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 schizo-phrenic 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 compa-rably effective in neuroleptic resistant patients, i.e., dem-onstrated the “noninferiority” of olanzapine when
com-pared to clozapine. Overall, significantly fewer
olanzapine-treated patients (4%) discontinued for an ad-verse event than their clozapine-treated (14%) counter-parts (p5 .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 nonin-ferior to clozapine and better tolerated among resistant
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 conven-tional dopamine-D2antagonist antipsychotic agents; esti-mates 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 syn-dromes (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 pre-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, Mont-Saint 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 0006-3223/01/$20.00
sented by an intolerant or resistant schizophrenic patient group. Subjects who have failed to benefit with conven-tional antipsychotic drugs constitute a particular and sig-nificant public health concern, by virtue of their sigsig-nificant morbidity, mortality, and societal cost (Malhotra et al 1996).
Clozapine, an atypical antipsychotic drug, with pharma-cologic 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 schizo-phrenic 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 symp-toms 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. Al-though 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 schizo-phrenic patients (Miller et al 1994).
This study was designed to evaluate the efficacy and safety of olanzapine compared with clozapine in schizo-phrenic 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 demonstra-tion of superiority for the investigademonstra-tional 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 equiva-lence to the active control, hence the study must be designed with the specific hypothesis of “noninferiority” in mind.
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.Dwas 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 Brit-ain, 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 appro-priate treatment at the end of the double-blind study period, patients were unblinded after 18 weeks of therapy.
Sample Size
The study was designed to be able to evaluate the “noninferior-ity” 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 accept-able limit (D) of24 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 specifi-cally 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 per-mitted. 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 BPRS1–7total 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 Administra-tion 1990). In addiAdministra-tion, adverse events were solicited by the investigator using the 40-item Association for Methodology and Documentation in Psychiatry (AMDP-5) adverse event question-naire (Association for Methodology and Documentation in Psy-chiatry [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 demon-strate 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
variables, although no predefined criteria for determining “non-inferiority” were stated.
An analysis of variance (ANOVA) model with terms for treatment, geographic region, and treatment-by-geographic re-gion 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 analy-ses 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 BPRS1–7total score from baseline to
end point, plus either an end point CGI-Severity scale score of
#3 or an end point BPRS1–7total 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 (demo-graphic variables, reasons for study discontinuation, treatment-emergent adverse events, solicited adverse events, incidence of EPS, and treatment-emergent abnormal laboratory analytes) were evaluated using a Pearsonx2
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-associ-ated 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 pa-tients 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 dyski-netic 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 cross-sectional 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: n590; clozapine: n5 90) were assigned to receive double-blind therapy. The
reduced sample size was declared before unblinding and reflected a significant decline in recruitment once olanza-pine 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 DSM-IV, 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%) olanza-pine-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 CGI-Severity 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.
Table 1. Patient Characteristics
Olanzapine (n 5 90)
Clozapine (n 5 90)
n % n %
Male 61 67.8 54 60.0
Female 29 32.2 36 40.0
White 86 95.6 87 96.7
Other 4 4.4 3 3.3
Schizophrenia subtype
Catatonic 2 2.2 1 1.1
Disorganized 21 23.3 13 14.4
Paranoid 51 56.7 50 55.6
Undifferentiated 12 13.3 22 24.4
Residual 4 4.4 4 4.4
Schizophrenia course
Residual symptoms 36 40.0 45 50.0
No residual symptoms 3 3.3 0 0
Continuous 49 54.4 43 47.8
In partial remission 1 1.1 1 1.1
Patient Disposition
A total of 107 (59.4%) patients completed the 18-week, double-blind treatment period (olanzapine: 60.0%; cloza-pine: 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 cloz-apine-treated patients [4.4% vs. 14.4%,x2(1)55.26, p5 .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 discontin-ued early in the double-blind therapy period in the cloza-pine 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: n588; clozapine: n5 83). For these patients, there were a total of 8802 patient-days of exposure to olanzapine and 8074 patient-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 clozapine-treated patients (44/83, 53.0%) received a maximum daily dose of 400 – 600 mg, and the majority of olanzapine-treated 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%). Investiga-tion of benzodiazepine use during the washout period and at the time of randomization indicated that a similarly greater proportion of olanzapine patients were using ben-zodiazepines compared to clozapine (57.8% vs. 44.4%,
Table 2. Mean Change in Efficacy Measures, Baseline to Endpoint (LOCF)
Measure Therapy n
Baseline Change
Treatment effecta
One-sided lower 95% confidence limitb
Mean (SD)
Mean (SD)
PANSS Total Olanzapine 89 108.2 (15.7) 225.6 (25.5) 3.5 22.2 Clozapine 87 104.6 (20.0) 222.1 (23.1)
PANSS Positive Olanzapine 89 26.2 (5.8) 26.8 (7.6) 0.4 21.4 Clozapine 87 25.3 (6.4) 26.4 (7.2)
PANSS Negative Olanzapine 89 29.1 (6.3) 27.1 (7.4) 1.5 20.1 Clozapine 87 28.4 (6.9) 25.6 (6.9)
CGI-Severity Olanzapine 89 5.5 (0.8) 21.1 (1.2) 0.2 20.02 Clozapine 87 5.4 (0.9) 20.9 (1.1)
BPRS1–7Total Olanzapine 89 60.4 (9.5) 215.2 (15.3) 1.2 22.1
Clozapine 87 59.0 (11.3) 214.0 (13.3)
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.
aCalculated as clozapine minus olanzapine.
bBased on the “absolute” group mean change from baseline.
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
Dose level
Maximum daily dose
Modal daily dose
n % n %
Olanzapine (N5 88)
15.0 mg 8 9.1 14 15.9
17.5 mg 7 8.0 6 6.8
20.0 mg 11 12.5 10 11.4
22.5 mg 3 3.4 4 4.5
25.0 mg 59 67.0 54 61.4
Clozapine (N5 83)
200 mg 19 22.9 27 32.5
250 mg 8 9.6 7 8.4
300 mg 8 9.6 8 9.6
350 mg 4 4.8 5 6.0
400 mg 10 12.0 8 9.6
450 mg 8 9.6 7 8.4
500 mg 7 8.4 7 8.4
550 mg 5 6.0 3 3.6
600 mg 14 16.9 11 13.3
respectively). Only seven olanzapine-treated patients and eight clozapine-treated patients initiated use of benzodiaz-epines 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 im-provement (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 hypoth-esis 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% confi-dence limit was22.2. 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% confi-dence 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) being23.7. 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
ob-jectives, 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 sponse definition (Table 5). Another definition of re-sponse, based on a 20%, 30%, 40%, and 50% change in PANSS Total score, yielded similar proportions of re-sponders 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
Table 4. Weekly Changes in PANSS Total Score Using LOCF and OC Techniques
Week of therapy
LOCF OC
Olanzapine (N5 89)
Clozapine
(N5 87) Olanzapine Clozapine
Mean (SD) Mean (SD) n Mean (SD) n Mean (SD)
1 week 24.2 (11.1) 22.9 (9.1) 88 24.2 (11.1) 86 22.9 (9.1) 2 weeks 29.4 (13.6) 29.2 (12.4) 85 29.8 (13.8) 82 210.3 (11.6) 3 weeks 214.6 (17.7) 213.5 (15.0) 84 214.8 (18.1) 75 215.9 (13.8) 4 weeks 217.1 (19.3) 215.4 (17.1) 84 217.3 (19.6) 72 218.2 (16.4) 6 weeks 220.7 (22.0) 220.5 (19.8) 81 222.4 (20.4) 69 225.2 (18.3) 8 weeks 220.8 (22.8) 220.5 (20.7) 69 224.0 (19.9) 65 226.8 (18.5) 10 weeks 223.0 (23.7) 221.0 (21.8) 66 227.4 (20.5) 61 228.1 (19.0) 14 weeks 224.0 (24.8) 221.5 (22.2) 57 231.5 (19.7) 58 229.5 (18.8) 18 weeks 225.6 (25.5) 222.1 (23.1) 55 234.2 (20.5) 53 230.6 (20.3)
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 re-sponse between treatments.
Safety
SPONTANEOUSLY REPORTED
TREATMENT-EMER-GENT ADVERSE EVENTS. Table 6 shows the
spontane-ously 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 olanza-pine 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 be-tween the treatment groups, the most notable being leu-kopenia, somnolence, and agitation. Leukopenia was re-ported 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
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 pa-tients 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
Event classification
Olanzapine (N5 90)
Clozapine (N 5 90)
p valuea
n % n %
Somnolence 12 13.3 22 24.4 .057
Agitation 10 11.1 4 4.4 .095
Headache 10 11.1 5 5.6 .178
Insomnia 7 7.8 3 3.3 .193
Constipation 6 6.7 17 18.9 .014
Weight gain 6 6.7 6 6.7 1.00
Anxiety 5 5.6 5 5.6 1.00
Rhinitis 5 5.6 3 3.3 .469
Dry mouth 4 4.4 0 0 .043
Vomiting 4 4.4 5 5.6 .732
Flu syndrome 3 3.3 5 5.6 .469
Asthenia 2 2.2 6 6.7 .148
Increased salivation 2 2.2 26 28.9 ,.001
Sweating 2 2.2 5 5.6 .247
Dizziness 1 1.1 8 8.9 .017
Fever 1 1.1 5 5.6 .097
Leukopenia 1 1.1 5 5.6 .097
Nausea 1 1.1 10 11.1 .005
Tooth disorder 0 0 4 4.4 .043
N, total number of patients randomized to each treatment group; n, number of
patients reporting each adverse event.
aFrequencies are analyzed using a Pearsonx2test with one degree of freedom.
Table 5. Response Rates
Response definition
Olanzapine (N 5 89)
Clozapine (N5 87)
Treatment effecta
One-sided lower 95% confidence
limit
n (%) n (%)
BPRS1–71CGI-Severity
b 34 (38.2) 30 (34.5) 3.7% 28.2%
PANSS Total score
$20% improvement 53 (59.6) 47 (54.0) 5.6% 26.7%
$30% improvement 41 (46.1) 28 (32.2) 13.9% 1.9%
$40% improvement 24 (27.0) 14 (16.1) 10.9% 0.8%
$50% improvement 9 (10.1) 9 (10.3) 20.2% 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.
aCalculated as olanzapine minus clozapine.
bResponder defined as a patient who achieved at least a 20% reduction in BPRS
1–7total score from baseline to end point,
SOLICITED TREATMENT-EMERGENT ADVERSE
EVENTS (AMDP-5). Based on the AMDP-5 solicited
adverse events scale, a statistically significantly greater proportion of clozapine-treated patients (p,.05) experi-enced 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 “with-drawal” dyskinesias.
TREATMENT-EMERGENT EXTRAPYRAMIDAL
SYMP-TOMS AS ASSESSED BY RATING SCALES. Categorical
analyses of the Simpson–Angus Scale, the Barnes Akathi-sia Scale, and the AIMS showed no statistically significant or clinically relevant differences between olanzapine and clozapine-treated patients in the incidence of treatment-emergent 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-treated patients compared to clozapine-olanzapine-treated patients [F(1,161)5 7.90, p5 .006].
WEIGHT AND ORTHOSTATIC BLOOD PRESSURE.
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; cloza-pine: 2.3 (4.9) kg; F(1,163) 5 0.39, p 5 .534]. In the olanzapine-treated group, patients had a mean (SD) de-crease 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 statis-tically 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)513.46, 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)55.53,
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 7. Solicited Adverse Events (AMDP-5) with a Statistically Significant Difference (p , .05) in Incidence
Event classification
Olanzapine (N 5 89)
Clozapine (N 5 86)
p valuea
n % n %
Drowsiness 23 25.8 41 47.7 .003
Hypersalivation 13 14.6 54 62.8 ,.001
Dry mouth 24 27.0 11 12.8 .019
Dizziness 6 6.7 26 30.2 ,.001
Increased perspiration 8 9.0 19 22.1 .016
Hypotonia 2 2.2 9 10.5 .025
Tardive dyskinesia 5 5.6 0 0 .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.
aFrequencies are analyzed using a Pearsonx2test with one degree of freedom.
Table 8. Mean Change in EPS Rating Scales, Baseline to Endpoint (LOCF)
Measure Therapy n
Baseline Change
p valuea
Mean (SD) Mean (SD)
Simpson-Angus total .006
Olanzapine 88 4.6 (5.6) 23.2 (4.8) Clozapine 84 3.7 (5.1) 21.4 (3.3)
AIMS Non-Global total .630
Olanzapine 89 1.5 (3.0) 20.8 (2.2) Clozapine 86 1.7 (3.2) 20.7 (2.5)
Barnes Global score .659
Olanzapine 89 0.7 (1.0) 20.3 (0.9) Clozapine 86 0.6 (1.0) 20.4 (1.0)
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.
ap value is treatment effect from the main effects model with terms for
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 compar-ison 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 olanza-pine was at least as effective as clozaolanza-pine in reducing the severity of overall psychotic symptoms and better toler-ated. 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 dem-onstrated 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 de-sign, severity of patient sample, completer’s only analysis, or the length of the observational period.
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, risperi-done (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 de-layed 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 compar-ative dose selections is speculcompar-ative, 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 methodol-ogies 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.
statistical modeling purpose, leading to satisfactory num-bers 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 wash-out conditions, the wash-wash-out period may have been con-sidered 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 com-pounds. 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 attribut-able 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 D2occupancy levels found in vitro and in vivo at clinical doses with positron emission tomography methods (Pilowsky et al 1996), it was antic-ipated 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
occurring at any point in time was numerically in favor of olanzapine. The observed results from the Simpson– Angus Scale, favoring olanzapine, may have been attrib-uted to the high incidence of hypersalivation in the clozapine group. To investigate this further, the Simpson– Angus Scale analysis was repeated, omitting item 10 (salivation). The improvement in the olanzapine group was still marginally significant [F(1,161) 5 3.79, p 5 .053].
One additional feature of this clinical study merits discussion: the choice of the dose range for both drugs that was determined to provide investigators flexibility to optimize the naturalistic dose best suited for each individ-ual patient. As the study was performed in a resistant patient population, the dose of olanzapine up to 25 mg per day was explored. The dose range of clozapine was dictated by the then current European package labeling and was consistent with the current practice in Europe (200 – 600 mg). The relatively more favorable rate of adverse events in the olanzapine group may have up-wardly biased the modal dose of olanzapine relative to clozapine. In agreement was the fact that in the majority of olanzapine-treated patients (61.4%), the dose was in-creased to the maximum authorized level. The mean daily clozapine dose (303.6 mg) is similar to the mean daily clozapine dose (280 mg) usually prescribed in clinical practice based on data from four European countries: France, Italy, Spain, and UK (IMS data, first quarter 1998) in the same resistant schizophrenic population.
In summary, little can be concluded around dose selec-tion in this study other than its congruence with the standard of practice in the particular clinical environment where the trial was conducted.
The rate of dose escalation, although perfectly blinded, was unbalanced in that a maximum permitted dose of olanzapine could have been reached earlier than with clozapine. This slow titration was part of the Kane et al approach also. Although in theory this might have favored an earlier therapeutic effect with olanzapine, it also likely retained more of the clozapine subjects, as the titration schedule was driven by tolerability concerns. Regardless, the 18-week therapy phase allowed adequate time for any patient to reach a maximum allowable dose. A time to peak dose analysis would not be appropriate for these reasons. Patients could have reached the maximum dose of olanzapine within four weekly visit intervals (possible minimal increases by 2.5 mg), whereas patients receiving clozapine would have required as many as eight weekly visit intervals (possible minimal increases by 50 mg). Only a few patients (n5 14) actually reached 600 mg, which makes the two groups more comparable in terms of dose escalation.
The use of benzodiazepine, although quite liberal in this study, should not have had a major impact on the outcome. The mean difference in benzodiazepines between the two groups was only 1 mg of lorazepam equivalent, which is not considered clinically relevant for a population of refractory schizophrenic patients. In addition, the majority of patients in each treatment group taking benzodiazepines during the study were also taking them before randomiza-tion, thus their baseline severity of illness will have accounted for such use.
As reported through the AMDP-5, 62.8% of clozapine patients reported hypersalivation, compared to 14.6% in the olanzapine group. In this respect the two groups may be seen as significantly different and the question of potential “unblinding” of investigators could be raised; however, these data show that the reported frequency with olanzapine is not so uncommon as to have accounted for unblinding. Other safety assessments, e.g., EPS also did not suggest such a phenomenon had occurred.
The trend toward greater lowering of neutrophil counts with olanzapine should also be discussed. It was probably related to the higher numerical values at baseline (5.07 vs. 4.66). Of note, the end point value in both groups were clinically identical (4.75 vs. 4.77).
It is notable that 43.3% of olanzapine-treated patients achieved a clinical response according to the most strin-gent definition (BPRS 1–7improvement$ 20% plus end point CGI-Severity#3 or end point BPRS1–7#35) at the 15–20 mg modal dose range, versus 36.4% in the 200 – 400 mg clozapine modal dose range. Above 20 mg of
olanzapine and 400 mg of clozapine the percentage of responders was similar and not clinically different (36.2% and 35.7%, respectively). This current study did not permit testing of dose versus time to maximal clinical benefit. It is suspected that titration may have been performed as quickly as possible according to protocol guidelines given the nature of this population.
In conclusion, both olanzapine in a dose range of 15–25 mg/day and clozapine in a dose range of 200 – 600 mg/day were similarly effective in reducing overall psychopathol-ogy in a patient population with chronic and resistant schizophrenia who are clinically eligible for treatment with clozapine. Moreover, considering the relative risk– benefit profile of these two agents, olanzapine exhibited a superior overall safety profile, including a significantly lower discontinuation rate due to adverse events. More-over, the lack of clinically significant hematologic find-ings in this study, and in turn the lack of blood monitoring requirements with olanzapine should further underscore its advantage among treatment-resistant schizophrenic patients.
The authors and The Lilly Resistant Schizophrenia Study Group thank their Lilly colleagues for their effort and their contribution to this study: Isma Benattia, Daniele Bravi, Per Cantor, Martha Colban, Joerg Czek-alla, Marijke Decroix, Manuela Destreel, Ralph Dittman, Danie Duples-sis, Conny Edlund, Jayne Fountain, Juan-Carlos Gomez, Sandrine Gosset, Mariana Guerreiro, Meena Hansen, Antonio Jordao, Kristine Kolling, Henrik Krog, Carmen Lopez-Carrero, Karena Meehan, Patrick J Mesters, Alison Mitchell, Robin Moschel, Khac-Trung Ngo, Birgitte Scharling, Corinne Schloesser, Francina Van Heerden, Isabella Velona, Pirkko Weurlander, and Juergen Wilschke.
The Lilly Resistant Schizophrenia Study Group: Drs. J. Gerlach, M. Abbar, E. Alvarez, J. Andersen, V. Arolt, S.K. Asserson, L. Barrelet, P. Baumann, M. Birket-Smith, J. Brabrand, P. Castrogiovanni, G. Clerc, G. Darcourt, E. De Bleeker, J.M. Dubroca, P. Ekdahl, G. Fazzari, L. Ferreira, C.A. Gagiano, J.D. Guelfi, D.J. Hall, J.O. Haug, L.A. Heikkila, A. Kasas, J.P. Lauzel, M. Llorca, A. Marneros, J.C. Martin, R. Mc-Creadie, Mesotten, R. Murray, B. Nylander, E. O’Callaghan, T. Palomo, J.C. Peuskens, E. Sacchetti, J.C. Scotto, P. Stonegger, E. Storval, G. Struwe, B. Stubhaug, J. Talbitzer, J.M. Vaadal, and H. Vartiainen.
References
Association for Methodology and Documentation in Psychiatry [Arbeltsgemeinschaft fur Methodik und Dokumentation in der Psychiatrie] (1981): Das AMDP-System: Manual zur
Documentation Psychiatriacher Befunde 4 (AMDP). Berlin:
Auflage.
Barnes TR (1989): A rating scale for drug-induced akathisia. Br J
Psychiatry 154:672– 676.
Beasley CM Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S (1996): Olanzapine versus placebo: Results of a double-blind, fixed-dose olanzapine trial.
Psychopharmacol-ogy 124:159 –167.
atypical antipsychotic olanzapine.
Neuropsychopharmacol-ogy 14:87–96.
Carlsson A (1988): The current status of the dopamine hypoth-esis of schizophrenia. Neuropsychopharmacology 1:179 – 186.
Chouinard G, Annable L, Ross-Chouinard A, Mercier P (1988): A 5-year prospective longitudinal study of tardive dyskinesia: Factors predicting appearance of new cases. J Clin
Psycho-pharmacol 8:21S–26S.
Ciompi L (1980): The natural history of schizophrenia in the long-term. Br J Psychiatry 136:413– 420.
Conley RR, Schulz SC, Baker RW, Collins JF, Bell JA (1988): Clozapine efficacy in schizophrenic nonresponders.
Psycho-pharmacol Bull 24:269 –274.
Conley RR, Tamminga CA, Bartko JJ, Richardson C, Peszke M, Lingle J, et al (1998): Olanzapine compared with chlorprom-azine in treatment-resistant schizophrenia. Am J Psychiatry 155:914 –920.
Corrigan PW, Liberman RP, Engel JD (1990): From noncompli-ance to collaboration in the treatment of schizophrenia. Hosp
Community Psychiatry 41:1203–1211.
Coward DM (1992): General pharmacology of clozapine. Br J
Psychiatry 160:5–11.
Dossenbach MRK, Tollefson GD, Kratky P, Beuzen JN (in press): Evidence for the effectiveness of olanzapine among treatment refractory patients non-responsive and/or intolerant to clozapine. Clin Ther.
Garbe E, Rohmel J Gundert-Remy U (1993): Clinical and statistical issues in therapeutic equivalence trials. Eur J Clin
Pharmacol 45:1–7.
Guy W (1976): ECDEU Assessment Manual for
Psychopharma-cology. Rockville, MD: U.S. Department of Health,
Educa-tion and Welfare.
Guy W, Ban TA (1982): The AMDP System. Berlin: Springer. Hirsch SR, Puri BK (1993): Clozapine: Progress in treating
resistant schizophrenia. Br Med J 306:1427–1428.
Kane J, Honigfeld G, Singer J, Meltzer H (1988): Clozapine for the treatment-resistant schizophrenic. A double-blind com-parison with chlorpromazine. Arch Gen Psychiatry 45:789 – 796.
Kane JM (1989): The current status of neuroleptic therapy. J Clin
Psychiatry 50: 322–328.
Kane JM (1996): Schizophrenia. N Engl J Med 334:34 – 41. Kay SR, Fiszbein A, Opler LA (1987): The Positive and
Negative Syndrome Scale (PANSS) for schizophrenia.
Schizophr Bull 13:261–276.
Kinon BJ, Lieberman JA (1996): Mechanisms of action of atypical antipsychotic drugs: A critical analysis.
Psychophar-macology 124:2–34.
Lindenmayer JP, Apergi FS (1996): The relationship between clozapine plasma levels and clinical response. Psychiatr Ann 26:406 – 412.
Malhotra AK, Pinsky DA, Breier A (1996): Future antipsychotic agents: Clinical implications. In: Breier A, editor. The New
Pharmacotherapy of Shizophrenia. Washington, DC:
Amer-ican Psychiatric Association Press, 41.
Martin J, Gomez JC, Garcia-Bernardo E, Cuesta M, Alvarez E, Gurpegui M, Spanish Group for the Study of Olanzapine in Treatment-Refractory Schizophrenia (1997): Olanzapine in treatment-refractory schizophrenia: Results of an open-label study. J Clin Psychiatry 58:11.
Meltzer HY (1989): Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizo-phrenia. Psychopharmacology 99(suppl):S18 –S27.
Meltzer HY (1991): The mechanism of action of novel antipsy-chotic drugs. Schizophr Bull 17:263–287.
Meltzer HY (1992): The importance of serotonin-dopamine interactions in the action of clozapine. Br J Psychiatry 160:22–29.
Miller DD, Perry PJ, Cadoret RJ, Andreason NC (1994): Cloz-apine’s effect on negative symptoms in treatment-refractory schizophrenics. Compr Psychiatry 35:8 –15.
Naber D, Hippius H (1990): The European experience with use of clozapine. Hosp Community Psychiatry 41:886 – 890. Pilowsky LS, Busatto GF, Taylor M, Costa DC, Sharma T,
Sigmundsson T, et al (1996): Dopamine D2 receptor occu-pancy in vivo by the novel atypical antipsychotic olanzap-ine—a 123I IBZM single photon emission tomography (SPET) study. Psychopharmacology 124:148 –153.
Pollack S, Lieberman JA, Fleischhacker WW, Borenstein M, Safferman AZ, Hummer M, Kurz M (1995): A comparison of European and American dosing regimens of schizophrenic patients on clozapine: Efficacy and side effects.
Psychophar-macol Bull 31:315–320.
Rohmel J (1998): Therapeutic equivalence investigations: Statis-tical considerations. Stat Med 17:1703–1714.
Schooler NR, Kane JM (1982): Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39:486 – 487.
Simpson GM, Angus JWS (1970): A rating scale for extrapyra-midal side effects. Acta Psychiatr Scand 212:S11–S19. Tollefson GD, Sanger TM (1997): Negative symptoms: A path
analytic approach to a double-blind, placebo- and haloperi-dol-controlled clinical trial with olanzapine. Am J Psychiatry 154:466 – 474.
Tran PV, Dellva MA, Tollefson GD, Beasley CM Jr, Potvin JH, Kiesler GM (1997): Extrapyramidal symptoms and tolerabil-ity of olanzapine versus haloperidol in the acute treatment of schizophrenia. J Clin Psychiatry 58:205–211.
U.S. Food and Drug Administration (1990): COSTART Coding
Symbols for Thesaurus of Adverse Reaction Terms. Rockville,
MD: U.S. Food and Drug Administration.
