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Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia
Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 173 – 180 www.elsevier.com/locate/pnpbp
Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia Istvan Bittera,b,*, Martin R.K. Dossenbachb, Shlomo Brookc, Peter D. Feldmand, Stephen Metcalfeb, Carlo A. Gagianoe, Ja´nos Fu¨redif, Gyo¨rgy Bartkog, Zoltan Jankah, Csaba M. Bankii, Gabor Kovacs j, Alan Breierd for the Olanzapine HGCK Study Group a
Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary b E. Lilly Area Medical Center, Vienna, Austria c Sterkfontein Hospital, Krugersdorp, South Africa d Lilly Research Laboratories, Indianapolis, IN, USA e Department of Psychiatry, University of the Free State, Bloemfontein, South Africa f National Institute of Psychiatry and Neurology, Budapest, Hungary g Department of Psychiatry, Ja´hn Ferenc Hospital, Budapest, Hungary h Department of Psychiatry, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary i Regional Neuropsychiatric Institute, Nagyka´llo´, Hungary j Department of Psychiatry, Central Military Hospital, Budapest, Hungary Accepted 17 September 2003
Abstract Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5 – 25 mg/day, n = 75) or clozapine (100 – 500 mg/day, n = 72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia. D 2003 Elsevier Inc. All rights reserved. Keywords: Clozapine; Drug resistance; Drug tolerance; Olanzapine; Schizophrenia; Treatment resistance
Abbreviations: AIMS, Abnormal Involuntary Movement Scale; ALT, Alanine transaminase; AST, Aspartate transaminase; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; GGT, Gamma-glutamyl transferase; HAS, Hillside Akathisia Scale; IMS, Intercontinental Marketing Services; LOCF, Last observation carried forward; PANSS, Positive and Negative Syndrome Scale; SGOT, Serum glutamic – oxaloacetic transaminase; SGPT, Serum glutamic – pyruvic transaminase. * Corresponding author. Department of Psychiatry and Psychotherapy, Semmelweis University, Balassa Str.6, 1083 Budapest, Hungary. Tel.: +361-210-0330; fax: +36-1-303-2352. E-mail address: [email protected] (I. Bitter). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2003.09.033
1. Introduction Approximately 20% to 25% of all patients with schizophrenia are resistant to repeated attempts at treatment (Conley and Buchanan, 1997; Meltzer, 1992), contributing disproportionately to the overall costs and resources needed to treat this illness (Revicki et al., 1990). For treating this patient population, clozapine has been shown in several multicenter clinical trials (Conley et al., 1988; Hirsch and
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Puri, 1993; Kane et al., 1988) to be the gold standard. Clozapine has demonstrated superior efficacy over that of the conventional antipsychotics for patients with treatmentresistant schizophrenia (Hirsch and Puri, 1993). The use of clozapine has been associated with the occurrence of a doseindependent and potentially fatal agranulocytosis (Alvir et al., 1993), prompting the need for regular blood monitoring. Its use is also limited by a host of other potentially serious adverse effects, including lowered seizure threshold, autonomic dysregulation, and changes in cardiac repolarization (Cohen et al., 2001; Devinsky and Pacia, 1994). While clozapine remains the treatment of choice for treatment-resistant schizophrenia, its safety liabilities have prompted the search for alternatives. To this end, other atypical antipsychotics have been proposed, but few large, double-blind studies involving these agents have been conducted. However, one such study (Tollefson et al., 2001) indicates that olanzapine may be as effective as clozapine but without the association with serious adverse reactions. Given the proven efficacy of clozapine for patients with treatment-resistant schizophrenia and the similarity of the pharmacology of clozapine and olanzapine (Bymaster et al., 1999), the current double-blind trial was designed to determine the relative efficacy of olanzapine versus clozapine for patients with schizophrenia who had experienced treatment failure due to either an inadequate response to treatment or intolerance of treatment.
2. Methods 2.1. Patient sample Male and female hospitalized patients, aged 18 to 65 years, who met the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994) were eligible to be enrolled in this study after having the protocol explained to them and providing written informed consent. Patients were recruited and studied at a total of six sites in Hungary and two sites in South Africa. The study was conducted in accordance with the ethical principles stated in the then most recent version of the Declaration of Helsinki (World Medical Association, 1991, 1996), the applicable guidelines on good clinical practice, or the applicable laws and regulations of Hungary and South Africa, whichever represented the greater protection of the individual. The study protocol, informed consent documents, and all other appropriate study-related documents were approved by an independent ethics committee of each participating center. A minimum initial score on the Brief Psychiatric Rating Scale (BPRS) (Guy, 1976), extracted from the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1986), of at least 42 (items scored 1 –7) was required at both the screening visit and the day of randomization. In addition, patients had to have failed to respond
adequately to standard acceptable treatment with a conventional antipsychotic medication (at least one treatment trial of 4– 6 weeks duration at 400– 600 mg—equivalents of chlorpromazine; Barnes and McEvedy, 1996) because of either insufficient effectiveness or intolerable side effects caused by the medication. Patients with a history of failure on clozapine due to adverse event or lack of efficacy were excluded from the study. Clozapine has been used in the participating centers in the treatment of schizophrenia before its registration was restricted to treatment-resistant patients based on the U.S. approval. Other exclusion criteria included a diagnosis of DSM-IV substance-related disorder, serious suicidal risk, pregnancy or breast-feeding, a history of seizures, a history of leukopenia without known etiology, leukocyte count less than 3.5 GI/L and/or neutrophilic granulocyte count less than 2.0 GI/L upon entering the study, or current jaundice or active hepatitis B. 2.2. Study design This was a Phase III, 18-week, randomized, doubleblind, parallel study consisting of a screening and washout period of 2– 9 days and randomized assignment of patients to treatment with either olanzapine (5 – 25 mg/day) or clozapine (100 – 500 mg/day) for 18 weeks. The study protocol was ready for submission (15 October 1996) to regulatory agencies and ethical review boards before olanzapine was marketed in the two participating countries. Study Period I, the screening and washout period, was used to evaluate patients’ psychiatric and physical status to ensure consistency with inclusion/exclusion criteria, including the minimum time requirement specified for washout from previous antipsychotic therapy. Screening tests, patient history, and psychiatric and physical examinations were conducted at Visit 1 (enrollment). The results of all screening tests, including clinical laboratory test results, were reviewed prior to Visit 2 (randomization). All inclusion/ exclusion criteria were verified at Visit 2 before assigning all eligible patients to a treatment group by random allocation in a 1:1 ratio and in a double-blind manner. Study Period II consisted of 19 visits over 18 weeks (Visit 2– Visit 20) with weekly visit intervals. In the first week of Study Period II, the starting dose of olanzapine was 10 mg/day. Clozapine was titrated in a fixed manner from 25 to 150 mg over the first 7 days of therapy. From Visit 3 onward, dose adjustments were allowed as deemed clinically necessary. The daily dose could be adjusted upward by increments of either 2.5 or 5 mg of olanzapine or 50 mg of clozapine and downward by any decrement within the allowed range of olanzapine 5, 10, 15, 17.5, 20, 22.5, 25 mg/day or clozapine 100, 150, 200, 250, 300, 350, 400, 450, 500 mg/day, as clinically indicated. Patients discontinuing clozapine treatment after randomization or who completed the acute treatment period but did not receive an open prescription for clozapine were required to undergo dose tapering over a maximum of a 2-week period.
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In general, concomitant medications with primarily central nervous system activity were not allowed. Any use of concomitant medications was recorded. At sites in Hungary, benzodiazepines were disallowed entirely due to a potential interaction with clozapine that can result in respiratory arrest (Edge et al., 1997). However, zopiclone and chloral hydrate were permitted. Chronic benzodiazepine/hypnotics users were maintained on their fixed dose for the duration of the study, but clinical prophylactic administration of benzodiazepines/hypnotics for nonchronic users was prohibited. The concurrent use of multiple benzodiazepines was also prohibited. Maximum allowable daily doses were as follows: diazepam 40 mg, oxazepam 60 mg, nitrazepam 15 mg, lorazepam 8 mg, temazepam 30 mg, bromazepam 12 mg, zopiclone 15 mg, and chloral hydrate 1500 mg. Anticholinergic medication (benztropine mesylate or biperiden), up to 6 mg/day, was allowed for the treatment of extrapyramidal symptoms. Anticholinergic medication was prescribed only at the occurrence of new extrapyramidal symptoms or after the worsening of previously existing ones. The use of anticholinergic medication as prophylaxis for extrapyramidal symptoms was prohibited. 2.3. Assessments The objectives of this study were to assess the comparative efficacy and safety of olanzapine (5 –25 mg/day) versus clozapine (100 – 500 mg/day) in the treatment of schizophrenia. To measure severity of illness and psychopathology, the PANSS (total score and positive, negative, general psychopathology, and mood subscales; Kay et al., 1986) and the Clinical Global Impression Scale (CGI) (Guy, 1976) were used. Safety was monitored by assessing adverse events, including extrapyramidal symptoms [parkinsonism as measured by the Simpson – Angus Scale; Simpson and Angus, 1970; dyskinesia as measured by the Abnormal Involuntary Movement Scale (AIMS); Guy, 1976; and akathisia as measured by the Hillside Akathisia Scale (HAS); Fleischhacker et al., 1989], laboratory measures, electrocardiography, and vital signs, including body weight. All treatmentemergent adverse events reported by patients during the study were recorded and coded using the United States Food and Drug Administration Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) dictionary (United States Food and Drug Administration, 1990). Clinical laboratory testings (clinical chemistry, electrolyte group, hematology, and urinalysis) were performed at Visits 1 and 2, at any time a patient completed the study or discontinued from the study, or if clinically indicated. Aspartate transaminase/serum glutamic– oxaloacetic transaminase (AST/SGOT), alanine transaminase/serum glutamic – pyruvic transaminase (ALT/SGPT), total bilirubin, alkaline phosphatase, and gamma-glutamyl transferase (GGT) were performed at Visits 3 to 8, 12, and 16. In addition, hematology was collected at all visits. Any clozapine-treated patient who discontinued from the study prior to
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completing 18 weeks of double blind therapy or those for whom continued treatment with an open prescription of clozapine from their investigator was not indicated would have been required to undergo weekly hematology monitoring for a further 4 weeks. 2.4. Statistical methods Patient data were analyzed on an intent-to-treat basis (Gillings and Koch, 1991), an analysis of data by groups to which patients are assigned by random allocation. All analyses of mean change from baseline to endpoint used the last-observation-carried-forward (LOCF) technique; patients with a baseline and at least one postbaseline measurement were included in these analyses. Patients’ endpoint measures were defined by their last measurement, whether at study completion or discontinuation. Mean changes from baseline to endpoint in the PANSS and Clinical Global Impression Severity (CGI-S) scores were calculated using analysis of variance (ANOVA), with terms for treatment, investigator, and Treatment Investigator interaction. Unless otherwise defined, baseline measurements were taken from the Visit 2 observation; if it was missing, the baseline measure was taken from the Visit 1 observation. Adverse events were captured as treatment-emergent adverse events, using the placebo lead-in period as a baseline. The incidence of treatment-emergent adverse events between the two treatment groups was analyzed using Pearson’s chi-square tests, as were other categorical variables, such as demographic data. The treatment effects on change from baseline to endpoint in laboratory measures and vital signs were assessed using an ANOVA model with terms for treatment, investigator, and Treatment Investigator interaction. All main effects were tested at a two-tailed alpha level of .05, and Treatment Investigator interactions were tested at an alpha level of .10. Two-sided 95% confidence intervals were calculated where appropriate.
3. Results 3.1. Patient characteristics From a total of 189 patients that were screened, 150 were enrolled, providing baseline demographic and safety data. Overall, patients had a mean age of 37.6 years. All enrolled patients met the DSM-IV criteria for schizophrenia. One hundred and forty-seven patients met the inclusion/exclusion criteria and were randomized, 52 coming from Hungary and 95 from South Africa. Seventy-five were randomized to olanzapine treatment and 72 to clozapine treatment. There was an almost equal distribution between patients of Caucasian (47.9%) or African descent (46.6%), and the majority of patients were male (59.9%). No statistically significant differences were seen between treatment groups in any demographic or baseline illness characteristic.
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3.2. Medication usage
Table 1 Mean change in efficacy measures, baseline to endpoint (LOCF)
For the olanzapine-treated patients, the final mean dose was 17.2 ( F 4.8) mg/day, while that for clozapine was 216.2 ( F 107.9) mg/day. Similar numbers of olanzapine-and clozapine-treated patients required benzodiazepines during this trial (olanzapine, 51.3%; clozapine, 55.4%; P = 0.252), and few patients used anticholinergics during this trial (olanzapine, 7.9%; clozapine, 4.1%; P = .418).
Measure
Therapy
n
Baseline
Change
Mean (S.D.)
Mean (S.D.)
PANSS total
Olanzapine Clozapine Olanzapine Clozapine Olanzapine Clozapine Olanzapine Clozapine
70 70 70 70 70 70 69 70
105.9 104.1 26.4 25.1 27.3 27.8 4.8 4.8
PANSS positive PANSS negative CGI-S
3.3. Efficacy 3.3.1. Changes in efficacy measure Of the 147 patients randomized, 140 provided complete efficacy data, 70 coming from each treatment group. On the PANSS total score, both treatment groups showed obvious improvement from baseline by Week 2 (Fig. 1). As the study progressed, improvements became more pronounced, with the largest improvements being observed at the 18-week endpoint. The decreases in PANSS score were very similar between treatment groups, and no statistically significant treatment differences were observed. Both treatment groups also showed statistically significant within-group improvement ( P < .001) from baseline to endpoint on all measures: PANSS total, PANSS positive, PANSS negative, and CGI-S. There were no statistically significant differences between treatment groups in the baseline-to-endpoint changes (LOCF) in any of the efficacy measures (Table 1). 3.3.2. Response rates Using the criteria for response of Kane et al. (1988) (BPRS1 – 7 improvement > 20% + CGI-S < 3 or BPRS1 – 7 < 35), there were no statistically significant differences between the number of olanzapine-treated (57.9%) and clozapine-treated patients (60.8%) who responded to treatment during this trial ( P = .716; Table 2). Additional definitions of response, based on percentage reductions in PANSS total score ( z 20%, z 30%, z 40%, or z 50%), also revealed no statistically significant differences between the two treatment groups.
37.7 (23.1) 37.9 (23.4) 11.7 (7.3) 11.8 (7.9) 7.6 (6.0) 7.7 (6.1) 1.4 (1.2) 1.5 (1.1)
.562 .574 .838 .829
Abbreviations: LOCF, last observation carried forward; n, number of patients with a baseline and at least one postbaseline measurement; S.D., standard deviation. a Versus clozapine, one-way analysis of variance.
3.4. Safety 3.4.1. Disposition Slightly more olanzapine-treated (60.5%) than clozapinetreated patients (55.4%) were able to complete the study, but this difference did not reach statistical significance ( P=.525, Fisher’s Exact Test). There were no significant differences between treatment groups in any of the reasons for discontinuation (adverse events: olanzapine, 9.2%; clozapine, 9.5%; lack of efficacy: olanzapine 5.3%, clozapine 4.2%; lack of compliance/lost to follow up: olanzapine 17.4%; clozapine 16.6%; protocol violation: olanzapine, 1.3%, clozapine: 4.2%; other: olanzapine 6.2%, clozapine 10.1%). Two patients (2.7%) in the clozapine group discontinued due to leukopenia or otherwise abnormal white blood cell count.
Table 2 Response rates Response definition
Olanzapine Clozapine P value Treatment 95% CIb (N = 76), (N = 74), effecta (%) n (%) n (%)
Kane et al. 44 (57.9) (1988) criteriac PANSS total score z 20% improvement z 30% improvement z 40% improvement z 50% improvement z 60% improvement
Fig. 1. Visit-wise change (LOCF) in mean PANSS total score over 18 weeks. No statistically significant differences between the olanzapine and clozapine treatment groups were noted at any time point.
(13.0) (13.7) (5.0) (6.0) (5.7) (4.7) (1.0) (1.0)
P valuea
45 (60.8) .716
2.9
0.2, 0.1
52 (74.3)
56 (80.0) .374
5.7
44 (62.9)
45 (64.3) .853
1.4
35 (50.0)
33 (47.1) 0.878
2.9
22 (31.4)
20 (28.6) .766
2.8
11 (15.7)
4.3
19.6, 8.2 17.4, 14.5 13.7, 19.4 12.3, 18.0 15.6, 7.0
8 (11.4)
.450
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CI, confidence interval; N = number of patients with a baseline and at least one postbaseline measurement; n = number of responders based upon each response definition; PANSS, Positive and Negative Syndrome Scale. a Calculated as olanzapine rate minus clozapine rate. b Based on olanzapine group response rate relative to clozapine group. c BPRS1 – 7 improvement > 20% + CGI-S < 3 or BPRS1 – 7 < 35.
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3.4.2. Spontaneously reported treatment-emergent adverse events As shown in Table 3, olanzapine-treated patients reported significantly more back pain than did clozapine-treated patients (olanzapine, 5.3%; clozapine, 0.0%; P = .045). In contrast, clozapine-treated patients reported statistically significantly more somnolence (olanzapine, 2.6%; clozapine, 14.9%; P = .008) and dizziness (olanzapine, 1.3%; clozapine, 8.1%; P = .049). 3.4.3. Treatment-emergent extrapyramidal symptoms as assessed by rating scales There were no statistically significant differences in baseline-to-endpoint measurements (LOCF) of akathisia (as measured by the HAS), parkinsonism (as measured by the Simpson – Angus Scale), or dyskinesia (as measured by the AIMS) between olanzapine- and clozapine-treated patients (Table 4). Treatment-emergent akathisia (defined in our study as an HAS total score of z 3 that was not present at baseline) was not significantly different between olanzapine-and clozapine-treated patients by endpoint (5.3% vs. 0.0%, P =.072). Treatment-emergent parkinsonism, defined as a Simpson – Angus total score of > 3 that was not present at baseline, was not seen in either treatment group. Treatment-emergent dyskinetic symptoms (defined in our study as one item score of 3 or more or two items scores of 2 or more on the AIMS that was not present at baseline) were similar between olanzapine- and clozapine-treated patients at endpoint (8.7% vs. 2.9%, respectively; P = .139). 3.4.4. Weight and vital signs There was no statistically significant difference between treatment groups in the mean change from baseline to endpoint (LOCF) of body weight (olanzapine, + 3.3 F 5.3 kg; clozapine, + 4.1 F 5.6 kg; P=.370). Clozapine use was associated with significantly greater baseline-to-endpoint changes in standing heart rate (supine: olanzapine, + 4.4 F 15.0 bpm, n = 75; clozapine, + 11.1 F 15.1 bpm, n = 72; P=.008; Table 3 Adverse eventsa Event classification
Olanzapine (N = 76), n (%)
Clozapine (N = 74), n (%)
P valuea
Weight gain Headache Back pain Asthenia Flu syndrome Somnolence Dizziness Hypersalivation Postural hypotension
7 6 4 3 2 2 1 1 1
7 4 0 7 4 11 6 5 4
.958 .541 .045 .176 .386 .008 .049 .089 .163
(9.2) (7.9) (5.3) (3.9) (2.6) (2.6) (1.3) (1.3) (1.3)
(9.5) (5.4) (0.0) (9.5) (5.4) (14.9) (8.1) (6.8) (5.4)
Abbreviations: N = total number of patients randomized to each treatment group; n = number of patients reporting each adverse event. a Spontaneously reported adverse events with an incidence of z 5% in either treatment group or with a statistically significant difference ( P < .05) between groups.
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Table 4 Mean change in extrapyramidal symptom rating scales, baseline to endpoint, 18 weeks (LOCF) Measure
Simpson – Angus Scale AIMS total score HAS
Therapy
n
Baseline
Change
Mean (S.D.)
Mean (S.D.)
P valuea
Olanzapine 69
4.7 (4.5)
3.0 (4.8)
.899
Clozapine 70 Olanzapine 69
4.3 (4.8) 1.6 (2.9)
2.9 (3.9) 0.6 (2.5)
.958
Clozapine 70 Olanzapine 68 Clozapine 69
1.6 (3.1) 3.6 (7.7) 3.4 (8.0)
0.9 (2.8) 2.3 (8.9) 2.7 (7.1)
.710
Abbreviations: LOCF, last observation carried forward; n = number of patients with a baseline and at least one postbaseline measurement. a Treatment effect from the main effects model with terms for treatment and geographic region.
standing: olanzapine, + 5.4 F 17.0 bpm, n = 75; clozapine, 12.7 F 16.2 bpm, n = 72; P=.009). Otherwise, there were no significant treatment-group differences in any vital sign. 3.4.5. Clinical laboratory evaluation Analysis of laboratory measures revealed significant treatment differences in baseline-to-endpoint changes in urinary pH (olanzapine, + 0.22 F 1.00, n = 67; clozapine, 0.12 F 0.77, n = 67; P=.027) and phosphate (olanzapine, 0.01 F 0.20, n = 67; clozapine, + 0.06 F 0.21, n = 70; P=.044), and clozapine treatment was associated with a significantly higher incidence of abnormally elevated alkaline phosphatase levels (olanzapine, 1.4%; clozapine, 8.3%; P=.050, Fisher’s Exact Test), but these were deemed not clinically significant. There were no other significant differences between olanzapine- and clozapine-treated patients on any other clinical laboratory parameter measured, including leukocyte, neutrophil, and lymphocyte counts.
4. Discussion In the present study, virtually no differences were seen between olanzapine and clozapine in any measure of efficacy. Both drugs reduced psychotic symptoms to levels at endpoint that were considered ‘‘minimal’’ (Guy, 1976; Kay et al., 1986). Likewise, response rates were similar between treatment groups, regardless of how they were defined. This supports the findings of Tollefson et al. (2001), who found olanzapine to be ‘‘noninferior’’ to clozapine on all measures of efficacy. Response rates in the current study, based on the criteria for improvement of Kane et al. (1988), were on the order of 58% to 61%, which somewhat approximates the rate of 50% seen in the study of Tollefson et al. (2001). This is notably higher than the response rate of 30% that was derived for clozapine by Kane et al. (1988). This may relate to the stringency with which the earlier study defined treatment resistance as the criteria for the current study required failure on only one previous trial with a conven-
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tional antipsychotic, compared with the three failures with a conventional agent that had been required in the Kane analysis. The current study also included patients who had merely shown treatment intolerance due to adverse reactions, rather than outright refractoriness to treatment. This latter explanation may be the more salient of the two, as it has been demonstrated that only 7% to 9% of patients who have failed to respond adequately during two treatment trials will go on to show improvement under subsequent treatment (Kinon et al., 1992; Kinon et al., 1993). It has accordingly been suggested that failure on just one trial is sufficient to demonstrate treatment resistance (Peuskens, 1999). Both treatment groups in this study were notable for their benign, largely mild measures of safety. A somewhat higher incidence of back pain was seen among olanzapine patients, while clozapine patients experienced more somnolence and dizziness. Motor side effects, of which clozapine has long been noted to be virtually devoid (Juul Povlsen et al., 1985), were nearly absent in both treatment groups, and there were no clinically and statistically significant changes in either group in any vital sign or laboratory measure, with the exception of weight gain, which was noted in both groups. This latter finding was not unexpected, as weight gain has been found to varying extents to be a liability of nearly all antipsychotics, both atypical and conventional (Allison et al., 1999; Kelly et al., 1998; Martin et al., 1999; Taylor and McAskill, 2000), with the highest liabilities being found for clozapine and olanzapine (Allison et al., 1999; Taylor and McAskill, 2000). Perhaps the most comprehensive study to date of atypical antipsychotics in treatment-refractory schizophrenia was the one conducted by Volavka et al. (2002). This study consisted of an 8-week period, during which patients’ previous antipsychotics were gradually discontinued while study drug was escalated to target levels, followed by a 6-week flexibledosing period, during which patients received clozapine, olanzapine, risperidone, or haloperidol. Both clozapine and olanzapine reduced PANSS total and negative symptom scores significantly more than did haloperidol. Risperidone appeared not to differ significantly from haloperidol, which in turn was found not to have had a significant effect on any measure. The effect sizes of the improvement in PANSS total scores at the 14-week endpoint were calculated to be 0.51 for olanzapine, 0.33 for clozapine, 0.18 for risperidone, and 0.11 for haloperidol. Clozapine was the most effective treatment for negative symptoms, but the overall pattern of efficacies suggested that clozapine and olanzapine had similar general antipsychotic efficacy. A number of limitations of the current study bear mentioning. For example, previous histories were not systematically collected. It is therefore not known what the durations of patients’ illness were or how many times they had been hospitalized. These measures would have given a clearer picture of how chronic or severe patients’ illnesses were. To this end, we instead depended on the severity criteria of Kane et al. (1988) of a BPRS total score of at least 45 plus a CGI-S
rating of at least 4. This study also did not allow us to differentiate between patients who were enrolled due to actual resistance to conventional antipsychotic treatment and those enrolled due to intolerance of side effects. This might have provided important data regarding the differential efficacy of olanzapine versus conventional medications, as opposed to differences in side-effect profiles. Finally, while the protocol for this study allowed doses of olanzapine up to 25 mg/day and doses of clozapine up to 500 mg/day, the overall mean modal doses of 16.7 and 223 mg/day, respectively, were substantially lower than those used in other comparator studies (Breier and Hamilton, 1999; Conley et al., 1999; Volavka et al., 2002). This appeared to be more a reflection of the positive efficacy of both drugs in this study, however, than of treatment intolerance. Although mean doses of clozapine above 400 mg/day are common in studies of refractory schizophrenia conducted in the United States, the doses used in this study were more in line with those used in European studies (Fleischhacker et al., 1994; Fleischhacker, 1999; Pollack et al., 1995) and in clinical practice (IMS database, first quarter, 1998). It has been suggested that the optimal dose range for clozapine in treating patients resistant to conventional antipsychotics is on the order of 300 –600 mg/day (Lublin, 1997). However, it has become apparent that, for patients who do respond to clozapine, doses below 300 mg/day are sufficient (Gordon and Milke, 1996; Pollack et al., 1995). Thus, higher doses are unnecessary as they are not likely to increase responsiveness, while use of lower doses is more likely to avoid the incurrence of adverse effects (Pollack et al., 1995).
5. Conclusions Olanzapine was found to have the same level of efficacy as the current gold standard, clozapine, in treating patients with treatment-resistant or treatment-intolerant schizophrenia who were candidates for treatment with an atypical antipsychotic. Measures of safety showed olanzapine’s risk of extrapyramidal symptoms to be equivalent to that of clozapine, while the absence of hematological abnormalities further underscored its safety benefits.
Acknowledgements The following individuals and institutions, in addition to the authors, participated in the Olanzapine HGCK Study Group: Csilla Bolyo´s, MD, Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; Zolta´n Danics, MD, National Institute of Psychiatry and Neurology, Budapest, Hungary; Alexander Kancsev, MD, Regional Neuropsychiatric Institute, Nagyka´llo´, Hungary; Lajos Karmacsi1, MD, Regional Neuropsychiatric 1
Deceased.
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Institute, Nagyka´llo´, Hungary; Zolta´n Kova´cs, MD, Department of Psychiatry, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary; Emese Linka, MD, Department of Psychiatry, Ja´hn Ferenc Hospital, Budapest, Hungary; Paul Janus Pretorius, MD, Department of Psychiatry, Oranje Hospital, University of the Free State, Bloemfontein, South Africa; Salumu Selemani, MD, Sterkfontein Hospital, Krugersdorp, South Africa; Martell Slabber, MD, Department of Psychiatry, Oranje Hospital, University of the Free State, Bloemfontein, South Africa; Gyo¨rgy Szekeres, MD, Department of Psychiatry, Albert SzentGyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary; Istva´n Szendi, MD, Department of Psychiatry, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary; Zsolt Tahin, MD, Department of Psychiatry, Central Military Hospital, Budapest, Hungary. In addition, the authors wish to express their deepest appreciation for the patience and dedication by all medical personnel involved in this clinical study. This work was sponsored by Eli Lilly and company. References Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Cappelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry 156, 1686 – 1696. Alvir, J.M., Lieberman, J.A., Safferman, A.Z., Schwimmer, J.L., Schaaf, J.A., 1993. Clozapine-induced agranulocytosis: incidence and risk factors in the United States. N. Engl. J. Med. 329, 162 – 167. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. Barnes, T.R., McEvedy, C.J., 1996. Pharmacological treatment strategies in the non-responsive schizophrenic patient. Int. Clin. Psychopharmacol. 11 (Suppl. 2), 67 – 71. Breier, A., Hamilton, S.H., 1999. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biol. Psychiatry 45, 403 – 411. Bymaster, F.P., Perry, K.W., Nelson, D.L., Wong, D.T., Rasmussen, K., Moore, N.A., Calligaro, D.O., 1999. Olanzapine: a basic science update. Br. J. Psychiatry 174, 36 – 40. Cohen, H., Loewenthal, U., Matar, M., Kotler, M., 2001. Heart rate variability and risk for sudden death in patients with schizophrenia on longterm psychotropic medication. Br. J. Psychiatry 179, 167 – 171. Conley, R.R., Buchanan, R.W., 1997. Evaluation of treatment-resistant schizophrenia. Schizophr. Bull. 23, 663 – 674. Conley, R.R., Schulz, C., Baker, R.W., Collins, J.F., Bell, J.A., 1988. Clozapine efficacy in schizophrenic nonresponders. Psychopharmacol. Bull. 24, 269 – 274. Conley, R.R., Tamminga, C.A., Kelly, D.L., Richardson, C.M., 1999. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol. Psychiatry 46, 73 – 77. Devinsky, O., Pacia, S.V., 1994. Seizures during clozapine therapy. J. Clin. Psychiatry 55, 153 – 156. Edge, S.C., Markowitz, J.S., Devane, C.L., 1997. Clozapine drug – drug interactions: a review of the literature. Hum. Psychopharmacol. 12, 5 – 20.
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Fleischhacker, W.W., 1999. Clozapine: a comparison with other novel antipsychotics. J. Clin. Psychiatry 60, 30 – 34. Fleischhacker, W.W., Bergmann, K.J., Perovich, R., Pestreich, L.K., Borenstein, M., Lieberman, J.A., Kane, J.M., 1989. The Hillside Akathisia Scale: a new rating instrument for neuroleptic-induced akathisia. Psychopharmacol. Bull. 25, 222 – 226. Fleischhacker, W.W., Hummer, M., Kurz, M., Kurzthaler, I., Lieberman, J.A., Pollack, S., Safferman, A.Z., Kane, J.M., 1994. Clozapine dose in the United States and Europe: implications for therapeutic and adverse effects. J. Clin. Psychiatry 55 (Suppl. B), 78 – 81. Gillings, D., Koch, G., 1991. The application of the principle of intentionto-treat to the analysis of clinical trials. Drug Inf. J. 25, 411 – 425. Gordon, B.J., Milke, D.J., 1996. Dose related response to clozapine in a state psychiatric hospital population: a naturalistic study. Psychiatr. Q. 67, 65 – 74. Guy, W., 1976. ECDEU Assessment Manual for Psychopharmacology, Revised. US Department of Health, Education, and Welfare, Bethesda, MD. Hirsch, S.R., Puri, B.K., 1993. Clozapine: progress in treating resistant schizophrenia. BMJ 306, 1427 – 1428. IMS Health: Sergeant Database, 1998. Juul Povlsen, U., Noring, U., Fog, R., Gerlach, J., 1985. Tolerability and therapeutic effect of clozapine. A retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr. Scand. 71, 176 – 185. Kane, J., Honigfeld, G., Singer, J., Meltzer, H., 1988. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45, 789 – 796. Kay, S., Opler, L., Fiszbein, A., 1986. Positive and Negative Syndrome Scale (PANSS) Manual. Multi-Health Systems, North Tonawanda, NY. Kelly, D.L., Conley, R.R., Love, R.C., Horn, D.S., Ushchak, C.M., 1998. Weight gain in adolescents treated with risperidone and conventional antipsychotics over six months. J. Child Adolesc. Psychopharmacol. 8, 151 – 159. Kinon, B., Kane, J.M., Perovish, R., Ismi, M., Koreen, A., 1992. Influence of neuroleptic dose and class in treatment-resistant schizophrenia relapse. Presented at the 32nd Annual Meeting of the New Clinical Drug Evaluation Unit. Key, Biscayne, FL. May. Kinon, B.J., Kane, J.M., Johns, C., Perovich, R., Ismi, M., Koreen, A., Weiden, P., 1993. Treatment of neuroleptic-resistant schizophrenic relapse. Psychopharmacol. Bull. 29, 309 – 314. Lublin, H.K., 1997. Psychopharmacological treatment of treatment-resistant schizophrenia [in Danish]. Ugeskr. Laeger 159, 7128 – 7133. Martin, A., Koenig, K., Scahill, L., Bregman, J., 1999. Open-label quetiapine in the treatment of children and adolescents with autistic disorder. J. Child Adolesc. Psychopharmacol. 9, 99 – 107. Meltzer, H.Y., 1992. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr. Bull. 18, 515 – 542. Peuskens, J., 1999. The evolving definition of treatment resistance. J. Clin. Psychiatry 60 (Suppl. 12), 4 – 8. Pollack, S., Lieberman, J.A., Fleischhacker, W.W., Borenstein, M., Safferman, A.Z., Hummer, M., Kurz, M., 1995. A comparison of European and American dosing regimens of schizophrenic patients on clozapine: efficacy and side effects. Psychopharmacol. Bull. 31, 315 – 320. Revicki, D.A., Luce, B.R., Weschler, J.M., Brown, R.E., Adler, M.A., 1990. Cost-effectiveness of clozapine for treatment-resistant schizophrenics. Hosp. Community Psychiatry 41, 850 – 854. Simpson, G.M., Angus, J.W.S., 1970. A rating scale for extrapyramidal side effects. Acta Psychiatr. Scand. 212, S11 – S19. Taylor, D.M., McAskill, R., 2000. Atypical antipsychotics and weight gaina systematic review. Acta Psychiatr. Scand. 101, 416 – 432. Tollefson, G.D., Birkett, M.A., Kiesler, G.M., Wood, A.J., 2001. Doubleblind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol. Psychiatry 49, 52 – 63. United States Food and Drug Administration, 1990. Coding Symbols for Thesaurus of Adverse Reaction Terms. Food and Drug Administration, Rockville, MD.
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Volavka, J., Czobor, P., Sheitman, B., Lindenmayer, J.P., Citrome, L., McEvoy, J.P., Cooper, T.B., Chakos, M., Lieberman, J.A., 2002. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am. J. Psychiatry 159, 255 – 262.
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Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia Istvan Bittera,b,*, Martin R.K. Dossenbachb, Shlomo Brookc, Peter D. Feldmand, Stephen Metcalfeb, Carlo A. Gagianoe, Ja´nos Fu¨redif, Gyo¨rgy Bartkog, Zoltan Jankah, Csaba M. Bankii, Gabor Kovacs j, Alan Breierd for the Olanzapine HGCK Study Group a
Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary b E. Lilly Area Medical Center, Vienna, Austria c Sterkfontein Hospital, Krugersdorp, South Africa d Lilly Research Laboratories, Indianapolis, IN, USA e Department of Psychiatry, University of the Free State, Bloemfontein, South Africa f National Institute of Psychiatry and Neurology, Budapest, Hungary g Department of Psychiatry, Ja´hn Ferenc Hospital, Budapest, Hungary h Department of Psychiatry, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary i Regional Neuropsychiatric Institute, Nagyka´llo´, Hungary j Department of Psychiatry, Central Military Hospital, Budapest, Hungary Accepted 17 September 2003
Abstract Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5 – 25 mg/day, n = 75) or clozapine (100 – 500 mg/day, n = 72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia. D 2003 Elsevier Inc. All rights reserved. Keywords: Clozapine; Drug resistance; Drug tolerance; Olanzapine; Schizophrenia; Treatment resistance
Abbreviations: AIMS, Abnormal Involuntary Movement Scale; ALT, Alanine transaminase; AST, Aspartate transaminase; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; GGT, Gamma-glutamyl transferase; HAS, Hillside Akathisia Scale; IMS, Intercontinental Marketing Services; LOCF, Last observation carried forward; PANSS, Positive and Negative Syndrome Scale; SGOT, Serum glutamic – oxaloacetic transaminase; SGPT, Serum glutamic – pyruvic transaminase. * Corresponding author. Department of Psychiatry and Psychotherapy, Semmelweis University, Balassa Str.6, 1083 Budapest, Hungary. Tel.: +361-210-0330; fax: +36-1-303-2352. E-mail address: [email protected] (I. Bitter). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2003.09.033
1. Introduction Approximately 20% to 25% of all patients with schizophrenia are resistant to repeated attempts at treatment (Conley and Buchanan, 1997; Meltzer, 1992), contributing disproportionately to the overall costs and resources needed to treat this illness (Revicki et al., 1990). For treating this patient population, clozapine has been shown in several multicenter clinical trials (Conley et al., 1988; Hirsch and
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Puri, 1993; Kane et al., 1988) to be the gold standard. Clozapine has demonstrated superior efficacy over that of the conventional antipsychotics for patients with treatmentresistant schizophrenia (Hirsch and Puri, 1993). The use of clozapine has been associated with the occurrence of a doseindependent and potentially fatal agranulocytosis (Alvir et al., 1993), prompting the need for regular blood monitoring. Its use is also limited by a host of other potentially serious adverse effects, including lowered seizure threshold, autonomic dysregulation, and changes in cardiac repolarization (Cohen et al., 2001; Devinsky and Pacia, 1994). While clozapine remains the treatment of choice for treatment-resistant schizophrenia, its safety liabilities have prompted the search for alternatives. To this end, other atypical antipsychotics have been proposed, but few large, double-blind studies involving these agents have been conducted. However, one such study (Tollefson et al., 2001) indicates that olanzapine may be as effective as clozapine but without the association with serious adverse reactions. Given the proven efficacy of clozapine for patients with treatment-resistant schizophrenia and the similarity of the pharmacology of clozapine and olanzapine (Bymaster et al., 1999), the current double-blind trial was designed to determine the relative efficacy of olanzapine versus clozapine for patients with schizophrenia who had experienced treatment failure due to either an inadequate response to treatment or intolerance of treatment.
2. Methods 2.1. Patient sample Male and female hospitalized patients, aged 18 to 65 years, who met the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994) were eligible to be enrolled in this study after having the protocol explained to them and providing written informed consent. Patients were recruited and studied at a total of six sites in Hungary and two sites in South Africa. The study was conducted in accordance with the ethical principles stated in the then most recent version of the Declaration of Helsinki (World Medical Association, 1991, 1996), the applicable guidelines on good clinical practice, or the applicable laws and regulations of Hungary and South Africa, whichever represented the greater protection of the individual. The study protocol, informed consent documents, and all other appropriate study-related documents were approved by an independent ethics committee of each participating center. A minimum initial score on the Brief Psychiatric Rating Scale (BPRS) (Guy, 1976), extracted from the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1986), of at least 42 (items scored 1 –7) was required at both the screening visit and the day of randomization. In addition, patients had to have failed to respond
adequately to standard acceptable treatment with a conventional antipsychotic medication (at least one treatment trial of 4– 6 weeks duration at 400– 600 mg—equivalents of chlorpromazine; Barnes and McEvedy, 1996) because of either insufficient effectiveness or intolerable side effects caused by the medication. Patients with a history of failure on clozapine due to adverse event or lack of efficacy were excluded from the study. Clozapine has been used in the participating centers in the treatment of schizophrenia before its registration was restricted to treatment-resistant patients based on the U.S. approval. Other exclusion criteria included a diagnosis of DSM-IV substance-related disorder, serious suicidal risk, pregnancy or breast-feeding, a history of seizures, a history of leukopenia without known etiology, leukocyte count less than 3.5 GI/L and/or neutrophilic granulocyte count less than 2.0 GI/L upon entering the study, or current jaundice or active hepatitis B. 2.2. Study design This was a Phase III, 18-week, randomized, doubleblind, parallel study consisting of a screening and washout period of 2– 9 days and randomized assignment of patients to treatment with either olanzapine (5 – 25 mg/day) or clozapine (100 – 500 mg/day) for 18 weeks. The study protocol was ready for submission (15 October 1996) to regulatory agencies and ethical review boards before olanzapine was marketed in the two participating countries. Study Period I, the screening and washout period, was used to evaluate patients’ psychiatric and physical status to ensure consistency with inclusion/exclusion criteria, including the minimum time requirement specified for washout from previous antipsychotic therapy. Screening tests, patient history, and psychiatric and physical examinations were conducted at Visit 1 (enrollment). The results of all screening tests, including clinical laboratory test results, were reviewed prior to Visit 2 (randomization). All inclusion/ exclusion criteria were verified at Visit 2 before assigning all eligible patients to a treatment group by random allocation in a 1:1 ratio and in a double-blind manner. Study Period II consisted of 19 visits over 18 weeks (Visit 2– Visit 20) with weekly visit intervals. In the first week of Study Period II, the starting dose of olanzapine was 10 mg/day. Clozapine was titrated in a fixed manner from 25 to 150 mg over the first 7 days of therapy. From Visit 3 onward, dose adjustments were allowed as deemed clinically necessary. The daily dose could be adjusted upward by increments of either 2.5 or 5 mg of olanzapine or 50 mg of clozapine and downward by any decrement within the allowed range of olanzapine 5, 10, 15, 17.5, 20, 22.5, 25 mg/day or clozapine 100, 150, 200, 250, 300, 350, 400, 450, 500 mg/day, as clinically indicated. Patients discontinuing clozapine treatment after randomization or who completed the acute treatment period but did not receive an open prescription for clozapine were required to undergo dose tapering over a maximum of a 2-week period.
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In general, concomitant medications with primarily central nervous system activity were not allowed. Any use of concomitant medications was recorded. At sites in Hungary, benzodiazepines were disallowed entirely due to a potential interaction with clozapine that can result in respiratory arrest (Edge et al., 1997). However, zopiclone and chloral hydrate were permitted. Chronic benzodiazepine/hypnotics users were maintained on their fixed dose for the duration of the study, but clinical prophylactic administration of benzodiazepines/hypnotics for nonchronic users was prohibited. The concurrent use of multiple benzodiazepines was also prohibited. Maximum allowable daily doses were as follows: diazepam 40 mg, oxazepam 60 mg, nitrazepam 15 mg, lorazepam 8 mg, temazepam 30 mg, bromazepam 12 mg, zopiclone 15 mg, and chloral hydrate 1500 mg. Anticholinergic medication (benztropine mesylate or biperiden), up to 6 mg/day, was allowed for the treatment of extrapyramidal symptoms. Anticholinergic medication was prescribed only at the occurrence of new extrapyramidal symptoms or after the worsening of previously existing ones. The use of anticholinergic medication as prophylaxis for extrapyramidal symptoms was prohibited. 2.3. Assessments The objectives of this study were to assess the comparative efficacy and safety of olanzapine (5 –25 mg/day) versus clozapine (100 – 500 mg/day) in the treatment of schizophrenia. To measure severity of illness and psychopathology, the PANSS (total score and positive, negative, general psychopathology, and mood subscales; Kay et al., 1986) and the Clinical Global Impression Scale (CGI) (Guy, 1976) were used. Safety was monitored by assessing adverse events, including extrapyramidal symptoms [parkinsonism as measured by the Simpson – Angus Scale; Simpson and Angus, 1970; dyskinesia as measured by the Abnormal Involuntary Movement Scale (AIMS); Guy, 1976; and akathisia as measured by the Hillside Akathisia Scale (HAS); Fleischhacker et al., 1989], laboratory measures, electrocardiography, and vital signs, including body weight. All treatmentemergent adverse events reported by patients during the study were recorded and coded using the United States Food and Drug Administration Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) dictionary (United States Food and Drug Administration, 1990). Clinical laboratory testings (clinical chemistry, electrolyte group, hematology, and urinalysis) were performed at Visits 1 and 2, at any time a patient completed the study or discontinued from the study, or if clinically indicated. Aspartate transaminase/serum glutamic– oxaloacetic transaminase (AST/SGOT), alanine transaminase/serum glutamic – pyruvic transaminase (ALT/SGPT), total bilirubin, alkaline phosphatase, and gamma-glutamyl transferase (GGT) were performed at Visits 3 to 8, 12, and 16. In addition, hematology was collected at all visits. Any clozapine-treated patient who discontinued from the study prior to
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completing 18 weeks of double blind therapy or those for whom continued treatment with an open prescription of clozapine from their investigator was not indicated would have been required to undergo weekly hematology monitoring for a further 4 weeks. 2.4. Statistical methods Patient data were analyzed on an intent-to-treat basis (Gillings and Koch, 1991), an analysis of data by groups to which patients are assigned by random allocation. All analyses of mean change from baseline to endpoint used the last-observation-carried-forward (LOCF) technique; patients with a baseline and at least one postbaseline measurement were included in these analyses. Patients’ endpoint measures were defined by their last measurement, whether at study completion or discontinuation. Mean changes from baseline to endpoint in the PANSS and Clinical Global Impression Severity (CGI-S) scores were calculated using analysis of variance (ANOVA), with terms for treatment, investigator, and Treatment Investigator interaction. Unless otherwise defined, baseline measurements were taken from the Visit 2 observation; if it was missing, the baseline measure was taken from the Visit 1 observation. Adverse events were captured as treatment-emergent adverse events, using the placebo lead-in period as a baseline. The incidence of treatment-emergent adverse events between the two treatment groups was analyzed using Pearson’s chi-square tests, as were other categorical variables, such as demographic data. The treatment effects on change from baseline to endpoint in laboratory measures and vital signs were assessed using an ANOVA model with terms for treatment, investigator, and Treatment Investigator interaction. All main effects were tested at a two-tailed alpha level of .05, and Treatment Investigator interactions were tested at an alpha level of .10. Two-sided 95% confidence intervals were calculated where appropriate.
3. Results 3.1. Patient characteristics From a total of 189 patients that were screened, 150 were enrolled, providing baseline demographic and safety data. Overall, patients had a mean age of 37.6 years. All enrolled patients met the DSM-IV criteria for schizophrenia. One hundred and forty-seven patients met the inclusion/exclusion criteria and were randomized, 52 coming from Hungary and 95 from South Africa. Seventy-five were randomized to olanzapine treatment and 72 to clozapine treatment. There was an almost equal distribution between patients of Caucasian (47.9%) or African descent (46.6%), and the majority of patients were male (59.9%). No statistically significant differences were seen between treatment groups in any demographic or baseline illness characteristic.
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3.2. Medication usage
Table 1 Mean change in efficacy measures, baseline to endpoint (LOCF)
For the olanzapine-treated patients, the final mean dose was 17.2 ( F 4.8) mg/day, while that for clozapine was 216.2 ( F 107.9) mg/day. Similar numbers of olanzapine-and clozapine-treated patients required benzodiazepines during this trial (olanzapine, 51.3%; clozapine, 55.4%; P = 0.252), and few patients used anticholinergics during this trial (olanzapine, 7.9%; clozapine, 4.1%; P = .418).
Measure
Therapy
n
Baseline
Change
Mean (S.D.)
Mean (S.D.)
PANSS total
Olanzapine Clozapine Olanzapine Clozapine Olanzapine Clozapine Olanzapine Clozapine
70 70 70 70 70 70 69 70
105.9 104.1 26.4 25.1 27.3 27.8 4.8 4.8
PANSS positive PANSS negative CGI-S
3.3. Efficacy 3.3.1. Changes in efficacy measure Of the 147 patients randomized, 140 provided complete efficacy data, 70 coming from each treatment group. On the PANSS total score, both treatment groups showed obvious improvement from baseline by Week 2 (Fig. 1). As the study progressed, improvements became more pronounced, with the largest improvements being observed at the 18-week endpoint. The decreases in PANSS score were very similar between treatment groups, and no statistically significant treatment differences were observed. Both treatment groups also showed statistically significant within-group improvement ( P < .001) from baseline to endpoint on all measures: PANSS total, PANSS positive, PANSS negative, and CGI-S. There were no statistically significant differences between treatment groups in the baseline-to-endpoint changes (LOCF) in any of the efficacy measures (Table 1). 3.3.2. Response rates Using the criteria for response of Kane et al. (1988) (BPRS1 – 7 improvement > 20% + CGI-S < 3 or BPRS1 – 7 < 35), there were no statistically significant differences between the number of olanzapine-treated (57.9%) and clozapine-treated patients (60.8%) who responded to treatment during this trial ( P = .716; Table 2). Additional definitions of response, based on percentage reductions in PANSS total score ( z 20%, z 30%, z 40%, or z 50%), also revealed no statistically significant differences between the two treatment groups.
37.7 (23.1) 37.9 (23.4) 11.7 (7.3) 11.8 (7.9) 7.6 (6.0) 7.7 (6.1) 1.4 (1.2) 1.5 (1.1)
.562 .574 .838 .829
Abbreviations: LOCF, last observation carried forward; n, number of patients with a baseline and at least one postbaseline measurement; S.D., standard deviation. a Versus clozapine, one-way analysis of variance.
3.4. Safety 3.4.1. Disposition Slightly more olanzapine-treated (60.5%) than clozapinetreated patients (55.4%) were able to complete the study, but this difference did not reach statistical significance ( P=.525, Fisher’s Exact Test). There were no significant differences between treatment groups in any of the reasons for discontinuation (adverse events: olanzapine, 9.2%; clozapine, 9.5%; lack of efficacy: olanzapine 5.3%, clozapine 4.2%; lack of compliance/lost to follow up: olanzapine 17.4%; clozapine 16.6%; protocol violation: olanzapine, 1.3%, clozapine: 4.2%; other: olanzapine 6.2%, clozapine 10.1%). Two patients (2.7%) in the clozapine group discontinued due to leukopenia or otherwise abnormal white blood cell count.
Table 2 Response rates Response definition
Olanzapine Clozapine P value Treatment 95% CIb (N = 76), (N = 74), effecta (%) n (%) n (%)
Kane et al. 44 (57.9) (1988) criteriac PANSS total score z 20% improvement z 30% improvement z 40% improvement z 50% improvement z 60% improvement
Fig. 1. Visit-wise change (LOCF) in mean PANSS total score over 18 weeks. No statistically significant differences between the olanzapine and clozapine treatment groups were noted at any time point.
(13.0) (13.7) (5.0) (6.0) (5.7) (4.7) (1.0) (1.0)
P valuea
45 (60.8) .716
2.9
0.2, 0.1
52 (74.3)
56 (80.0) .374
5.7
44 (62.9)
45 (64.3) .853
1.4
35 (50.0)
33 (47.1) 0.878
2.9
22 (31.4)
20 (28.6) .766
2.8
11 (15.7)
4.3
19.6, 8.2 17.4, 14.5 13.7, 19.4 12.3, 18.0 15.6, 7.0
8 (11.4)
.450
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CI, confidence interval; N = number of patients with a baseline and at least one postbaseline measurement; n = number of responders based upon each response definition; PANSS, Positive and Negative Syndrome Scale. a Calculated as olanzapine rate minus clozapine rate. b Based on olanzapine group response rate relative to clozapine group. c BPRS1 – 7 improvement > 20% + CGI-S < 3 or BPRS1 – 7 < 35.
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3.4.2. Spontaneously reported treatment-emergent adverse events As shown in Table 3, olanzapine-treated patients reported significantly more back pain than did clozapine-treated patients (olanzapine, 5.3%; clozapine, 0.0%; P = .045). In contrast, clozapine-treated patients reported statistically significantly more somnolence (olanzapine, 2.6%; clozapine, 14.9%; P = .008) and dizziness (olanzapine, 1.3%; clozapine, 8.1%; P = .049). 3.4.3. Treatment-emergent extrapyramidal symptoms as assessed by rating scales There were no statistically significant differences in baseline-to-endpoint measurements (LOCF) of akathisia (as measured by the HAS), parkinsonism (as measured by the Simpson – Angus Scale), or dyskinesia (as measured by the AIMS) between olanzapine- and clozapine-treated patients (Table 4). Treatment-emergent akathisia (defined in our study as an HAS total score of z 3 that was not present at baseline) was not significantly different between olanzapine-and clozapine-treated patients by endpoint (5.3% vs. 0.0%, P =.072). Treatment-emergent parkinsonism, defined as a Simpson – Angus total score of > 3 that was not present at baseline, was not seen in either treatment group. Treatment-emergent dyskinetic symptoms (defined in our study as one item score of 3 or more or two items scores of 2 or more on the AIMS that was not present at baseline) were similar between olanzapine- and clozapine-treated patients at endpoint (8.7% vs. 2.9%, respectively; P = .139). 3.4.4. Weight and vital signs There was no statistically significant difference between treatment groups in the mean change from baseline to endpoint (LOCF) of body weight (olanzapine, + 3.3 F 5.3 kg; clozapine, + 4.1 F 5.6 kg; P=.370). Clozapine use was associated with significantly greater baseline-to-endpoint changes in standing heart rate (supine: olanzapine, + 4.4 F 15.0 bpm, n = 75; clozapine, + 11.1 F 15.1 bpm, n = 72; P=.008; Table 3 Adverse eventsa Event classification
Olanzapine (N = 76), n (%)
Clozapine (N = 74), n (%)
P valuea
Weight gain Headache Back pain Asthenia Flu syndrome Somnolence Dizziness Hypersalivation Postural hypotension
7 6 4 3 2 2 1 1 1
7 4 0 7 4 11 6 5 4
.958 .541 .045 .176 .386 .008 .049 .089 .163
(9.2) (7.9) (5.3) (3.9) (2.6) (2.6) (1.3) (1.3) (1.3)
(9.5) (5.4) (0.0) (9.5) (5.4) (14.9) (8.1) (6.8) (5.4)
Abbreviations: N = total number of patients randomized to each treatment group; n = number of patients reporting each adverse event. a Spontaneously reported adverse events with an incidence of z 5% in either treatment group or with a statistically significant difference ( P < .05) between groups.
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Table 4 Mean change in extrapyramidal symptom rating scales, baseline to endpoint, 18 weeks (LOCF) Measure
Simpson – Angus Scale AIMS total score HAS
Therapy
n
Baseline
Change
Mean (S.D.)
Mean (S.D.)
P valuea
Olanzapine 69
4.7 (4.5)
3.0 (4.8)
.899
Clozapine 70 Olanzapine 69
4.3 (4.8) 1.6 (2.9)
2.9 (3.9) 0.6 (2.5)
.958
Clozapine 70 Olanzapine 68 Clozapine 69
1.6 (3.1) 3.6 (7.7) 3.4 (8.0)
0.9 (2.8) 2.3 (8.9) 2.7 (7.1)
.710
Abbreviations: LOCF, last observation carried forward; n = number of patients with a baseline and at least one postbaseline measurement. a Treatment effect from the main effects model with terms for treatment and geographic region.
standing: olanzapine, + 5.4 F 17.0 bpm, n = 75; clozapine, 12.7 F 16.2 bpm, n = 72; P=.009). Otherwise, there were no significant treatment-group differences in any vital sign. 3.4.5. Clinical laboratory evaluation Analysis of laboratory measures revealed significant treatment differences in baseline-to-endpoint changes in urinary pH (olanzapine, + 0.22 F 1.00, n = 67; clozapine, 0.12 F 0.77, n = 67; P=.027) and phosphate (olanzapine, 0.01 F 0.20, n = 67; clozapine, + 0.06 F 0.21, n = 70; P=.044), and clozapine treatment was associated with a significantly higher incidence of abnormally elevated alkaline phosphatase levels (olanzapine, 1.4%; clozapine, 8.3%; P=.050, Fisher’s Exact Test), but these were deemed not clinically significant. There were no other significant differences between olanzapine- and clozapine-treated patients on any other clinical laboratory parameter measured, including leukocyte, neutrophil, and lymphocyte counts.
4. Discussion In the present study, virtually no differences were seen between olanzapine and clozapine in any measure of efficacy. Both drugs reduced psychotic symptoms to levels at endpoint that were considered ‘‘minimal’’ (Guy, 1976; Kay et al., 1986). Likewise, response rates were similar between treatment groups, regardless of how they were defined. This supports the findings of Tollefson et al. (2001), who found olanzapine to be ‘‘noninferior’’ to clozapine on all measures of efficacy. Response rates in the current study, based on the criteria for improvement of Kane et al. (1988), were on the order of 58% to 61%, which somewhat approximates the rate of 50% seen in the study of Tollefson et al. (2001). This is notably higher than the response rate of 30% that was derived for clozapine by Kane et al. (1988). This may relate to the stringency with which the earlier study defined treatment resistance as the criteria for the current study required failure on only one previous trial with a conven-
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tional antipsychotic, compared with the three failures with a conventional agent that had been required in the Kane analysis. The current study also included patients who had merely shown treatment intolerance due to adverse reactions, rather than outright refractoriness to treatment. This latter explanation may be the more salient of the two, as it has been demonstrated that only 7% to 9% of patients who have failed to respond adequately during two treatment trials will go on to show improvement under subsequent treatment (Kinon et al., 1992; Kinon et al., 1993). It has accordingly been suggested that failure on just one trial is sufficient to demonstrate treatment resistance (Peuskens, 1999). Both treatment groups in this study were notable for their benign, largely mild measures of safety. A somewhat higher incidence of back pain was seen among olanzapine patients, while clozapine patients experienced more somnolence and dizziness. Motor side effects, of which clozapine has long been noted to be virtually devoid (Juul Povlsen et al., 1985), were nearly absent in both treatment groups, and there were no clinically and statistically significant changes in either group in any vital sign or laboratory measure, with the exception of weight gain, which was noted in both groups. This latter finding was not unexpected, as weight gain has been found to varying extents to be a liability of nearly all antipsychotics, both atypical and conventional (Allison et al., 1999; Kelly et al., 1998; Martin et al., 1999; Taylor and McAskill, 2000), with the highest liabilities being found for clozapine and olanzapine (Allison et al., 1999; Taylor and McAskill, 2000). Perhaps the most comprehensive study to date of atypical antipsychotics in treatment-refractory schizophrenia was the one conducted by Volavka et al. (2002). This study consisted of an 8-week period, during which patients’ previous antipsychotics were gradually discontinued while study drug was escalated to target levels, followed by a 6-week flexibledosing period, during which patients received clozapine, olanzapine, risperidone, or haloperidol. Both clozapine and olanzapine reduced PANSS total and negative symptom scores significantly more than did haloperidol. Risperidone appeared not to differ significantly from haloperidol, which in turn was found not to have had a significant effect on any measure. The effect sizes of the improvement in PANSS total scores at the 14-week endpoint were calculated to be 0.51 for olanzapine, 0.33 for clozapine, 0.18 for risperidone, and 0.11 for haloperidol. Clozapine was the most effective treatment for negative symptoms, but the overall pattern of efficacies suggested that clozapine and olanzapine had similar general antipsychotic efficacy. A number of limitations of the current study bear mentioning. For example, previous histories were not systematically collected. It is therefore not known what the durations of patients’ illness were or how many times they had been hospitalized. These measures would have given a clearer picture of how chronic or severe patients’ illnesses were. To this end, we instead depended on the severity criteria of Kane et al. (1988) of a BPRS total score of at least 45 plus a CGI-S
rating of at least 4. This study also did not allow us to differentiate between patients who were enrolled due to actual resistance to conventional antipsychotic treatment and those enrolled due to intolerance of side effects. This might have provided important data regarding the differential efficacy of olanzapine versus conventional medications, as opposed to differences in side-effect profiles. Finally, while the protocol for this study allowed doses of olanzapine up to 25 mg/day and doses of clozapine up to 500 mg/day, the overall mean modal doses of 16.7 and 223 mg/day, respectively, were substantially lower than those used in other comparator studies (Breier and Hamilton, 1999; Conley et al., 1999; Volavka et al., 2002). This appeared to be more a reflection of the positive efficacy of both drugs in this study, however, than of treatment intolerance. Although mean doses of clozapine above 400 mg/day are common in studies of refractory schizophrenia conducted in the United States, the doses used in this study were more in line with those used in European studies (Fleischhacker et al., 1994; Fleischhacker, 1999; Pollack et al., 1995) and in clinical practice (IMS database, first quarter, 1998). It has been suggested that the optimal dose range for clozapine in treating patients resistant to conventional antipsychotics is on the order of 300 –600 mg/day (Lublin, 1997). However, it has become apparent that, for patients who do respond to clozapine, doses below 300 mg/day are sufficient (Gordon and Milke, 1996; Pollack et al., 1995). Thus, higher doses are unnecessary as they are not likely to increase responsiveness, while use of lower doses is more likely to avoid the incurrence of adverse effects (Pollack et al., 1995).
5. Conclusions Olanzapine was found to have the same level of efficacy as the current gold standard, clozapine, in treating patients with treatment-resistant or treatment-intolerant schizophrenia who were candidates for treatment with an atypical antipsychotic. Measures of safety showed olanzapine’s risk of extrapyramidal symptoms to be equivalent to that of clozapine, while the absence of hematological abnormalities further underscored its safety benefits.
Acknowledgements The following individuals and institutions, in addition to the authors, participated in the Olanzapine HGCK Study Group: Csilla Bolyo´s, MD, Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; Zolta´n Danics, MD, National Institute of Psychiatry and Neurology, Budapest, Hungary; Alexander Kancsev, MD, Regional Neuropsychiatric Institute, Nagyka´llo´, Hungary; Lajos Karmacsi1, MD, Regional Neuropsychiatric 1
Deceased.
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Institute, Nagyka´llo´, Hungary; Zolta´n Kova´cs, MD, Department of Psychiatry, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary; Emese Linka, MD, Department of Psychiatry, Ja´hn Ferenc Hospital, Budapest, Hungary; Paul Janus Pretorius, MD, Department of Psychiatry, Oranje Hospital, University of the Free State, Bloemfontein, South Africa; Salumu Selemani, MD, Sterkfontein Hospital, Krugersdorp, South Africa; Martell Slabber, MD, Department of Psychiatry, Oranje Hospital, University of the Free State, Bloemfontein, South Africa; Gyo¨rgy Szekeres, MD, Department of Psychiatry, Albert SzentGyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary; Istva´n Szendi, MD, Department of Psychiatry, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, Szeged, Hungary; Zsolt Tahin, MD, Department of Psychiatry, Central Military Hospital, Budapest, Hungary. In addition, the authors wish to express their deepest appreciation for the patience and dedication by all medical personnel involved in this clinical study. This work was sponsored by Eli Lilly and company. References Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Cappelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry 156, 1686 – 1696. Alvir, J.M., Lieberman, J.A., Safferman, A.Z., Schwimmer, J.L., Schaaf, J.A., 1993. Clozapine-induced agranulocytosis: incidence and risk factors in the United States. N. Engl. J. Med. 329, 162 – 167. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. Barnes, T.R., McEvedy, C.J., 1996. Pharmacological treatment strategies in the non-responsive schizophrenic patient. Int. Clin. Psychopharmacol. 11 (Suppl. 2), 67 – 71. Breier, A., Hamilton, S.H., 1999. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biol. Psychiatry 45, 403 – 411. Bymaster, F.P., Perry, K.W., Nelson, D.L., Wong, D.T., Rasmussen, K., Moore, N.A., Calligaro, D.O., 1999. Olanzapine: a basic science update. Br. J. Psychiatry 174, 36 – 40. Cohen, H., Loewenthal, U., Matar, M., Kotler, M., 2001. Heart rate variability and risk for sudden death in patients with schizophrenia on longterm psychotropic medication. Br. J. Psychiatry 179, 167 – 171. Conley, R.R., Buchanan, R.W., 1997. Evaluation of treatment-resistant schizophrenia. Schizophr. Bull. 23, 663 – 674. Conley, R.R., Schulz, C., Baker, R.W., Collins, J.F., Bell, J.A., 1988. Clozapine efficacy in schizophrenic nonresponders. Psychopharmacol. Bull. 24, 269 – 274. Conley, R.R., Tamminga, C.A., Kelly, D.L., Richardson, C.M., 1999. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol. Psychiatry 46, 73 – 77. Devinsky, O., Pacia, S.V., 1994. Seizures during clozapine therapy. J. Clin. Psychiatry 55, 153 – 156. Edge, S.C., Markowitz, J.S., Devane, C.L., 1997. Clozapine drug – drug interactions: a review of the literature. Hum. Psychopharmacol. 12, 5 – 20.
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