 (0.8)
5.4 (0.9)
60.4 (9.5)
59.0 (11.3)
225.6 (25.5)
222.1 (23.1)
26.8 (7.6)
26.4 (7.2)
27.1 (7.4)
25.6 (6.9)
21.1 (1.2)
20.9 (1.1)
215.2 (15.3)
214.0 (13.3)
3.5
22.2
0.4
21.4
1.5
20.1
0.2
20.02
1.2
22.1
Baseline
Change
LOCF, last observation carried forward; N, number of patients with a baseline and at least one postbaseline measurement;
PANSS, Positive and Negative Syndrome Scale; CGI-Severity, Clinical Global Impressions Severity of Illness Scale; BPRS,
Brief Psychiatric Rating Scale.
a
Calculated as clozapine minus olanzapine.
b
Based on the “absolute” group mean change from baseline.
Patient Disposition
A total of 107 (59.4%) patients completed the 18-week,
double-blind treatment period (olanzapine: 60.0%; clozapine: 58.9%). Completion rates after 6 weeks and 12
weeks of therapy for olanzapine-treated patients were
85.6% and 70.0%, respectively, and for clozapine-treated
patients were 75.6% and 65.6%, respectively. Rates of
discontinuation from the study because of adverse events
were significantly lower for olanzapine compared to clozapine-treated patients [4.4% vs. 14.4%, x2(1) 5 5.26, p 5
.022]. There were no statistically significant differences
between the two treatment groups for any other reason of
discontinuation (lack of efficacy, 13.3% vs. 10.0%; patient
decision, 10.0% vs. 4.4%; lost to follow-up, 2.2% vs.
2.2%; other, 10.1% vs. 10.1%). More patients discontinued early in the double-blind therapy period in the clozapine treatment group [Kaplan–Meier survival estimates;
log-rank x2(1) 5 0.206, p 5 .650; mainly owing to
adverse events].
Dosage, Compliance, and Medication Use
Only patients who received therapy beyond the 1-week
titration period were included in the summary of exposure
and modal drug dose (olanzapine: n 5 88; clozapine: n 5
83). For these patients, there were a total of 8802 patientdays of exposure to olanzapine and 8074 patient-days of
exposure to clozapine. Table 3 shows the distribution of
patients maximum daily dose and modal daily dose for
each treatment group. A high incidence of clozapinetreated patients (44/83, 53.0%) received a maximum daily
dose of 400 – 600 mg, and the majority of olanzapinetreated patients (59/88, 67.0%) received a maximum daily
dose of 25 mg. The mean (SD) daily dose for olanzapine-
treated patients was 20.5 (2.8) mg/day (starting dosage of
15 mg/day) and for clozapine-treated patients was 303.6
(108.7) mg/day (starting dosage of 200 mg/day after
1-week titration period).
The numbers of patients using benzodiazepines at any
time during the study were similar for the two treatment
groups (olanzapine: 64.4%; clozapine: 53.3%). Investigation of benzodiazepine use during the washout period and
at the time of randomization indicated that a similarly
greater proportion of olanzapine patients were using benzodiazepines compared to clozapine (57.8% vs. 44.4%,
Table 3. Summary of Maximum and Modal Daily Dosage
During 18 Weeks Double-Blind Therapy for Patients Who
Received Study Drug after the Initial Titration Period
Maximum
daily dose
Dose level
Olanzapine (N 5 88)
15.0 mg
17.5 mg
20.0 mg
22.5 mg
25.0 mg
Clozapine (N 5 83)
200 mg
250 mg
300 mg
350 mg
400 mg
450 mg
500 mg
550 mg
600 mg
Modal daily
dose
n
%
n
%
8
7
11
3
59
9.1
8.0
12.5
3.4
67.0
14
6
10
4
54
15.9
6.8
11.4
4.5
61.4
19
8
8
4
10
8
7
5
14
22.9
9.6
9.6
4.8
12.0
9.6
8.4
6.0
16.9
27
7
8
5
8
7
7
3
11
32.5
8.4
9.6
6.0
9.6
8.4
8.4
3.6
13.3
N, number of patients who received study drug after the initial titration period;
n, frequency at each dose level.
Olanzapine vs. Clozapine in Schizophrenia
BIOL PSYCHIATRY
2001;49:52– 63
57
Table 4. Weekly Changes in PANSS Total Score Using LOCF and OC Techniques
LOCF
Week of therapy
1 week
2 weeks
3 weeks
4 weeks
6 weeks
8 weeks
10 weeks
14 weeks
18 weeks
OC
Olanzapine
(N 5 89)
Clozapine
(N 5 87)
Mean (SD)
Mean (SD)
n
Mean (SD)
n
Mean (SD)
24.2 (11.1)
29.4 (13.6)
214.6 (17.7)
217.1 (19.3)
220.7 (22.0)
220.8 (22.8)
223.0 (23.7)
224.0 (24.8)
225.6 (25.5)
22.9 (9.1)
29.2 (12.4)
213.5 (15.0)
215.4 (17.1)
220.5 (19.8)
220.5 (20.7)
221.0 (21.8)
221.5 (22.2)
222.1 (23.1)
88
85
84
84
81
69
66
57
55
24.2 (11.1)
29.8 (13.8)
214.8 (18.1)
217.3 (19.6)
222.4 (20.4)
224.0 (19.9)
227.4 (20.5)
231.5 (19.7)
234.2 (20.5)
86
82
75
72
69
65
61
58
53
22.9 (9.1)
210.3 (11.6)
215.9 (13.8)
218.2 (16.4)
225.2 (18.3)
226.8 (18.5)
228.1 (19.0)
229.5 (18.8)
230.6 (20.3)
Olanzapine
Clozapine
PANSS, Positive and Negative Syndrome Scale; LOCF, last observation carried forward; OC, Observed; N, Number of
patients with a baseline and at least one postbaseline measurement qualifying for LOCF analysis; n, number of patients with
measurements at each visit eligible for OC analysis.
respectively). Only seven olanzapine-treated patients and
eight clozapine-treated patients initiated use of benzodiazepines during the study, and one olanzapine-treated patient
used a benzodiazepine during the washout period but not
during the study. Few patients used an anticholinergic
agent (olanzapine: 4.4%; clozapine: 10.0%).
The mean (SD) daily benzodiazepine medication use,
expressed in lorazepam equivalents (mg/day), was not
clinically different in the two groups (olanzapine: 4.2 (3.0)
mg; clozapine: 3.2 (2.8) mg) nor was the mean (SD) daily
anticholinergic medication use, expressed in benztropine
equivalents (mg/day) (olanzapine: 1.3 (1.7) mg; clozapine:
1.8 (0.7) mg).
Efficacy
CHANGES IN EFFICACY MEASURES. There were no
statistically significant differences between treatment
groups on baseline efficacy measures, and although the
PANSS Total scores were numerically different, they were
not statistically significantly different (p 5 .888). Both
treatment groups showed significant within-group improvement (p , .001) from baseline to end point (LOCF)
in PANSS Total, PANSS Positive, PANSS Negative,
BPRS1–7 Total, and CGI-Severity scores (Table 2).
PANSS Total scores were used to test the primary hypothesis that olanzapine was not inferior to clozapine in this
study. Using the “absolute” observed group mean changes
from baseline, the difference in means was 3.5 units in
favor of olanzapine, and the one-sided lower 95% confidence limit was 22.2. Because this lower limit was $24
and #0, it indicated there was no clinical difference
between the two treatments and “noninferiority” could be
concluded. Using the “adjusted” group mean changes from
baseline (obtained using the least squares means from the
main effects model with terms for treatment and geo-
graphic region), the difference in means was 3.8 units in
favor of olanzapine, and the one-sided lower 95% confidence limit was 21.9, leading to the same conclusion.
Because of the apparent imbalance in baseline PANSS
Total scores between the two treatment groups, an analysis
of covariance was performed post hoc, where the covariate
was the baseline PANSS Total score and the end point
score was the dependent variable. The adjusted end point
least squares means from this analysis were 80.3 for
olanzapine and 83.4 for clozapine, with a one-sided 95%
confidence interval for the difference (3.1 units in favor of
olanzapine) being 23.7. Therefore, “noninferiority” could
still be concluded.
The visitwise mean change in PANSS Total score is
shown in Table 4 using both an LOCF and OC method.
The pattern of change over time was similar for the two
treatment groups. Examination of mean changes from
baseline for OC patients shows numerically greater
changes during weeks 2 through 10 for clozapine, but for
patients who receive treatment for 14 or 18 weeks there is
a similar treatment effect in favor of olanzapine as
calculated using the LOCF approach.
RESPONSE RATES. Among the secondary study objectives, a similar proportion of olanzapine- (38.2%) and
clozapine-treated patients (34.5%) achieved a response
based on the combined BPRS1–7 and CGI-Severity response definition (Table 5). Another definition of response, based on a 20%, 30%, 40%, and 50% change in
PANSS Total score, yielded similar proportions of responders across the two treatment groups. The one-sided
lower 95% confidence limits at the 30% and 40% criteria
are .0, providing evidence of a significantly greater
response with olanzapine.
The incidence of patients showing no improvement or
58
G.D. Tollefson et al
BIOL PSYCHIATRY
2001;49:52– 63
Table 5. Response Rates
Olanzapine
(N 5 89)
Response definition
BPRS1–7 1 CGI-Severityb
PANSS Total score
$20% improvement
$30% improvement
$40% improvement
$50% improvement
Clozapine
(N 5 87)
Treatment
effecta
One-sided lower
95% confidence
limit
n (%)
n (%)
34 (38.2)
30 (34.5)
3.7%
28.2%
53 (59.6)
41 (46.1)
24 (27.0)
9 (10.1)
47 (54.0)
28 (32.2)
14 (16.1)
9 (10.3)
5.6%
13.9%
10.9%
20.2%
26.7%
1.9%
0.8%
27.7%
N, number of patients with a baseline and at least one postbaseline measurement; n, number of responders based upon each
response definition; BPRS, Brief Psychiatric Rating Scale; CGI-Severity, Clinical Global Impressions Severity of Illness Scale;
PANSS, Positive and Negative Syndrome Scale.
a
Calculated as olanzapine minus clozapine.
b
Responder defined as a patient who achieved at least a 20% reduction in BPRS1–7 total score from baseline to end point,
plus either an end point CGI-Severity scale score of #3 or an end point BPRS1–7 total score of #35.
worsening of symptoms (defined as a percent change $0)
was 11/89 (12.4%) for olanzapine-treated patients and
14/87 (16.1%) for clozapine-treated patients. Analysis of
response rates controlling for gender and geographic
region showed no evidence of differing patterns of response between treatments.
Safety
SPONTANEOUSLY
REPORTED
TREATMENT-EMER-
Table 6 shows the spontaneously reported adverse events that were reported by at
least 5% of the patients in either treatment group or with
a statistically significant difference in the rate of reporting
(p , .05) between treatment groups. The most frequently
reported treatment-emergent adverse events in the olanzapine group were somnolence (13.3%), agitation (11.1%),
and headache (11.1%). The most frequently reported
treatment-emergent adverse events in the clozapine group
were increased salivation (28.9%), somnolence (24.4%),
constipation (18.9%), and nausea (11.1%). Throughout the
18 weeks of double-blind therapy, only one event (dry
mouth) was reported statistically significantly (p , .05)
more often among the olanzapine-treated patients, whereas
five events (increased salivation, constipation, nausea,
dizziness, and tooth disorder) were reported statistically
significantly more often among clozapine-treated patients.
Other adverse events showed numerical differences between the treatment groups, the most notable being leukopenia, somnolence, and agitation. Leukopenia was reported for six patients (clozapine: five; olanzapine: one).
The five clozapine-treated patients had leukocytes counts
ranging from 3.1 109/L to 4.5 109/L (lower limit of normal
range: 3.6 109/L), with only two out of five below the
lower limit, and neutrophil counts ranging from 1.3 109/L
to 2.1 109/L (lower limit of normal range: 1.79 109/L) with
three below the lower limit. The one olanzapine-treated
patient entered the trial with a low neutrophil count (1.82
GENT ADVERSE EVENTS.
109/L), which then normalized throughout the study, with
the exception of one value after 1 week (1.55 109/L)
considered as a laboratory error and consequently re-tested
(2.66 109/L). Some investigators discontinued patients
before they had reached the lower normal limit for these
analytes. For instance, of the two clozapine-treated patients who discontinued for leukopenia after 2 months of
treatment, only one had a neutrophil count below the
normal limit, and in the one olanzapine-treated patient
who discontinued after 5 weeks of therapy the neutrophil
count was within the normal range.
Table 6. Spontaneously Reported Treatment-Emergent
Adverse Events with an Incidence of $5% in Either Treatment
Group, or with a Statistically Significant Difference (p ,
.05) between Treatment Groups
Olanzapine
(N 5 90)
Clozapine
(N 5 90)
Event classification
n
%
n
%
p valuea
Somnolence
Agitation
Headache
Insomnia
Constipation
Weight gain
Anxiety
Rhinitis
Dry mouth
Vomiting
Flu syndrome
Asthenia
Increased salivation
Sweating
Dizziness
Fever
Leukopenia
Nausea
Tooth disorder
12
10
10
7
6
6
5
5
4
4
3
2
2
2
1
1
1
1
0
13.3
11.1
11.1
7.8
6.7
6.7
5.6
5.6
4.4
4.4
3.3
2.2
2.2
2.2
1.1
1.1
1.1
1.1
0
22
4
5
3
17
6
5
3
0
5
5
6
26
5
8
5
5
10
4
24.4
4.4
5.6
3.3
18.9
6.7
5.6
3.3
0
5.6
5.6
6.7
28.9
5.6
8.9
5.6
5.6
11.1
4.4
.057
.095
.178
.193
.014
1.00
1.00
.469
.043
.732
.469
.148
,.001
.247
.017
.097
.097
.005
.043
N, total number of patients randomized to each treatment group; n, number of
patients reporting each adverse event.
a
Frequencies are analyzed using a Pearson x2 test with one degree of freedom.
Olanzapine vs. Clozapine in Schizophrenia
Table 7. Solicited Adverse Events (AMDP-5) with a
Statistically Significant Difference (p , .05) in Incidence
Olanzapine
(N 5 89)
treated patients compared to clozapine-treated patients
[F(1,161) 5 7.90, p 5 .006].
Clozapine
(N 5 86)
WEIGHT AND ORTHOSTATIC BLOOD PRESSURE.
a
Event classification
n
%
n
%
p value
Drowsiness
Hypersalivation
Dry mouth
Dizziness
Increased perspiration
Hypotonia
Tardive dyskinesia
23
13
24
6
8
2
5
25.8
14.6
27.0
6.7
9.0
2.2
5.6
41
54
11
26
19
9
0
47.7
62.8
12.8
30.2
22.1
10.5
0
.003
,.001
.019
,.001
.016
.025
.026
AMDP-5, Association for Methodology and Documentation in Psychiatry; N,
number of randomly assigned patients with a postbaseline AMDP-5 assessment; n,
number of patients reporting each adverse event.
a
Frequencies are analyzed using a Pearson x2 test with one degree of freedom.
SOLICITED
59
BIOL PSYCHIATRY
2001;49:52– 63
TREATMENT-EMERGENT
ADVERSE
Based on the AMDP-5 solicited
adverse events scale, a statistically significantly greater
proportion of clozapine-treated patients (p , .05) experienced treatment-emergent drowsiness, hypersalivation,
dizziness, increased perspiration, and hypotonia, whereas
only the event terms of dry mouth and dyskinesia were
reported significantly more often in olanzapine-treated
patients (Table 7); however, of the five olanzapine-treated
patients reported on the AMDP-5 to exhibit dyskinesia,
only two patients met the criteria for treatment-emergent
tardive dyskinesia (Schooler and Kane 1982) on the AIMS
(one exhibited a probable withdrawal dyskinesia with
evidence of a moderate dyskinesia first appearing in the
first week, and the second experienced mild dyskinesia
between weeks 4 and 10, which resolved spontaneously
with continued treatment). The others only had transient
mild or moderate dyskinetic episodes lasting from 1 to 4
weeks. It is doubtful that such symptoms represented
tardive dyskinesia, as the usual duration criteria were not
fulfilled. Rather these cases appeared to represent “withdrawal” dyskinesias.
EVENTS (AMDP-5).
There was no significant difference between treatment
groups in the mean (SD) change from baseline to end point
(LOCF) of body weight [olanzapine: 1.8 (5.0) kg; clozapine: 2.3 (4.9) kg; F(1,163) 5 0.39, p 5 .534]. In the
olanzapine-treated group, patients had a mean (SD) decrease in orthostatic blood pressure of 0.5 mm Hg (14.5)
from baseline to end point, compared to 3.7 mm Hg (18.1)
in the clozapine-treated group [F(1,161) 5 1.64, p 5
.202).
CLINICAL LABORATORY EVALUATION. Monitoring
of leukocyte, neutrophil, and lymphocyte counts was
performed extensively during the study, as specified in the
clozapine monitoring requirements of the manufacturer.
Comparisons between treatment groups showed no statistically significant differences from baseline to end point in
leukocytes or neutrophils, although for lymphocytes there
was a significantly greater baseline to end point decrease
in clozapine-treated patients [F(1,159) 5 13.46, p , .001].
Baseline and end point prolactin levels were obtained
from 120 patients, 46 of whom (38.3%) had baseline
prolactin levels above the normal range. The mean change
from baseline to end point in prolactin levels [olanzapine:
0.18 nmol/L; clozapine: 20.14 nmol/L; F(1,109) 5 5.53,
p 5 .021] was significantly but not clinically different
between the two treatment groups with olanzapine-treated
patients demonstrating a greater increase compared to
clozapine-treated patients.
Five of the 17 discontinuations due to adverse events
were laboratory related. Two clozapine-treated patients
discontinued for “leukopenia,” after 8 and 10 weeks of
Table 8. Mean Change in EPS Rating Scales, Baseline to
Endpoint (LOCF)
Baseline
TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMP-
Categorical
analyses of the Simpson–Angus Scale, the Barnes Akathisia Scale, and the AIMS showed no statistically significant
or clinically relevant differences between olanzapine and
clozapine-treated patients in the incidence of treatmentemergent pseudoparkinsonism (7.5% vs. 10.5%), akathisia
(9.7% vs. 11.3%), and dyskinesia (5.0% vs. 4.0%),
respectively.
Changes from baseline to end point in the Simpson–
Angus total score, the AIMS Non-Global total score (items
1–7), and the Barnes Global score (item 4) are shown in
Table 8. There was a statistically significantly greater
decrease in the Simpson-Angus total score for olanzapine-
TOMS AS ASSESSED BY RATING SCALES.
Measure
Therapy
Simpson-Angus total
Olanzapine
Clozapine
AIMS Non-Global total
Olanzapine
Clozapine
Barnes Global score
Olanzapine
Clozapine
Change
n Mean (SD) Mean (SD) p valuea
.006
88
84
4.6 (5.6)
3.7 (5.1)
23.2 (4.8)
21.4 (3.3)
89
86
1.5 (3.0)
1.7 (3.2)
20.8 (2.2)
20.7 (2.5)
89
86
0.7 (1.0)
0.6 (1.0)
20.3 (0.9)
20.4 (1.0)
.630
.659
EPS, extrapyramidal symptoms; LOCF, last observation carried forward; n,
number of patients with a baseline and at least one postbaseline measurement;
AIMS, Abnormal Involuntary Movement Scale.
a
p value is treatment effect from the main effects model with terms for
treatment and geographic region using raw data.
60
BIOL PSYCHIATRY
2001;49:52– 63
treatment, although only one of the two had a neutrophil
count (1.65 109/L) below the lower normal limit of the
Lilly reference range (1.7 109/L). One olanzapine-treated
patient discontinued after 5 weeks for a similar reason,
despite a neutrophil count (1.87 109/L) above the lower
normal limit. One clozapine-treated patient discontinued
after 2 weeks for abnormal liver function test (ALT: 429
units/L; GGT: 798 units/L; alkaline phosphatase: 358
units/L) and one olanzapine-treated patient discontinued
after 2 weeks for jaundice (AST: 361 units/L; ALT: 2786
units/L; GGT: 202 units/L; alkaline phosphatase: 189
units/L).
Discussion
This study represents the first direct head-to-head comparison of olanzapine and clozapine in a nonresponsive
sample with schizophrenia. A significant strength was the
large scale, prospective, double-blind nature of the trial.
The study results confirmed that clozapine was effective in
a treatment-resistant cohort as originally described by
Kane et al (1988). Moreover, it demonstrated that olanzapine was at least as effective as clozapine in reducing the
severity of overall psychotic symptoms and better tolerated. Thus, the results support early consideration of
olanzapine in treatment-resistant schizophrenia based on a
favorable risk-benefit profile. The nature of the olanzapine
treatment effect, in such a sample, is concordant with the
open-label reports of Martin et al (1997) and Dossenbach
et al (in press), as well as interim results from a four-arm,
blinded comparison of olanzapine, clozapine, risperidone,
and haloperidol (personal communication, Jan Volavka);
however, a similar magnitude of effectiveness was not
apparent in a study by Conley et al (1998). In an effort to
model aspects of the Kane design (Kane et al 1988),
Conley followed 84 DMS-III schizophrenic patients who
had failed an open-label run-in with haloperidol (10 – 40
mg/day) and were subsequently randomized to an 8-week,
fixed-dose course of either olanzapine (25 mg/day) or
chlorpromazine (1200 mg/day). Neither study arm demonstrated a high rate of a therapeutic response, defined as
a 20% or greater reduction in BPRS and a posttreatment
CGI less than 3 or a posttreatment BPRS score less than 35
(olanzapine: 7%; chlorpromazine: 0%). Of note, though,
the results of Kane et al (1988) were clozapine 30% and
chlorpromazine 4%, a seven-fold difference. Thus, the
relative between-group comparisons may not be that
disparate.
This contrasting absolute response rate difference could
have been attributed to one or more of the following
design features: olanzapine dose, subject age, study design, severity of patient sample, completer’s only analysis,
or the length of the observational period.
G.D. Tollefson et al
For example, it may have been that study participants at
the Conley et al site represented an especially refractory
cohort, perhaps by nature of that research center. Of note,
only one of 103 subjects responded to haloperidol (10 – 40
mg) during the open 6-week qualifying phase. To that
possibility, subjects also could have been previously
treated with clozapine, since over half of those enrolled
had previously not responded to an atypical agent, risperidone (Conley et al 1998). Thus, their response rates may
not be directly comparable to either our study or that of
Kane et al (1988). Relative to the duration of treatment, it
is interesting to note that observed cases at weeks 7 and 8
began to diverge among the Conley sample favoring
olanzapine. Subsequently, Conley et al (1998) rolled these
double-blind subjects over to open-label olanzapine trial
and subsequently noted a higher response rate (personal
communication, Robert Conley). This may suggest that
even among severely ill patients, responses may be delayed relative to those less severely ill. Conversely, this
enhanced response rate may have only reflected the open
nature of the follow-up. Although the impact of comparative dose selections is speculative, the utility of doses of
olanzapine in excess of 25 mg has been suggested. Thus,
it is plausible that such higher doses might have been
associated with higher rates of response in the Conley
sample.
Last, it should be emphasized that the study methodologies across our study, Kane et al (1988), and Conley et al
(1998) differed in both design and primary objectives.
Most notably Conley et al (1998) did not include a
clozapine arm. Thus, conclusions about the treatment
responsivity of their cohort vis a vis another is limited.
Several features of our methodology merit discussion.
Our study was not intended to be a replicate of the Kane
study. The primary purpose of our study was not to
demonstrate that olanzapine was more effective than
clozapine, but to show that olanzapine was not inferior to
clozapine in treating refractory schizophrenic patients. To
achieve this goal, only the population for which the use of
clozapine was not restricted in Europe (i.e., resistant
patients) could be studied. The definition of resistance was
therefore based on clinical criteria obtained by history
(defined as a lack of satisfactory clinical response to at
least two previous oral neuroleptic treatments, each of a
different chemical class, given for a duration of at least 6
weeks at an appropriate daily dosage). To accommodate
ethical concerns in several Northern European countries,
the “appropriate daily dosage” had to be restricted to at
least 500 mg chlorpromazine equivalent. In addition, a
sentence referring to the maximum tolerated daily dosage
due to intolerable side effects had to be incorporated in the
protocol, and investigators were asked to document it.
Investigator sites were pooled within each country for
Olanzapine vs. Clozapine in Schizophrenia
statistical modeling purpose, leading to satisfactory numbers investigating the homogeneity of treatment effects
from a geographic region point of view. This is common
practice when many investigator sites have to be used to
recruit sufficient patient numbers in a reasonable amount
of time. Because our inclusion/exclusion criteria were
quite strict to try to obtain a true population of resistant
patients, enrollment had to take place across many centers.
The criteria for resistance did not specify whether it
needed to be within the current episode or was to be based
on the history of previously treated episodes, although the
data suggest the latter was used. The mean baseline BPRS
score of 60 for patients in this study is similar to the range
of mean scores of 51– 60 obtained from patients who
participated in previoius clinical trials of olanzapine;
however, patients with treatment-resistant schzophrenia
need not necessarily exhibit more severe symptoms, and
thus the baseline scores obtained are fully compatible with
treatment resistance.
Although there are no formal rules applicable to washout conditions, the wash-out period may have been considered as too short in this study. Again, ethics and
feasibility had to be taken into consideration. A longer
period of wash-out would have been highly criticized by
investigators and possibly rejected by Ethical Review
Committees. Such a resistant population had already been
treated with multiple conventional antipsychotic compounds. It is unlikely that 10 –15 additional “drug-free”
days would have changed the final outcome. After several
weeks of wash-out, patients would have likely been even
more severely ill and would have demonstrated a higher
PANSS score at baseline. Any possible carry-over effect
potentially operative at the beginning of the study would
have been equally distributed across the two study arms
and not contributory to the final results. All but one
adverse event (anxiety) causing discontinuation were not
present at baseline and therefore were not likely attributable to a carry-over effect from previous treatment.
The failure to complete rate, although high (around
40%), is consistent with that expected in clinical trials with
the population targeted in this study (exclusively resistant
schizophrenic patients).
Considering the known pharmacologic and clinical
profile of the two drugs (higher serotonin 2 than D2
activity, as well as the low activity of the two drugs for D2
receptors, with relatively low D2 occupancy levels found
in vitro and in vivo at clinical doses with positron emission
tomography methods (Pilowsky et al 1996), it was anticipated that only a few patients would report EPS (Tran et
al 1997). Earlier treatments with neuroleptics may also
have had an impact on the emergence of EPS. The
proportion of patients with emergent EPS was low in both
groups. On all EPS scales the categorical incidence of EPS
BIOL PSYCHIATRY
2001;49:52– 63
61
occurring at any point in time was numerically in favor of
olanzapine. The ob