International Journal of Psychiatry in Clinical Practice, 2005; 9(1): 3 /15
REVIEW ARTICLE
A comparison of olanzapine versus risperidone for the treatment of schizophrenia: a meta-analysis of randomised clinical trials
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MIA A. C. MUDGE1, PETER J. DAVEY1, KRISTINA A. COLEMAN1, WILLIAM MONTGOMERY2, VICTORIA S. CROKER2, KAREN MULLEN2 & DAVID J. CASTLE3 1
M-TAG, Chatswood West NSW, Australia, 2Eli Lilly Australia, West Ryde NSW, Australia and 3Mental Health Research Institute & University of Melbourne, Victoria, Australia
Abstract Objective. This meta-analysis was carried out to compare the efficacy and safety of olanzapine with risperidone in the treatment of schizophrenia. Methods. Data from randomised, double-blind studies were analysed according to short(5/12 weeks) and longer-term ( /12 weeks) treatment, and included all-doses analyses and a sensitivity analysis of clinically relevant doses. A range of efficacy and safety parameters was measured. Results. Olanzapine produced statistically significant improvements in efficacy and safety parameters compared with risperidone over both the short and longer term. Anticholinergic use, study dropouts, changes in Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores, and Quality-of-Life Scale changes, were often significantly in favour of olanzapine. Results from the sensitivity analyses of only clinically relevant doses further favoured olanzapine compared with the all-doses analyses. Conclusion. Small changes in the presence or severity of psychotic symptoms and side-effects can affect a patient’s prognosis and quality of life. With this in mind, the efficacy and safety advantages of olanzapine suggested by this study may convey clinical relevance to certain aspects of schizophrenia. However, further research / especially into longerterm efficacy and safety / is needed to confirm the differences between the available antipsychotics.
Key Words: Meta-analysis, efficacy, antipsychotics, olanzapine, risperidone
Introduction The relative merits of available antipsychotic medications for schizophrenia are not fully established, and treatment decisions are complex [1]. Advantages have been reported for the newer ‘‘atypical’’ antipsychotic agents, including a lower potential for movement disorders [2] and a greater effect on negative symptoms [3,4]. To date, however, metaanalyses that have compared these agents with older ‘‘typical’’ antipsychotics have produced inconsistent results [5 /12]. Some previous analyses have found advantages with the newer ‘‘atypical’’ agents [5 /9,12], while other studies have returned more equivocal results [10,11]. Indeed, the meta-analysis by Geddes et al concluded that there is insufficient evidence that atypical agents are more effective or better tolerated than conventional agents in the treatment of schizophrenia [10].
There are a number of methodological differences that could account for these diverse results, including the grouping together of atypical and typical antipsychotics and the use of odds ratios in some studies and relative risk in others. Another factor contributing to inconsistent conclusions of previous meta-analyses is that in many fixed-dose trials, patients receive subtherapeutic or supratherapeutic levels of medication. Subtherapeutic doses have the potential to limit efficacy gains that would likely be seen in clinical practice, while supratherapeutic doses can exacerbate side-effects / such as extrapyramidal symptoms (EPS) / over what would normally be seen clinically. Some metaanalyses have failed to control for this factor, or have controlled for clinically relevant doses of some agents but not others [5/7]. The current meta-analysis aimed to address these methodological shortfalls. In particular, clear distinctions were drawn regarding which agents were
Correspondence: Peter J. Davey, M-TAG, PO Box 5639, Chatswood West NSW 1515, Australia. Tel: /61-2-9419-7722. Fax: /61-2-9419-7922. E-mail: [email protected]
(Received 20 January 2004; accepted 19 November 2004) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510014783
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being compared; ‘‘clinically relevant’’ doses were established and interrogated in the analysis; randomeffects rather than fixed-effect statistics were applied in cases of heterogeneity between studies; and results were presented as odds ratios rather than risk ratios. Olanzapine and risperidone, two well-tolerated and efficacious atypical antipsychotic agents, were chosen as the focus for this analysis as they are two of the most commonly prescribed antipsychotic agents used globally in the treatment of schizophrenia.
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Aims There were two main aims of this study. The first was to compare the atypical antipsychotics olanzapine and risperidone using head-to-head trials. The second was to compare olanzapine indirectly with risperidone via a common comparator, haloperidol. This indirect analysis was essential to supplement the few published data directly comparing olanzapine with risperidone. Methods All appropriate randomised double-blind studies comparing the efficacy and safety of olanzapine with risperidone were included. For the common comparator analysis, all studies comparing olanzapine or risperidone with haloperidol were retrieved. Studies were identified via several routes. For the direct head-to-head comparison between olanzapine and risperidone, the Cochrane review, Olanzapine for Schizophrenia by Duggan et al [7], provided the basis for identifying relevant trials. This was current in mid-1999, hence further systematic searches of MEDLINE, EMBASE and the Cochrane Clinical Trials Register were also carried out to capture all additional trials published up to the search date of March 2001, using the Cochrane Schizophrenia Group’s search strategy. This search was updated in June 2002. Studies excluded from this meta-analysis included those not randomised, not double-blind, wrong outcomes measured, no comparator used, different comparator used to those analysed in this study, medications switched, and medications given after previous therapy failure. Furthermore, studies were excluded if patients treated with haloperidol received benztropine while the other treatment arm(s) received placebo, as this may have influenced the results. Unpublished data of olanzapine versus risperidone and olanzapine versus haloperidol were also included. Details of the search strategies used, and of papers included or excluded, can be obtained from the authors. For the indirect common-comparator analysis, trials comparing olanzapine with haloperidol were identified by the search strategy described above. Trials comparing risperidone with haloperidol were
identified in a similar manner via the most recent Cochrane reviews of risperidone [13], again supplemented by searches using MEDLINE, EMBASE and the Cochrane Clinical Trials Register to identify trials published up to June 2002. Data analysis Although some studies analysed data on an evaluable-patients basis, for this meta-analysis all dichotomous efficacy data were analysed on a full intention-to-treat (ITT) basis (i.e. all randomised patients were included in the denominator); for all safety and tolerability analysis, only treated patients were included in the denominator. Data from continuous efficacy scales were analysed using the last observation carried forward (LOCF) method [14], and all patients with at least one post-baseline score were assessed. This included over 90% of randomised patients for all but one trial [15]. The LOCF imputation method may lead to invalid inferences if the underlying difference between treatment groups, with respect to the outcome of interest, changes uniformly over time. For the trials being considered, it was assumed that patients who dropped out got worse. However, using LOCF to impute missing final values was considered to be conservative in this case, as the difference between olanzapine and risperidone treatment groups would have been more in favour of the olanzapine groups had the patients who dropped out been measured at the endpoint Quality of life was analysed in the head-to-head olanzapine versus risperidone comparison only, as this outcome was available for only two studies. This analysis included all patients who had baseline and post-baseline measures at 8 and 28 weeks for the trial by Tran et al [16] and at 30 weeks for the study by Gureje et al [17]. This included approximately 71% of patients in the short- and long-term analyses of the Tran study and 95% of patients in the Gureje study. Primary analyses Olanzapine was compared with risperidone over the short term ( 5/12 weeks) and longer term (/12 weeks). To supplement the results of the direct method of comparison, an indirect comparison was made between olanzapine and risperidone over the short term, via a common comparator, haloperidol. Sensitivity analyses of clinically relevant doses All studies included in the head-to-head comparisons were flexible-dosing studies in which the dose was titrated according to each individual patient’s needs. Hence, the direct comparison between olan-
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Olanzapine versus risperidone for schizophrenia zapine and risperidone is based on all doses used in these studies. Many of the trials used in the common comparator analyses were fixed-dose trials, which included subtherapeutic and supratherapeutic doses of haloperidol and risperidone. Therefore, in addition to an all-dose analysis, a more clinically relevant sensitivity analysis was conducted including only those doses of antipsychotic agents deemed to be ‘‘clinically relevant’’ according to current clinical use. ‘‘Clinically relevant’’ doses were determined from both the Product Information and from doses reported in recently published literature. For fixed dose trials, the relevant treatment arms were included in the sensitivity analysis. For flexible dose trials, the mean daily dose and/or the mean dose plus or minus one standard deviation was required to fall within the dose range deemed to be clinically relevant, in order to be included in this analysis. The following dose ranges were selected as clinically relevant.
Olanzapine. According to the Product Information, the starting dose should be 5 /10 mg/day, and may be adjusted up to 20 mg/day after clinical reassessment. Clinical experience suggests mean doses are about 13 mg/day [18,19]. Hence, for the purposes of this trial, the clinically relevant dose of olanzapine was considered to be 10 /15 mg/day [19].
Risperidone. The Product Information states that the dose range should be 4/6 mg/day. This is in line with clinical practice, and the results of dose-ranging studies [18,19]. Thus 4 /6 mg/day was considered to be the clinically relevant dose [19 /21].
Haloperidol. The Product Information states that doses of 1 /5 or 5 /15 mg/day should be used, depending on whether the patient has moderate or severe symptoms. Doses of 5 /15 mg/day were therefore considered to be clinically relevant. This is in line with recent clinical practice [18,21].
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. Response rate at a number of levels of Positive and Negative Syndrome Scale (PANSS) scores (direct analysis only). . Mean change from baseline scores in PANSS total, PANSS positive, PANSS negative and PANSS general psychopathology scales, Brief Psychiatric Rating Scale (BPRS) total and Clinical Global Impression (CGI) severity scale. . Number of patient discontinuations for (i) any reason, (ii) adverse events, and (iii) lack of efficacy. . Number of patients requiring anticholinergic medication / an indication of the extent of EPS. . Mean change from baseline score in the Quality-of-Life Scale (QLS) [24]. Statistical methods All analyses (using Meta View version 4 software) were carried out on an ITT basis, apart from the analyses of mean change from baseline of efficacy or quality of life (QoL) scales, in which patients were required to have at least one post-baseline measure to calculate the change. This captured 91% of patients in all trials, apart from the trial by Wirshing et al. [25], in which only 85% of randomised patients were included in the efficacy analysis, and the trial by Tran et al. [16], where 71% of patients were included in the QoL analysis. Dichotomous variables such as discontinuations, anticholinergic use and response rates were assessed using odds ratio and risk difference analyses, while continuous variables were assessed using weighted mean difference analyses. Non-heterogeneous comparisons (x2-test for heterogeneity ]/0.05) were calculated using the fixed-effects method, with heterogeneous comparisons (determined by x2-test for heterogeneity B/0.05 and visual inspection of Forest plots) being calculated using the randomeffects method. A P value of B/0.05 was taken as the level of significance for all comparisons. Indirect comparison methodology
The doses selected represent an assessment of the highest level of evidence from randomised clinical trials and are supported by recent dosing recommendations [22,23]. Outcomes for pooling The following outcomes were selected for pooling. . Number of patients achieving a clinical response, according to that study’s protocol (indirect atypical analyses only; see Table Ib and Table Ic for definitions of clinical response for each trial).
For the indirect comparison of olanzapine versus risperidone via the common comparator, haloperidol, the following methodology was used. First, olanzapine and risperidone were each compared with haloperidol and the odds ratio (for dichotomous outcomes) and weighted mean difference (for continuous outcomes) results were calculated. For dichotomous outcomes, results were then compared indirectly for each study drug (olanzapine versus haloperidol compared with risperidone versus haloperidol) using meta-regression statistical analyses [24]. This approach extends a randomeffects meta-analysis to estimate the extent to which
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one or more covariates account for differences between treatment effects. In this case, the treatment effect is the log odds ratio, although the results can be back-transformed and interpreted on the odds ratio scale. The covariates of interest are the different comparisons in a set of studies with a common outcome. By definition, if only a single study is included in a set, no comparison can be made as the covariate only takes one value; the same applies to a set of studies with the same comparator. For continuous outcomes, normal approximation of each pair of confidence intervals was carried out to get point estimates, estimated standard errors and a zstatistic. There is a one-to-one correspondence between odds ratios and log odds ratios: values of odds ratios greater than 1 will be positive on the log odds ratio scale while values of odds ratios less than 1 will be negative on the log odds ratio scale. Results Four randomised controlled trials (RCTs) that directly compared olanzapine with risperidone were included in the meta-analysis (Table Ia). This direct comparison was supplemented by a common comparator analysis that included seven RCTs comparing olanzapine with haloperidol (Table Ib) and 15 RCTs comparing risperidone with haloperidol (Table Ic). The results of selected drug-pair comparisons are shown in Figures 1/4 and data on all outcomes assessed are presented in Tables II /IV. Although results presented here are primarily based on the odds ratio statistic, parallel analysis via the method of risk difference revealed essentially similar results (data not shown). Short term Olanzapine and risperidone were compared directly and indirectly using a common comparator analysis via haloperidol (Tables Ia /c). Over the short term, the direct comparison revealed a significant difference in anticholinergic use in favour of olanzapine (Figure 1, Table III). Anticholinergic use was also significantly different in favour of olanzapine in the indirect comparison via haloperidol, both in the alldose analysis and in the sensitivity analysis that included only clinically relevant doses of olanzapine, risperidone and haloperidol (Figure 1, Table III).
For those other outcomes included in both analyses, the results of the indirect comparison via haloperidol were similar to the results of the shortterm direct comparison, with the exception of the weighted mean difference in PANSS positive change. However, none of these outcomes were statistically significant. Longer term Over the longer term, trends seen in short-term studies became more pronounced. Significant differences in favour of olanzapine were found in the odds ratios for the following dichotomous outcomes: anticholinergic use (Figure 1, Table III), dropouts for any reason (Figure 2, Table III), and patients responding with ]/40 and ]/50% improvement in PANSS score (Table II). For continuous outcomes, the weighted mean difference was significantly in favour of olanzapine for PANSS total change (Figure 3, Table II), PANSS negative change, PANSS general psychopathology change, BPRS total change (Figure 4, Table II), QLS total change, and QLS interpersonal relations change (Table IV). Discussion The meta-analysis reported here suggests that olanzapine exhibits a favourable clinical profile with significant benefit found for a number of efficacy and safety parameters versus risperidone. Clinical relevance of findings While advantages were seen with olanzapine in a number of parameters, differences were small and the clinical relevance of these advantages remains unclear. What is clear, however, is that even small changes in the presence or severity of symptoms and side-effects can affect a patient’s prognosis and quality of life. Given the high attrition rates encountered in schizophrenia studies (as in clinical practice), many studies have limitations, which necessarily have an influence in the current meta-analysis. It is therefore difficult to draw strong conclusions about future clinical practices. Further research / especially into the efficacy and safety of these agents over the longer
Table Ia. Olanzapine versus risperidone studies included in the meta-analysis.
Study
Study duration
Conley [44] 8 weeks Tran [16] 28 weeks (unpublished 8-week data available also) Gureje [17] 30 weeks Purdon [45] 12 months (6-week data available also for some outcomes)
Total no. of patients 407 339 65 42a
Daily dose of antipsychotic
Olanzapine Olanzapine Olanzapine Olanzapine
5 /20 mg, risperidone 2 /6 mg 10 /20 mg, risperidone 4 /12 mg 10 /20 mg, risperidone 4 /8 mg 5 /20 mg, risperidone 4 /10 mg
a Trial included three arms comparing olanzapine, risperidone and haloperidol. Of the total of 65 patients randomised in this trial, 42 were in the olanzapine and risperidone arms.
Excludeda Excluded Excluded Includeda (44)
Included (1996)
Includedb (202)
Excluded
Methodological issues
mg/day (12.4 mg) mg (mean not given) mg (mean not given) mg (11.0 mg) 24 31 54 44 weeks weeks weeks monthsc 14 14 14 12 Altamura [48] Tran [49] Zhang [50] Purdon [45]
Abbreviations: BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation. a Sensitivity analysis was only undertaken in the short term for the comparison of olanzapine and haloperidol. b Olanzapine 10 mg and 15 mg9/2.5 mg. c Data available at 6 weeks also.
(12.3 mg) (mean not given) (mean not given) (9.7 mg) 5 /20 5 /20 5 /20 5 /20 5 /20 5 /20 5 /20 5 /20
mg mg mg mg
5 /20 mg (11.8 mg) 5 /20 mg (13.2 mg) 6 weeks Tollefson [31]
1996
159/5 mg (16.49/4 mg) 5, 10, 159/2.5 mg (6.69/1.4, 11.69/1.5, 16.39/1.6 mg, respectively) 335 6 weeks Beasley [47]
7
term / is needed to confirm the differences suggested in this meta-analysis.
]/40% improvement in BPRS total score or endpoint BPRS total scoreB/18 ]/40% improvement in BPRS total score or endpoint BPRS total scoreB/18 in patients completing ]/ visit 7 ]/40% improvement in BPRS total score in patients completing ]/ 3 weeks of study ]/40% improvement in BPRS total score Not given ]/40% improvement in BPRS total score Non-relapser. Relapse defined as ]/ 20% worsening of PANSS scores or hospitalisation due to a change in psychopathology 159/5 mg 5, 10, 159/2.5 mg 431 6 weeks Beasley [46]
Definition of responder Daily dose of haloperidol (mean dose9/SD) Daily dose of olanzapine (mean dose9/SD) Total no. of patients Study duration Study
Table Ib. Olanzapine versus haloperidol studies included in the indirect meta-analysis.
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Inclusion in the sensitivity analysis (N )
Olanzapine versus risperidone for schizophrenia
The x2-test for heterogeneity was used to identify comparisons in which there was significant heterogeneity. However, in some cases this test lacks the power to detect heterogeneity, particularly when there are few studies [26]. In this meta-analysis, the majority of heterogeneous results came from the all-doses analyses of olanzapine versus haloperidol and risperidone versus haloperidol, and of the different outcomes examined, in the analysis of responders. This is as expected given the wide range of doses and different definitions of response for each trial. Meta-regression of summary data may lead to incorrect inferences when the treatment, or other effect of interest, is confounded with further variables being examined as potential sources of heterogeneity. However, the only variable included in each meta-regression model in these analyses was the treatment group of interest, in order to estimate the indirect difference between olanzapine and risperidone groups, via the common comparator (haloperidol). In general, the trials included patients with schizophrenia (without limiting the severity or duration of illness), although some also included patients with schizoaffective and schizophreniform disorders. Two trials included in the risperidone versus haloperidol analysis had restricted patient groups: in the study by Emsley et al [27], patients undergoing treatment for their first psychotic episode were included, while the study by Wirshing et al [25] included only patients considered to be treatment-resistant. However, these trials were included in the analysis as the patients made up only 10% of the available population for the risperidone versus haloperidol comparison. It should be noted that the more relevant clinical-dose analyses included few trials and hence there was little heterogeneity. In order to adjust for heterogeneity, the random-effects method, which makes an adjustment for the variation between individual studies, was used. Due to the differences in endpoints measured and lack of sufficient data provided in the included studies, changes in patients’ weight before and after antipsychotic treatment could not be included in this meta-analysis. Nearly all antipsychotics on the market today have been reported to cause weight gain [28]. In particular, those with high affinity for serotonin receptors like olanzapine have been shown to cause weight gain in the short-term [29]. In the longer-term, however, patients’ weight tends to stabilise and any form of weight gain is usually driven by other factors, such as lack of exercise, drug use, increased food intake, and poor
M. A. C. Mudge et al.
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Table Ic. Risperidone versus haloperidol studies included in the indirect meta-analysis.
Study Blin [51] Borison [52] Cavallaro [53] Ceskova [54] Chouinard [55] Claus [56] Emsley [27] Liu [57] Marder [21] Messotten [58] Min [59] Peuskens [20] Purdon [45]
Wirshing [25] Zhang [60]
Total no. Study duration of patients 4 6 6 8
weeks weeks weeks weeks
8 weeks 12 weeks 6 weeks 12 weeks 8 weeks 8 weeks 8 weeks 8 weeks 12 monthsc
41a 36 29 62 135 42 183 56 388 60 35 1362 44
Daily dose of risperidone (mean dose) 4 /12 2 /10 5 /10 2 /20
mg mg mg mg
(7.4 mg) (9.7 mg) (mean not given) (mean not given)
Daily dose of haloperidol (mean dose) 4 /12 4 /20 5 /10 2 /20
mg mg mg mg
(7.6 mg) (18.0 mg) (mean not given) (mean not given)
2, 6, 10, 16 mg 1 /10 mg (12.0 mg) 4 /16 mg (6.1 mg) No dose details given 2, 6, 10, 16 mg (9.1 mg) 5 /10 mg (mean not given) 1, 4, 8, 12, 16 mg 4 /10 mg (6.0 mg)
20 mg/day 1 /10 mg (10.3 mg) 4 /16 mg (5.6 mg) No dose details given 20 mg (9.4 mg) 5 /10 mg (mean not given) 10 mg 5 /20 mg (9.7 mg)
8 weeks
67
3 /5 mg (7.5 mg9/1.9)
5 /30 mg (19.4 mg9/5.6)
12 weeks
78
6 mg
20 mg
Definition of responder ]/20% improvement in PANSS total score ]/20% improvement in BPRS total score Not reported ]/25% improvement in BPRS total score (partial or good remission) ]/20% improvement in PANSS total score ]/20% improvement in PANSS total score ]/50% improvement in PANSS total score Not given ]/20% improvement in PANSS total score Not given ]/20% improvement in PANSS total score ]/20% improvement in PANSS total score Non-relapser. Relapse defined as ]/ 20% worsening of PANSS scores or hospitalisation due to a change in psychopathology ]/20% improvement in BPRS total score or total score B/35, and CGI severity score 5/ 3 ]/20% improvement in PANSS total score
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; PANSS, Positive and Negative Syndrome Scale. a Trial included three arms comparing risperidone, haloperidol and methotrimeprazine. Of the total of 65 patients in this trial, 41 were in the haloperidol and risperidone arms. b Risperidone 4 mg. c Data available at 6 weeks also.
Inclusion in the sensitivity analysis (N ) Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Includedb (453) Included (44)
Included (67) Excluded
Olanzapine versus risperidone for schizophrenia
9
1.4
1 0.8 0.6
Favours olanzapine
Odds ratio
1.2
Favours risperidone
1.6
0.4 0.2 0 Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 1. Effect of olanzapine versus risperidone on anticholinergic use for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
1.5
The indirect comparisons carried out to back-up the results from direct comparisons have limitations, given the varying trial conditions and patient prognostic factors across different trials [35]. However, to minimise any discrepancy arising from the difference between the conditions under which the data were obtained, the random-effects method was employed. In addition, all studies were double-blind, randomised controlled trials in patients with schizophrenia, thus trial characteristics are likely to have been similar. Further, the short-term comparison was completed using both the direct and indirect methods. The strikingly homologous results from these two analyses suggest that similar indirect comparison may provide equally reliable data in other comparisons for which there are no headto-head trials. Given the lack of direct comparisons between many of the atypical antipsychotics, this method may be useful [35] for future comparisons to
Favours risperidone
nutritional habits [30]. For example, in the olanzapine versus haloperidol study by Tollefson et al [31] included in our meta-analysis, the mean rate of weight gain over the first 6 weeks was 0.32 kg/week in olanzapine-treated patients (N /1996). This was reduced to 0.11 kg/week after 30 weeks of therapy and 0.07 kg/week after 52 weeks. When few or no direct head-to-head clinical trials exist, an indirect analysis between two active treatment arms can be performed via a common comparator (in this case the active comparator, haloperidol). There are a number of published studies and reviews that attest to the robustness of indirect meta-analysis methodology if strict procedural controls are used to restrict which outcomes are pooled [32 /34]. Indeed, using strict criteria for pooling data and analysis of heterogeneity enhances the validity of the procedure and prevents incorrect inferences that occur without sound methodology.
0.5
Favours olanzapine
1
Odds ratio
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Olz vs risp: short term
0
–0.5
–1 Olz vs risp: short term
Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 2. Effect of olanzapine versus risperidone on dropouts for any reason for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
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2 0 –2 Favours olanzapine
Weighted mean difference
4
–4 –6 –8 –10
Olz vs risp: short term
Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 3. Effect of olanzapine versus risperidone on weighted mean difference of PANSS total scores for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
help elucidate the relative merits of other atypical antipsychotics. Results versus results of other meta-analyses Some meta-analyses comparing antipsychotic agents support the findings of this study / that the efficacy of olanzapine is superior to haloperidol and risperidone [5,6,8,12]. However, these results differ from those of other meta-analyses in which olanzapine was found to be equivalent to other agents for safety and efficacy outcomes [7,10,11,15]. This could be due to methodological differences such as the use of different summary statistics, the inclusion of studies using drugs at doses different to those used in clinical practice, the under-rating of severe side-effects such as EPS, and the grouping of the newer agents into a single ‘‘atypical’’ group, so diluting the validity of conclusions drawn. The meta-
analysis by Geddes et al, in particular, has been criticised for insufficient recognition of the debilitating effects of EPS [36 /39], incorrect dosage considerations [37,39], and the grouping of all atypical drugs together [40]. There is no sound pharmacological or therapeutic basis for combining all atypical drugs together [41,42]. Data suggest that the efficacy of atypical antipsychotics is not equivalent, and analyses that group these agents together may downplay the efficacy of individual agents such as olanzapine via a ‘‘dilution’’ effect. In this study, only comparisons of single agents (olanzapine versus risperidone and olanzapine or risperidone versus haloperidol) were made, thus avoiding the diluting effects of grouping together agents with differing efficacy. The more recent meta-analysis conducted by Davis et al. [15] grouped a variety of efficacy endpoints to obtain an overall effect size estimate.
3 2 1 0 –1 –2 –3 –4 –5
Favours olanzapine
Weighted mean difference
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–12
–6 –7 Olz vs risp: short term
Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 4. Effect of olanzapine versus risperidone on weighted mean difference of BPRS total scores for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
Table II. Efficacy results. Olz vs risp short term
Respondersa OR (95% CI) Included trials
Olz vs risp longer term
/
/
0.99 (0.73, 1.34) Tran [16]; Conley [44] 1.12 (0.73, 1.73) Tran [16] 1.12 (0.69, 1.81) Tran [16] 1.18 (0.63, 2.21) Tran [16] /0.86 (/3.82, 2.11) Tran [16]; Conley [44]
2.01 (0.35, 11.48) Tran [16]; Gureje [17] 1.47$ (0.99, 2.17) Tran [16]; Gureje [17] 1.63* (1.05, 2.53) Tran [16]; Gureje [17] 1.91* (1.09, 3.37) Tran [16]; Gureje [17] /5.35* ( /10.15, /0.55) Tran [16]; Gureje [17]
PANSS positive changeb WMD (95% CI) Included trials
0.39 (/0.60, 1.37) Tran [16]; Conley [44]
/0.81 (/2.01, 0.39) Tran [16]; Gureje [17]; Purdon [45]
PANSS negative changeb WMD (95% CI) Included trials
/0.31 (/1.23, 0.61) Tran [16]; Conley [44]
/1.39* ( /2.66, /0.13) Tran [16]; Gureje [17]; Purdon [45]
PANSS GPS changeb WMD (95% CI) Included trials BPRS total changeb WMD (95% CI) Included trials
/0.63 (/3.21, 1.95) Tran [16] /0.97 (/3.86, 1.92) Tran [16]
/2.88* ( /5.20, /0.57) Tran [16]; Gureje [17]; Purdon [45] /3.23* ( /6.00, /0.46) Tran [16]; Gureje [17]
CGI-severity changeb WMD (95% CI) Included trials
0.00 (/0.23, 0.23) Tran [16]
/0.42 (/1.10, 0.27) Tran [16]; Gureje [17]
]/20% PANSS improvementa OR (95% Included trials ]/30% PANSS improvementa OR (95% Included trials ]/40% PANSS improvementa OR (95% Included trials ]/50% PANSS improvementa OR (95% Included trials PANSS total changeb WMD (95% CI) Included trials
CI) CI) CI) CI)
Olz vs risp via hal short term
Olz vs risp via hal short term (clinical doses)
/0.01 (/0.53, 0.51) Olz vs hal: Tollefson [31]; Beasley [46]; Beasley47 Risp vs hal : Blin [51]; Borison [52]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Marder [21]; Min [59]; Peuskens [20]; Wirshing [25]; Zhang [60] /
0.08 (/0.88, 1.04) Olz vs hal : Tollefson [31]; Beasley [47] Risp vs hal : Peuskens [20]; Wirshing [25]
/
/
/
/
/
/
/1.68 (/4.77, 1.40) Olz vs hal : Tollefson [31]; Beasley [46] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Liu [57]; Marder [21]; Peuskens [20] /0.64 (/1.59, 0.30) Olz vs hal : Tollefson [31]; Beasley [46] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Liu [57]; Marder [21]; Peuskens [20] /0.53 (/1.48, 0.42) Olz vs hal : Tollefson [31]; Beasley [46] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Liu [57]; Marder [21]; Peuskens [20] /
/0.7 (/5.34, 3.94) Olz vs hal : Tollefson [31] Risp vs hal : Peuskens [20]
/
/0.6 (/1.97, 0.77) Olz vs hal : Tollefson [31] Risp vs hal : Peuskens [20] /0.6 (/2.08, 0.88) Olz vs hal : Tollefson [31] Risp vs hal : Peuskens [20] /
/0.96 (/2.75, 0.84) /0.76 (/3.36, 1.85) Olz vs hal : Tollefson [31]; Beasley [46]; Beasley [47] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Olz vs hal : Tollefson [31]; Marder [21]; Peuskens [20] Beasley [47] Risp vs hal : Peuskens [20] 0.09 (/0.32, 0.51) / Olz vs hal : includes Tollefson [31]; Beasley [46]; Beasley [47] Risp vs hal : Blin [51]; Chouinard [55]; Marder [21]
11
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; CI, confidence interval; GPS, General Psychopathology Scale; hal, haloperidol; olz, olanzapine; OR, odds ratio; PANSS, Positive and Negative Syndrome Scale; risp, risperidone; WMD, weighted mean difference; /, data not available. *P B/0.05 in favour of olanzapine, $0.055/ P B/ 0.1 in favour of olanzapine. a Dichotomous variables: ORs used for direct comparisons, difference (log OR) used for indirect comparisons. b Continuous variables: WMD used.
Olanzapine versus risperidone for schizophrenia
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Outcomes
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Outcomes
Anticholinergic usea OR (95% CI) Included studies
Dropouts / adverse eventsa OR (95% CI) Included studies
Dropouts / lack of efficacya OR (95% CI) Included studies
Dropouts / any reasona OR (95% CI) Included studies
Olz vs risp short term
Olz vs risp longer term
Olz vs risp via hal short term
Olz vs risp via hal short term (clinical doses)
0.65* (0.47, 0.90)
0.45* (0.29, 0.70)
0.97* (0.44, 1.50)
0.88* (0.41, 1.34)
Conley [44]; Tran [16]; Purdon [45]
Tran [16]; Purdon [45]; Gureje [17]
Olz vs hal : Tollefson [31]; Purdon [45]; Beasley [47] Risp vs hal : Peuskens [20]; Purdon [45]
0.88 (0.51, 1.51)
0.92 (0.47, 1.78)
Olz vs hal : Purdon [45]; Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Marder [21]; Purdon [45]; Peuskens [20]; Zhang [60] 0.20 (/0.31, 0.71)
Conley [44]; Tran [16]
Tran [16]; Purdon [45]
1.04 (0.52, 2.06)
0.66 (0.40, 1.10)
Conley [44]; Tran [16]
Tran [16]; Purdon [45]; Gureje [17]
0.81 (0.58, 1.13)
0.60* (0.42, 0.88)
Conley [44]; Tran [16]; Purdon [45]
Tran [16]; Purdon [45]; Gureje [17]
0.19 (/0.57, 0.95)
Olz vs hal : Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Mesotten [58]; Peuskens [20]; Wirshing [25]; Cavallaro [53]; Zhang [60] /0.09 (/0.74, 0.55)
Olz vs hal : Tollefson [31]; Beasley [47] Risp vs hal : includes Peuskens [20]; Wirshing [25]
Olz vs hal : Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Marder [21]; Mesotten [58]; Min [59]; Peuskens [20]; Wirshing [25]; Cavallaro [53]; Zhang [60] 0.13 (/0.31, 0.57)
Olz vs hal : Tollefson [31]; Beasley [47] Risp vs hal : includes Peuskens [20]; Wirshing [25]
Olz vs hal : Purdon [45]; Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Liu [57]; Marder [21]; Mesotten [58]; Min [59]; Purdon [45]; Peuskens [20]; Wirshing [25]; Cavallaro [53]; Zhang [60]
Abbreviations: CI, confidence interval; hal, haloperidol; olz, olanzapine; OR, odds ratio; risp, risperidone. *P B/0.05 in favour of olanzapine. a Dichotomous variables: ORs used for direct comparisons, difference (log OR) used for indirect comparisons.
/0.13 ( /1.17, 0.92)
0.15 (/0.70, 1.00) Olz vs hal : Tollefson [31]; Purdon [45]; Beasley [47] Risp vs hal : Peuskens [20]; Purdon [45]; Wirshing [25]
M. A. C. Mudge et al.
Table III. Safety and tolerability results.
Olanzapine versus risperidone for schizophrenia
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Table IV. Quality of life results. Outcomes
Olz vs risp short term
QLS total changea WMD (95% CI) QLS common objective and activities changea WMD (95% CI) QLS instrumental role changea WMD (95% CI) QLS interpersonal relations changea WMD (95% CI) QLS intrapsychic foundations changea WMD (95% CI)
2.39 (/1.24, 6.02) (includes Tran [16]) 0.33 (/0.13, 0.79) (includes Tran [16]) 0.14 (/0.91, 1.19) (includes Tran [16]) 0.84 (/0.75, 2.43) (includes Tran [16]) 1.10 (/0.37, 2.57) (includes Tran [16])
Olz vs risp longer term 5.23* (1.32, 9.15) (includes Tran [16]; Gureje [17]) 0.50$ (/0.02, 1.02) (includes Tran [16]; Gureje [17]) 0.40 (/0.70, 1.51) (includes Tran [16]; Gureje [17]) 2.53* (0.83, 4.23) (includes Tran [16]; Gureje [17]) 2.66 (/0.66, 5.98) (includes Tran [16]; Gureje [17])
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Abbreviations: CI, confidence interval; olz, olanzapine; QLS, Quality-of-Life Scale; risp, risperidone; WMD, weighted mean difference. *P B/0.05 in favour of olanzapine, $0.05 5/P B/0.1. a Continuous variables: WMD used.
An indirect analysis of olanzapine versus risperidone found no statistical difference in the overall estimated effect sizes. One reason for this may be the use of different efficacy measurements, including PANSS, BPRS, CGI and endpoint scores, to form an overall effect size. The diversity of symptoms measured by these scales could introduce bias into an overall effect size measurement and therefore the results should be interpreted with caution. Speed of onset of antipsychotic action was not examined in this meta-analysis. However, this can be an important consideration in treating acute psychotic symptoms [43], and it would be an interesting parameter to be studied in future meta-analyses of this kind. Similarly, it would be interesting to compare the effects of antipsychotics on additional parameters, such as cognition, that were not measured in these trials, and also other side-effects commonly associated with antipsychotic medications, such as weight gain or prolactogenic effect. This study is a comprehensive, methodologically sound and up-to-date meta-analysis of the best available data comparing the atypical agents olanzapine and risperidone. The results should reinforce the message to clinicians that not all ‘‘atypicals’’ are the same in terms of efficacy and side-effects. Further analyses comparing other atypical antipsychotics will provide information on therapeutic and safety differences between the atypical antipsychotics and help to establish efficacy for particular subgroups of patients. Such data will aid clinicians in their decision-making with respect to which drug will be best for each individual patient.
Key points . This meta-analysis was carried out to compare the efficacy and safety of olanzapine with risperidone in the treatment of schizophrenia using both a direct and an indirect approach
. Data from randomised, double-blind studies were analysed according to short- ( 5/12 weeks) and longer-term ( /12 weeks) treatment, and included all-doses analyses and a sensitivity analysis of clinically relevant doses . Olanzapine produced statistically significant improvements in efficacy and safety parameters compared with risperidone over both the short and longer term . Results from the sensitivity analyses of only clinically relevant doses further favoured olanzapine compared with the all-doses analyses Acknowledgements This study was supported by a grant from Eli Lilly Australia Pty Ltd. Editorial assistance was provided by Frank Pilling, BSc (Hons), Elixir Healthcare Education Pty Ltd. Statement of interest At no time did the authors agree with the sponsor that the publications of the results of this study would be contingent on the sponsor’s approval or censorship of the manuscript.
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[6] Cummins C, Stevens A, Kisely S. The use of olanzapine as a first and second choice treatment in schizophrenia. In: DEC report. Birmingham: West Midlands; 1998. p 1 /29. [7] Duggan L, Fenton M, Dardennes RM, et al. Olanzapine for schizophrenia. Cochrane Database Syst Rev 2000, issue 1; Art. No. CD001359. [8] Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A metaanalysis of randomized controlled trials. Schizophr Res 1999;35:51 /68. [9] Tuunainen A, Wahlbeck K, Gilbody SM. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database Syst Rev 2000, issue 2; Art. No. CD000966. [10] Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: Systematic overview and meta-regression analysis. Br Med J 2000;321:1371 /6. [11] Gilbody SM, Bagnall AM, Duggan L, Tuunainen A. Risperidone versus other atypical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev 2000, Issue 3; Art. No. CD002306. [12] Cheine M, Wahlbeck K, Rimon R. Pharmacological treatment of schizophrenia resistant to first-line treatment: A critical systematic review and meta-analysis. Int J Psychiatry Clin Pract 1999;3:159 /69. [13] Hunter RH, Joy CB, Kennedy E, et al. Risperidone versus typical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev 2003, issue 2; Art. No. CD000440. [14] Streiner DL. The case of the missing data: Methods for dealing with dropouts and other research vagaries. Can J Psychiatry 2002;47:68 /75. [15] Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553 /64. [16] Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407 /18. [17] Gureje O, Miles W, Keks N, et al. Olanzapine versus risperidone in the management of schizophrenia: A randomized double-blind trial in Australia and New Zealand. Schizophr Res 2003;61:303 /14. [18] Sacrista´n JA, Go´mez JC, Montejo AL, et al. Doses of olanzapine, risperidone, and haloperidol used in clinical practice: Results of a prospective pharmacoepidemiologic study. EFESO Study Group. Estudio Farmacoepidemiologico en la Esquizofrenia con Olanzapina. Clin Ther 2000;22:583 /99. [19] Kasper S. Risperidone and olanzapine: Optimal dosing for efficacy and tolerability in patients with schizophrenia. Int Clin Psychopharmacol 1998;13:253 /62. [20] Peuskens J. Risperidone in the treatment of patients with chronic schizophrenia: A multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Risperidone Study Group. Br J Psychiatry 1995;166:712 /33. [21] Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825 /35. [22] Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765 /74. [23] Williams R. Optimal dosing with risperidone: Updated recommendations. J Clin Psychiatry 2001;62:282 /9. [24] Heinrichs DW, Hanlon TE, Carpenter WT. The quality of life scale: An instrument for rating the schizophrenic deficit syndrome. Schizophr Bull 1984;10(3):388 /98.
[25] Wirshing DA, Marshall BD, Green MF, et al. Risperidone in treatment-refractory schizophrenia. Am J Psychiatry 1999;156:1374 /9. [26] Deeks J, Altman D, Bradburn M. Meta-analysis in context, 2nd ed. London: BMJ Publishing Group, 2001. [27] Emsley RA. Risperidone in the treatment of first-episode psychotic patients: A double-blind multicenter study. Risperidone Working Group. Schizophr Bull 1999;25:721 /9. [28] Schwartz TL, Nihalani N, Jindal S, Virk S, Jones N. Psychotic medication-induced obesity: a review. Obes Rev 2004;5:115 /21. [29] Lambert TJR, Velakoulis D, Pantelis C. Medical comorbidity in schizophrenia. Med J Aust 2003;178:S67 /70. [30] Lambert T, Pantelis C. Hares and tortoises: Differential neuroleptic-associated weight gain in the community. [Abstract.] 7th Biennial Australasian Schizophrenia Conference, 24 /26 October 2002, Sydney, Australia. [31] Tollefson GD, Beasley CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: Results of an international collaborative trial. Am J Psychiatry 1997;154:457 /65. [32] Enas GG, Goldstein DJ. Defining monitoring and combining safety information in clinical trials. Stat Med 1995; 14:1099 /111. [33] Von Frenckell R, Copp J, Essers H, Theeuwes A. Format/ content of overviews (integrated efficacy and safety report). Drug Info J 1995;29:503 /5. [34] McEntegart DJ. Pooling in integrated safety databases. Drug Info J 2000;34:495 /9. [35] Song F, Glenny AM, Altman DG. Indirect comparison in evaluating relative efficacy illustrated by antimicrobial prophylaxis in colorectal surgery. Control Clin Trials 2000;21:488 /97. [36] Prior C, Clements J, Rowett M. Atypical antipsychotics in the treatment of schizophrenia. Users’ experiences of treatments must be considered. Br Med J 2001;322(7291): 924 /5. [37] Taylor D. Atypical antipsychotics in the treatment of schizophrenia. Pragmatic considerations are important when considering which drug to prescribe. Br Med J 2001;322(7291):925. [38] Lee S. Atypical antipsychotics in the treatment of schizophrenia. Informed relationship between doctor and patient does not exist in many parts of the world. Br Med J 2001;322(7291):925 /6. [39] Anderson I. Atypical antipsychotics in the treatment of schizophrenia. Users’ views are important. Br Med J 2001;32(7291):926. [40] Rowsell R, Link C, Donoghue J. Atypical antipsychotics in the treatment of schizophrenia. Validity of dropout rates as proxy measure of tolerability is unknown. Br Med J 2001;322(7291):925. [41] Remington G, Kapur S. Atypical antipsychotics: Are some more atypical than others? Psychopharmacology 2000; 148:3 /15. [42] Tamminga CA. ‘‘New’’ rather than ‘‘atypical’’. Psychopharmacology 2000;148:20 /1. [43] Tohen M, Jacobs TG, Feldman PD. Onset of action of antipsychotics in the treatment of mania. Bipolar Disorders 2000;2:261 /8. [44] Conley R, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765 /74. [45] Purdon SE, Jones BD, Stip E, et al. Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Arch Gen Psychiatry 2000;57:249 /58. [46] Beasley CM, Hamilton SH, Crawford AM, et al. Group TOES. Olanzapine versus haloperidol: acute-phase results of
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[54] Ceskova E, Svestka J. Double-blind comparison of risperidone and haloperidol in schizophrenic and schizoaffective psychoses. Pharmacopsychiatry 1993;26:121 /4. [55] Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13:25 /40. [56] Claus A, Bollen J, De Cuyper H, et al. Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study. Acta Psychiatr Scand 1992;85:295 /305. [57] Liu SK, Chen WJ, Chang CJ, Lin HN. Effects of atypical neuroleptics on sustained attention deficits in schizophrenia: A trial of risperidone versus haloperidol. Neuropsychopharmacology 2000;22:311 /9. [58] Messotten F. Risperidone versus haloperidol in the treatment of chronic psychotic patients: A multicentre doubleblind study. Clinical research report. RIS-INT-2, 1991; N 85163 (unpublished data, Janssen). [59] Min SK, Rhee CS, Kim CE, Kang DY. Risperidone versus haloperidol in the treatment of chronic schizophrenic patients: A parallel group double-blind comparative trial. Yonsei Med J 1993;34:179 /90. [60] Zhang XY, Zhou DF, Cao LY, et al. Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: A randomised double-blind study. Int Clin Psychopharmacol 2001;16:325 /30.
REVIEW ARTICLE
A comparison of olanzapine versus risperidone for the treatment of schizophrenia: a meta-analysis of randomised clinical trials
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MIA A. C. MUDGE1, PETER J. DAVEY1, KRISTINA A. COLEMAN1, WILLIAM MONTGOMERY2, VICTORIA S. CROKER2, KAREN MULLEN2 & DAVID J. CASTLE3 1
M-TAG, Chatswood West NSW, Australia, 2Eli Lilly Australia, West Ryde NSW, Australia and 3Mental Health Research Institute & University of Melbourne, Victoria, Australia
Abstract Objective. This meta-analysis was carried out to compare the efficacy and safety of olanzapine with risperidone in the treatment of schizophrenia. Methods. Data from randomised, double-blind studies were analysed according to short(5/12 weeks) and longer-term ( /12 weeks) treatment, and included all-doses analyses and a sensitivity analysis of clinically relevant doses. A range of efficacy and safety parameters was measured. Results. Olanzapine produced statistically significant improvements in efficacy and safety parameters compared with risperidone over both the short and longer term. Anticholinergic use, study dropouts, changes in Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores, and Quality-of-Life Scale changes, were often significantly in favour of olanzapine. Results from the sensitivity analyses of only clinically relevant doses further favoured olanzapine compared with the all-doses analyses. Conclusion. Small changes in the presence or severity of psychotic symptoms and side-effects can affect a patient’s prognosis and quality of life. With this in mind, the efficacy and safety advantages of olanzapine suggested by this study may convey clinical relevance to certain aspects of schizophrenia. However, further research / especially into longerterm efficacy and safety / is needed to confirm the differences between the available antipsychotics.
Key Words: Meta-analysis, efficacy, antipsychotics, olanzapine, risperidone
Introduction The relative merits of available antipsychotic medications for schizophrenia are not fully established, and treatment decisions are complex [1]. Advantages have been reported for the newer ‘‘atypical’’ antipsychotic agents, including a lower potential for movement disorders [2] and a greater effect on negative symptoms [3,4]. To date, however, metaanalyses that have compared these agents with older ‘‘typical’’ antipsychotics have produced inconsistent results [5 /12]. Some previous analyses have found advantages with the newer ‘‘atypical’’ agents [5 /9,12], while other studies have returned more equivocal results [10,11]. Indeed, the meta-analysis by Geddes et al concluded that there is insufficient evidence that atypical agents are more effective or better tolerated than conventional agents in the treatment of schizophrenia [10].
There are a number of methodological differences that could account for these diverse results, including the grouping together of atypical and typical antipsychotics and the use of odds ratios in some studies and relative risk in others. Another factor contributing to inconsistent conclusions of previous meta-analyses is that in many fixed-dose trials, patients receive subtherapeutic or supratherapeutic levels of medication. Subtherapeutic doses have the potential to limit efficacy gains that would likely be seen in clinical practice, while supratherapeutic doses can exacerbate side-effects / such as extrapyramidal symptoms (EPS) / over what would normally be seen clinically. Some metaanalyses have failed to control for this factor, or have controlled for clinically relevant doses of some agents but not others [5/7]. The current meta-analysis aimed to address these methodological shortfalls. In particular, clear distinctions were drawn regarding which agents were
Correspondence: Peter J. Davey, M-TAG, PO Box 5639, Chatswood West NSW 1515, Australia. Tel: /61-2-9419-7722. Fax: /61-2-9419-7922. E-mail: [email protected]
(Received 20 January 2004; accepted 19 November 2004) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510014783
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being compared; ‘‘clinically relevant’’ doses were established and interrogated in the analysis; randomeffects rather than fixed-effect statistics were applied in cases of heterogeneity between studies; and results were presented as odds ratios rather than risk ratios. Olanzapine and risperidone, two well-tolerated and efficacious atypical antipsychotic agents, were chosen as the focus for this analysis as they are two of the most commonly prescribed antipsychotic agents used globally in the treatment of schizophrenia.
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Aims There were two main aims of this study. The first was to compare the atypical antipsychotics olanzapine and risperidone using head-to-head trials. The second was to compare olanzapine indirectly with risperidone via a common comparator, haloperidol. This indirect analysis was essential to supplement the few published data directly comparing olanzapine with risperidone. Methods All appropriate randomised double-blind studies comparing the efficacy and safety of olanzapine with risperidone were included. For the common comparator analysis, all studies comparing olanzapine or risperidone with haloperidol were retrieved. Studies were identified via several routes. For the direct head-to-head comparison between olanzapine and risperidone, the Cochrane review, Olanzapine for Schizophrenia by Duggan et al [7], provided the basis for identifying relevant trials. This was current in mid-1999, hence further systematic searches of MEDLINE, EMBASE and the Cochrane Clinical Trials Register were also carried out to capture all additional trials published up to the search date of March 2001, using the Cochrane Schizophrenia Group’s search strategy. This search was updated in June 2002. Studies excluded from this meta-analysis included those not randomised, not double-blind, wrong outcomes measured, no comparator used, different comparator used to those analysed in this study, medications switched, and medications given after previous therapy failure. Furthermore, studies were excluded if patients treated with haloperidol received benztropine while the other treatment arm(s) received placebo, as this may have influenced the results. Unpublished data of olanzapine versus risperidone and olanzapine versus haloperidol were also included. Details of the search strategies used, and of papers included or excluded, can be obtained from the authors. For the indirect common-comparator analysis, trials comparing olanzapine with haloperidol were identified by the search strategy described above. Trials comparing risperidone with haloperidol were
identified in a similar manner via the most recent Cochrane reviews of risperidone [13], again supplemented by searches using MEDLINE, EMBASE and the Cochrane Clinical Trials Register to identify trials published up to June 2002. Data analysis Although some studies analysed data on an evaluable-patients basis, for this meta-analysis all dichotomous efficacy data were analysed on a full intention-to-treat (ITT) basis (i.e. all randomised patients were included in the denominator); for all safety and tolerability analysis, only treated patients were included in the denominator. Data from continuous efficacy scales were analysed using the last observation carried forward (LOCF) method [14], and all patients with at least one post-baseline score were assessed. This included over 90% of randomised patients for all but one trial [15]. The LOCF imputation method may lead to invalid inferences if the underlying difference between treatment groups, with respect to the outcome of interest, changes uniformly over time. For the trials being considered, it was assumed that patients who dropped out got worse. However, using LOCF to impute missing final values was considered to be conservative in this case, as the difference between olanzapine and risperidone treatment groups would have been more in favour of the olanzapine groups had the patients who dropped out been measured at the endpoint Quality of life was analysed in the head-to-head olanzapine versus risperidone comparison only, as this outcome was available for only two studies. This analysis included all patients who had baseline and post-baseline measures at 8 and 28 weeks for the trial by Tran et al [16] and at 30 weeks for the study by Gureje et al [17]. This included approximately 71% of patients in the short- and long-term analyses of the Tran study and 95% of patients in the Gureje study. Primary analyses Olanzapine was compared with risperidone over the short term ( 5/12 weeks) and longer term (/12 weeks). To supplement the results of the direct method of comparison, an indirect comparison was made between olanzapine and risperidone over the short term, via a common comparator, haloperidol. Sensitivity analyses of clinically relevant doses All studies included in the head-to-head comparisons were flexible-dosing studies in which the dose was titrated according to each individual patient’s needs. Hence, the direct comparison between olan-
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Olanzapine versus risperidone for schizophrenia zapine and risperidone is based on all doses used in these studies. Many of the trials used in the common comparator analyses were fixed-dose trials, which included subtherapeutic and supratherapeutic doses of haloperidol and risperidone. Therefore, in addition to an all-dose analysis, a more clinically relevant sensitivity analysis was conducted including only those doses of antipsychotic agents deemed to be ‘‘clinically relevant’’ according to current clinical use. ‘‘Clinically relevant’’ doses were determined from both the Product Information and from doses reported in recently published literature. For fixed dose trials, the relevant treatment arms were included in the sensitivity analysis. For flexible dose trials, the mean daily dose and/or the mean dose plus or minus one standard deviation was required to fall within the dose range deemed to be clinically relevant, in order to be included in this analysis. The following dose ranges were selected as clinically relevant.
Olanzapine. According to the Product Information, the starting dose should be 5 /10 mg/day, and may be adjusted up to 20 mg/day after clinical reassessment. Clinical experience suggests mean doses are about 13 mg/day [18,19]. Hence, for the purposes of this trial, the clinically relevant dose of olanzapine was considered to be 10 /15 mg/day [19].
Risperidone. The Product Information states that the dose range should be 4/6 mg/day. This is in line with clinical practice, and the results of dose-ranging studies [18,19]. Thus 4 /6 mg/day was considered to be the clinically relevant dose [19 /21].
Haloperidol. The Product Information states that doses of 1 /5 or 5 /15 mg/day should be used, depending on whether the patient has moderate or severe symptoms. Doses of 5 /15 mg/day were therefore considered to be clinically relevant. This is in line with recent clinical practice [18,21].
5
. Response rate at a number of levels of Positive and Negative Syndrome Scale (PANSS) scores (direct analysis only). . Mean change from baseline scores in PANSS total, PANSS positive, PANSS negative and PANSS general psychopathology scales, Brief Psychiatric Rating Scale (BPRS) total and Clinical Global Impression (CGI) severity scale. . Number of patient discontinuations for (i) any reason, (ii) adverse events, and (iii) lack of efficacy. . Number of patients requiring anticholinergic medication / an indication of the extent of EPS. . Mean change from baseline score in the Quality-of-Life Scale (QLS) [24]. Statistical methods All analyses (using Meta View version 4 software) were carried out on an ITT basis, apart from the analyses of mean change from baseline of efficacy or quality of life (QoL) scales, in which patients were required to have at least one post-baseline measure to calculate the change. This captured 91% of patients in all trials, apart from the trial by Wirshing et al. [25], in which only 85% of randomised patients were included in the efficacy analysis, and the trial by Tran et al. [16], where 71% of patients were included in the QoL analysis. Dichotomous variables such as discontinuations, anticholinergic use and response rates were assessed using odds ratio and risk difference analyses, while continuous variables were assessed using weighted mean difference analyses. Non-heterogeneous comparisons (x2-test for heterogeneity ]/0.05) were calculated using the fixed-effects method, with heterogeneous comparisons (determined by x2-test for heterogeneity B/0.05 and visual inspection of Forest plots) being calculated using the randomeffects method. A P value of B/0.05 was taken as the level of significance for all comparisons. Indirect comparison methodology
The doses selected represent an assessment of the highest level of evidence from randomised clinical trials and are supported by recent dosing recommendations [22,23]. Outcomes for pooling The following outcomes were selected for pooling. . Number of patients achieving a clinical response, according to that study’s protocol (indirect atypical analyses only; see Table Ib and Table Ic for definitions of clinical response for each trial).
For the indirect comparison of olanzapine versus risperidone via the common comparator, haloperidol, the following methodology was used. First, olanzapine and risperidone were each compared with haloperidol and the odds ratio (for dichotomous outcomes) and weighted mean difference (for continuous outcomes) results were calculated. For dichotomous outcomes, results were then compared indirectly for each study drug (olanzapine versus haloperidol compared with risperidone versus haloperidol) using meta-regression statistical analyses [24]. This approach extends a randomeffects meta-analysis to estimate the extent to which
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M. A. C. Mudge et al.
one or more covariates account for differences between treatment effects. In this case, the treatment effect is the log odds ratio, although the results can be back-transformed and interpreted on the odds ratio scale. The covariates of interest are the different comparisons in a set of studies with a common outcome. By definition, if only a single study is included in a set, no comparison can be made as the covariate only takes one value; the same applies to a set of studies with the same comparator. For continuous outcomes, normal approximation of each pair of confidence intervals was carried out to get point estimates, estimated standard errors and a zstatistic. There is a one-to-one correspondence between odds ratios and log odds ratios: values of odds ratios greater than 1 will be positive on the log odds ratio scale while values of odds ratios less than 1 will be negative on the log odds ratio scale. Results Four randomised controlled trials (RCTs) that directly compared olanzapine with risperidone were included in the meta-analysis (Table Ia). This direct comparison was supplemented by a common comparator analysis that included seven RCTs comparing olanzapine with haloperidol (Table Ib) and 15 RCTs comparing risperidone with haloperidol (Table Ic). The results of selected drug-pair comparisons are shown in Figures 1/4 and data on all outcomes assessed are presented in Tables II /IV. Although results presented here are primarily based on the odds ratio statistic, parallel analysis via the method of risk difference revealed essentially similar results (data not shown). Short term Olanzapine and risperidone were compared directly and indirectly using a common comparator analysis via haloperidol (Tables Ia /c). Over the short term, the direct comparison revealed a significant difference in anticholinergic use in favour of olanzapine (Figure 1, Table III). Anticholinergic use was also significantly different in favour of olanzapine in the indirect comparison via haloperidol, both in the alldose analysis and in the sensitivity analysis that included only clinically relevant doses of olanzapine, risperidone and haloperidol (Figure 1, Table III).
For those other outcomes included in both analyses, the results of the indirect comparison via haloperidol were similar to the results of the shortterm direct comparison, with the exception of the weighted mean difference in PANSS positive change. However, none of these outcomes were statistically significant. Longer term Over the longer term, trends seen in short-term studies became more pronounced. Significant differences in favour of olanzapine were found in the odds ratios for the following dichotomous outcomes: anticholinergic use (Figure 1, Table III), dropouts for any reason (Figure 2, Table III), and patients responding with ]/40 and ]/50% improvement in PANSS score (Table II). For continuous outcomes, the weighted mean difference was significantly in favour of olanzapine for PANSS total change (Figure 3, Table II), PANSS negative change, PANSS general psychopathology change, BPRS total change (Figure 4, Table II), QLS total change, and QLS interpersonal relations change (Table IV). Discussion The meta-analysis reported here suggests that olanzapine exhibits a favourable clinical profile with significant benefit found for a number of efficacy and safety parameters versus risperidone. Clinical relevance of findings While advantages were seen with olanzapine in a number of parameters, differences were small and the clinical relevance of these advantages remains unclear. What is clear, however, is that even small changes in the presence or severity of symptoms and side-effects can affect a patient’s prognosis and quality of life. Given the high attrition rates encountered in schizophrenia studies (as in clinical practice), many studies have limitations, which necessarily have an influence in the current meta-analysis. It is therefore difficult to draw strong conclusions about future clinical practices. Further research / especially into the efficacy and safety of these agents over the longer
Table Ia. Olanzapine versus risperidone studies included in the meta-analysis.
Study
Study duration
Conley [44] 8 weeks Tran [16] 28 weeks (unpublished 8-week data available also) Gureje [17] 30 weeks Purdon [45] 12 months (6-week data available also for some outcomes)
Total no. of patients 407 339 65 42a
Daily dose of antipsychotic
Olanzapine Olanzapine Olanzapine Olanzapine
5 /20 mg, risperidone 2 /6 mg 10 /20 mg, risperidone 4 /12 mg 10 /20 mg, risperidone 4 /8 mg 5 /20 mg, risperidone 4 /10 mg
a Trial included three arms comparing olanzapine, risperidone and haloperidol. Of the total of 65 patients randomised in this trial, 42 were in the olanzapine and risperidone arms.
Excludeda Excluded Excluded Includeda (44)
Included (1996)
Includedb (202)
Excluded
Methodological issues
mg/day (12.4 mg) mg (mean not given) mg (mean not given) mg (11.0 mg) 24 31 54 44 weeks weeks weeks monthsc 14 14 14 12 Altamura [48] Tran [49] Zhang [50] Purdon [45]
Abbreviations: BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation. a Sensitivity analysis was only undertaken in the short term for the comparison of olanzapine and haloperidol. b Olanzapine 10 mg and 15 mg9/2.5 mg. c Data available at 6 weeks also.
(12.3 mg) (mean not given) (mean not given) (9.7 mg) 5 /20 5 /20 5 /20 5 /20 5 /20 5 /20 5 /20 5 /20
mg mg mg mg
5 /20 mg (11.8 mg) 5 /20 mg (13.2 mg) 6 weeks Tollefson [31]
1996
159/5 mg (16.49/4 mg) 5, 10, 159/2.5 mg (6.69/1.4, 11.69/1.5, 16.39/1.6 mg, respectively) 335 6 weeks Beasley [47]
7
term / is needed to confirm the differences suggested in this meta-analysis.
]/40% improvement in BPRS total score or endpoint BPRS total scoreB/18 ]/40% improvement in BPRS total score or endpoint BPRS total scoreB/18 in patients completing ]/ visit 7 ]/40% improvement in BPRS total score in patients completing ]/ 3 weeks of study ]/40% improvement in BPRS total score Not given ]/40% improvement in BPRS total score Non-relapser. Relapse defined as ]/ 20% worsening of PANSS scores or hospitalisation due to a change in psychopathology 159/5 mg 5, 10, 159/2.5 mg 431 6 weeks Beasley [46]
Definition of responder Daily dose of haloperidol (mean dose9/SD) Daily dose of olanzapine (mean dose9/SD) Total no. of patients Study duration Study
Table Ib. Olanzapine versus haloperidol studies included in the indirect meta-analysis.
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Inclusion in the sensitivity analysis (N )
Olanzapine versus risperidone for schizophrenia
The x2-test for heterogeneity was used to identify comparisons in which there was significant heterogeneity. However, in some cases this test lacks the power to detect heterogeneity, particularly when there are few studies [26]. In this meta-analysis, the majority of heterogeneous results came from the all-doses analyses of olanzapine versus haloperidol and risperidone versus haloperidol, and of the different outcomes examined, in the analysis of responders. This is as expected given the wide range of doses and different definitions of response for each trial. Meta-regression of summary data may lead to incorrect inferences when the treatment, or other effect of interest, is confounded with further variables being examined as potential sources of heterogeneity. However, the only variable included in each meta-regression model in these analyses was the treatment group of interest, in order to estimate the indirect difference between olanzapine and risperidone groups, via the common comparator (haloperidol). In general, the trials included patients with schizophrenia (without limiting the severity or duration of illness), although some also included patients with schizoaffective and schizophreniform disorders. Two trials included in the risperidone versus haloperidol analysis had restricted patient groups: in the study by Emsley et al [27], patients undergoing treatment for their first psychotic episode were included, while the study by Wirshing et al [25] included only patients considered to be treatment-resistant. However, these trials were included in the analysis as the patients made up only 10% of the available population for the risperidone versus haloperidol comparison. It should be noted that the more relevant clinical-dose analyses included few trials and hence there was little heterogeneity. In order to adjust for heterogeneity, the random-effects method, which makes an adjustment for the variation between individual studies, was used. Due to the differences in endpoints measured and lack of sufficient data provided in the included studies, changes in patients’ weight before and after antipsychotic treatment could not be included in this meta-analysis. Nearly all antipsychotics on the market today have been reported to cause weight gain [28]. In particular, those with high affinity for serotonin receptors like olanzapine have been shown to cause weight gain in the short-term [29]. In the longer-term, however, patients’ weight tends to stabilise and any form of weight gain is usually driven by other factors, such as lack of exercise, drug use, increased food intake, and poor
M. A. C. Mudge et al.
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Table Ic. Risperidone versus haloperidol studies included in the indirect meta-analysis.
Study Blin [51] Borison [52] Cavallaro [53] Ceskova [54] Chouinard [55] Claus [56] Emsley [27] Liu [57] Marder [21] Messotten [58] Min [59] Peuskens [20] Purdon [45]
Wirshing [25] Zhang [60]
Total no. Study duration of patients 4 6 6 8
weeks weeks weeks weeks
8 weeks 12 weeks 6 weeks 12 weeks 8 weeks 8 weeks 8 weeks 8 weeks 12 monthsc
41a 36 29 62 135 42 183 56 388 60 35 1362 44
Daily dose of risperidone (mean dose) 4 /12 2 /10 5 /10 2 /20
mg mg mg mg
(7.4 mg) (9.7 mg) (mean not given) (mean not given)
Daily dose of haloperidol (mean dose) 4 /12 4 /20 5 /10 2 /20
mg mg mg mg
(7.6 mg) (18.0 mg) (mean not given) (mean not given)
2, 6, 10, 16 mg 1 /10 mg (12.0 mg) 4 /16 mg (6.1 mg) No dose details given 2, 6, 10, 16 mg (9.1 mg) 5 /10 mg (mean not given) 1, 4, 8, 12, 16 mg 4 /10 mg (6.0 mg)
20 mg/day 1 /10 mg (10.3 mg) 4 /16 mg (5.6 mg) No dose details given 20 mg (9.4 mg) 5 /10 mg (mean not given) 10 mg 5 /20 mg (9.7 mg)
8 weeks
67
3 /5 mg (7.5 mg9/1.9)
5 /30 mg (19.4 mg9/5.6)
12 weeks
78
6 mg
20 mg
Definition of responder ]/20% improvement in PANSS total score ]/20% improvement in BPRS total score Not reported ]/25% improvement in BPRS total score (partial or good remission) ]/20% improvement in PANSS total score ]/20% improvement in PANSS total score ]/50% improvement in PANSS total score Not given ]/20% improvement in PANSS total score Not given ]/20% improvement in PANSS total score ]/20% improvement in PANSS total score Non-relapser. Relapse defined as ]/ 20% worsening of PANSS scores or hospitalisation due to a change in psychopathology ]/20% improvement in BPRS total score or total score B/35, and CGI severity score 5/ 3 ]/20% improvement in PANSS total score
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; PANSS, Positive and Negative Syndrome Scale. a Trial included three arms comparing risperidone, haloperidol and methotrimeprazine. Of the total of 65 patients in this trial, 41 were in the haloperidol and risperidone arms. b Risperidone 4 mg. c Data available at 6 weeks also.
Inclusion in the sensitivity analysis (N ) Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Excluded Includedb (453) Included (44)
Included (67) Excluded
Olanzapine versus risperidone for schizophrenia
9
1.4
1 0.8 0.6
Favours olanzapine
Odds ratio
1.2
Favours risperidone
1.6
0.4 0.2 0 Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 1. Effect of olanzapine versus risperidone on anticholinergic use for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
1.5
The indirect comparisons carried out to back-up the results from direct comparisons have limitations, given the varying trial conditions and patient prognostic factors across different trials [35]. However, to minimise any discrepancy arising from the difference between the conditions under which the data were obtained, the random-effects method was employed. In addition, all studies were double-blind, randomised controlled trials in patients with schizophrenia, thus trial characteristics are likely to have been similar. Further, the short-term comparison was completed using both the direct and indirect methods. The strikingly homologous results from these two analyses suggest that similar indirect comparison may provide equally reliable data in other comparisons for which there are no headto-head trials. Given the lack of direct comparisons between many of the atypical antipsychotics, this method may be useful [35] for future comparisons to
Favours risperidone
nutritional habits [30]. For example, in the olanzapine versus haloperidol study by Tollefson et al [31] included in our meta-analysis, the mean rate of weight gain over the first 6 weeks was 0.32 kg/week in olanzapine-treated patients (N /1996). This was reduced to 0.11 kg/week after 30 weeks of therapy and 0.07 kg/week after 52 weeks. When few or no direct head-to-head clinical trials exist, an indirect analysis between two active treatment arms can be performed via a common comparator (in this case the active comparator, haloperidol). There are a number of published studies and reviews that attest to the robustness of indirect meta-analysis methodology if strict procedural controls are used to restrict which outcomes are pooled [32 /34]. Indeed, using strict criteria for pooling data and analysis of heterogeneity enhances the validity of the procedure and prevents incorrect inferences that occur without sound methodology.
0.5
Favours olanzapine
1
Odds ratio
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Olz vs risp: short term
0
–0.5
–1 Olz vs risp: short term
Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 2. Effect of olanzapine versus risperidone on dropouts for any reason for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
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M. A. C. Mudge et al. 6
2 0 –2 Favours olanzapine
Weighted mean difference
4
–4 –6 –8 –10
Olz vs risp: short term
Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 3. Effect of olanzapine versus risperidone on weighted mean difference of PANSS total scores for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
help elucidate the relative merits of other atypical antipsychotics. Results versus results of other meta-analyses Some meta-analyses comparing antipsychotic agents support the findings of this study / that the efficacy of olanzapine is superior to haloperidol and risperidone [5,6,8,12]. However, these results differ from those of other meta-analyses in which olanzapine was found to be equivalent to other agents for safety and efficacy outcomes [7,10,11,15]. This could be due to methodological differences such as the use of different summary statistics, the inclusion of studies using drugs at doses different to those used in clinical practice, the under-rating of severe side-effects such as EPS, and the grouping of the newer agents into a single ‘‘atypical’’ group, so diluting the validity of conclusions drawn. The meta-
analysis by Geddes et al, in particular, has been criticised for insufficient recognition of the debilitating effects of EPS [36 /39], incorrect dosage considerations [37,39], and the grouping of all atypical drugs together [40]. There is no sound pharmacological or therapeutic basis for combining all atypical drugs together [41,42]. Data suggest that the efficacy of atypical antipsychotics is not equivalent, and analyses that group these agents together may downplay the efficacy of individual agents such as olanzapine via a ‘‘dilution’’ effect. In this study, only comparisons of single agents (olanzapine versus risperidone and olanzapine or risperidone versus haloperidol) were made, thus avoiding the diluting effects of grouping together agents with differing efficacy. The more recent meta-analysis conducted by Davis et al. [15] grouped a variety of efficacy endpoints to obtain an overall effect size estimate.
3 2 1 0 –1 –2 –3 –4 –5
Favours olanzapine
Weighted mean difference
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–12
–6 –7 Olz vs risp: short term
Olz vs risp: longer term
Olz vs risp via hal: short term
Olz vs risp via hal: short term (clinical doses)
Figure 4. Effect of olanzapine versus risperidone on weighted mean difference of BPRS total scores for both the direct and indirect analyses, including the sensitivity analyses using only clinically relevant doses.
Table II. Efficacy results. Olz vs risp short term
Respondersa OR (95% CI) Included trials
Olz vs risp longer term
/
/
0.99 (0.73, 1.34) Tran [16]; Conley [44] 1.12 (0.73, 1.73) Tran [16] 1.12 (0.69, 1.81) Tran [16] 1.18 (0.63, 2.21) Tran [16] /0.86 (/3.82, 2.11) Tran [16]; Conley [44]
2.01 (0.35, 11.48) Tran [16]; Gureje [17] 1.47$ (0.99, 2.17) Tran [16]; Gureje [17] 1.63* (1.05, 2.53) Tran [16]; Gureje [17] 1.91* (1.09, 3.37) Tran [16]; Gureje [17] /5.35* ( /10.15, /0.55) Tran [16]; Gureje [17]
PANSS positive changeb WMD (95% CI) Included trials
0.39 (/0.60, 1.37) Tran [16]; Conley [44]
/0.81 (/2.01, 0.39) Tran [16]; Gureje [17]; Purdon [45]
PANSS negative changeb WMD (95% CI) Included trials
/0.31 (/1.23, 0.61) Tran [16]; Conley [44]
/1.39* ( /2.66, /0.13) Tran [16]; Gureje [17]; Purdon [45]
PANSS GPS changeb WMD (95% CI) Included trials BPRS total changeb WMD (95% CI) Included trials
/0.63 (/3.21, 1.95) Tran [16] /0.97 (/3.86, 1.92) Tran [16]
/2.88* ( /5.20, /0.57) Tran [16]; Gureje [17]; Purdon [45] /3.23* ( /6.00, /0.46) Tran [16]; Gureje [17]
CGI-severity changeb WMD (95% CI) Included trials
0.00 (/0.23, 0.23) Tran [16]
/0.42 (/1.10, 0.27) Tran [16]; Gureje [17]
]/20% PANSS improvementa OR (95% Included trials ]/30% PANSS improvementa OR (95% Included trials ]/40% PANSS improvementa OR (95% Included trials ]/50% PANSS improvementa OR (95% Included trials PANSS total changeb WMD (95% CI) Included trials
CI) CI) CI) CI)
Olz vs risp via hal short term
Olz vs risp via hal short term (clinical doses)
/0.01 (/0.53, 0.51) Olz vs hal: Tollefson [31]; Beasley [46]; Beasley47 Risp vs hal : Blin [51]; Borison [52]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Marder [21]; Min [59]; Peuskens [20]; Wirshing [25]; Zhang [60] /
0.08 (/0.88, 1.04) Olz vs hal : Tollefson [31]; Beasley [47] Risp vs hal : Peuskens [20]; Wirshing [25]
/
/
/
/
/
/
/1.68 (/4.77, 1.40) Olz vs hal : Tollefson [31]; Beasley [46] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Liu [57]; Marder [21]; Peuskens [20] /0.64 (/1.59, 0.30) Olz vs hal : Tollefson [31]; Beasley [46] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Liu [57]; Marder [21]; Peuskens [20] /0.53 (/1.48, 0.42) Olz vs hal : Tollefson [31]; Beasley [46] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Liu [57]; Marder [21]; Peuskens [20] /
/0.7 (/5.34, 3.94) Olz vs hal : Tollefson [31] Risp vs hal : Peuskens [20]
/
/0.6 (/1.97, 0.77) Olz vs hal : Tollefson [31] Risp vs hal : Peuskens [20] /0.6 (/2.08, 0.88) Olz vs hal : Tollefson [31] Risp vs hal : Peuskens [20] /
/0.96 (/2.75, 0.84) /0.76 (/3.36, 1.85) Olz vs hal : Tollefson [31]; Beasley [46]; Beasley [47] Risp vs hal : Blin [51]; Chouinard [55]; Emsley [27]; Olz vs hal : Tollefson [31]; Marder [21]; Peuskens [20] Beasley [47] Risp vs hal : Peuskens [20] 0.09 (/0.32, 0.51) / Olz vs hal : includes Tollefson [31]; Beasley [46]; Beasley [47] Risp vs hal : Blin [51]; Chouinard [55]; Marder [21]
11
Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; CI, confidence interval; GPS, General Psychopathology Scale; hal, haloperidol; olz, olanzapine; OR, odds ratio; PANSS, Positive and Negative Syndrome Scale; risp, risperidone; WMD, weighted mean difference; /, data not available. *P B/0.05 in favour of olanzapine, $0.055/ P B/ 0.1 in favour of olanzapine. a Dichotomous variables: ORs used for direct comparisons, difference (log OR) used for indirect comparisons. b Continuous variables: WMD used.
Olanzapine versus risperidone for schizophrenia
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Outcomes
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Outcomes
Anticholinergic usea OR (95% CI) Included studies
Dropouts / adverse eventsa OR (95% CI) Included studies
Dropouts / lack of efficacya OR (95% CI) Included studies
Dropouts / any reasona OR (95% CI) Included studies
Olz vs risp short term
Olz vs risp longer term
Olz vs risp via hal short term
Olz vs risp via hal short term (clinical doses)
0.65* (0.47, 0.90)
0.45* (0.29, 0.70)
0.97* (0.44, 1.50)
0.88* (0.41, 1.34)
Conley [44]; Tran [16]; Purdon [45]
Tran [16]; Purdon [45]; Gureje [17]
Olz vs hal : Tollefson [31]; Purdon [45]; Beasley [47] Risp vs hal : Peuskens [20]; Purdon [45]
0.88 (0.51, 1.51)
0.92 (0.47, 1.78)
Olz vs hal : Purdon [45]; Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Marder [21]; Purdon [45]; Peuskens [20]; Zhang [60] 0.20 (/0.31, 0.71)
Conley [44]; Tran [16]
Tran [16]; Purdon [45]
1.04 (0.52, 2.06)
0.66 (0.40, 1.10)
Conley [44]; Tran [16]
Tran [16]; Purdon [45]; Gureje [17]
0.81 (0.58, 1.13)
0.60* (0.42, 0.88)
Conley [44]; Tran [16]; Purdon [45]
Tran [16]; Purdon [45]; Gureje [17]
0.19 (/0.57, 0.95)
Olz vs hal : Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Mesotten [58]; Peuskens [20]; Wirshing [25]; Cavallaro [53]; Zhang [60] /0.09 (/0.74, 0.55)
Olz vs hal : Tollefson [31]; Beasley [47] Risp vs hal : includes Peuskens [20]; Wirshing [25]
Olz vs hal : Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Marder [21]; Mesotten [58]; Min [59]; Peuskens [20]; Wirshing [25]; Cavallaro [53]; Zhang [60] 0.13 (/0.31, 0.57)
Olz vs hal : Tollefson [31]; Beasley [47] Risp vs hal : includes Peuskens [20]; Wirshing [25]
Olz vs hal : Purdon [45]; Beasley [46]; Beasley [47]; Tollefson [31] Risp vs hal : Blin [51]; Ceskova [54]; Chouinard [55]; Claus [56]; Emsley [27]; Liu [57]; Marder [21]; Mesotten [58]; Min [59]; Purdon [45]; Peuskens [20]; Wirshing [25]; Cavallaro [53]; Zhang [60]
Abbreviations: CI, confidence interval; hal, haloperidol; olz, olanzapine; OR, odds ratio; risp, risperidone. *P B/0.05 in favour of olanzapine. a Dichotomous variables: ORs used for direct comparisons, difference (log OR) used for indirect comparisons.
/0.13 ( /1.17, 0.92)
0.15 (/0.70, 1.00) Olz vs hal : Tollefson [31]; Purdon [45]; Beasley [47] Risp vs hal : Peuskens [20]; Purdon [45]; Wirshing [25]
M. A. C. Mudge et al.
Table III. Safety and tolerability results.
Olanzapine versus risperidone for schizophrenia
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Table IV. Quality of life results. Outcomes
Olz vs risp short term
QLS total changea WMD (95% CI) QLS common objective and activities changea WMD (95% CI) QLS instrumental role changea WMD (95% CI) QLS interpersonal relations changea WMD (95% CI) QLS intrapsychic foundations changea WMD (95% CI)
2.39 (/1.24, 6.02) (includes Tran [16]) 0.33 (/0.13, 0.79) (includes Tran [16]) 0.14 (/0.91, 1.19) (includes Tran [16]) 0.84 (/0.75, 2.43) (includes Tran [16]) 1.10 (/0.37, 2.57) (includes Tran [16])
Olz vs risp longer term 5.23* (1.32, 9.15) (includes Tran [16]; Gureje [17]) 0.50$ (/0.02, 1.02) (includes Tran [16]; Gureje [17]) 0.40 (/0.70, 1.51) (includes Tran [16]; Gureje [17]) 2.53* (0.83, 4.23) (includes Tran [16]; Gureje [17]) 2.66 (/0.66, 5.98) (includes Tran [16]; Gureje [17])
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Abbreviations: CI, confidence interval; olz, olanzapine; QLS, Quality-of-Life Scale; risp, risperidone; WMD, weighted mean difference. *P B/0.05 in favour of olanzapine, $0.05 5/P B/0.1. a Continuous variables: WMD used.
An indirect analysis of olanzapine versus risperidone found no statistical difference in the overall estimated effect sizes. One reason for this may be the use of different efficacy measurements, including PANSS, BPRS, CGI and endpoint scores, to form an overall effect size. The diversity of symptoms measured by these scales could introduce bias into an overall effect size measurement and therefore the results should be interpreted with caution. Speed of onset of antipsychotic action was not examined in this meta-analysis. However, this can be an important consideration in treating acute psychotic symptoms [43], and it would be an interesting parameter to be studied in future meta-analyses of this kind. Similarly, it would be interesting to compare the effects of antipsychotics on additional parameters, such as cognition, that were not measured in these trials, and also other side-effects commonly associated with antipsychotic medications, such as weight gain or prolactogenic effect. This study is a comprehensive, methodologically sound and up-to-date meta-analysis of the best available data comparing the atypical agents olanzapine and risperidone. The results should reinforce the message to clinicians that not all ‘‘atypicals’’ are the same in terms of efficacy and side-effects. Further analyses comparing other atypical antipsychotics will provide information on therapeutic and safety differences between the atypical antipsychotics and help to establish efficacy for particular subgroups of patients. Such data will aid clinicians in their decision-making with respect to which drug will be best for each individual patient.
Key points . This meta-analysis was carried out to compare the efficacy and safety of olanzapine with risperidone in the treatment of schizophrenia using both a direct and an indirect approach
. Data from randomised, double-blind studies were analysed according to short- ( 5/12 weeks) and longer-term ( /12 weeks) treatment, and included all-doses analyses and a sensitivity analysis of clinically relevant doses . Olanzapine produced statistically significant improvements in efficacy and safety parameters compared with risperidone over both the short and longer term . Results from the sensitivity analyses of only clinically relevant doses further favoured olanzapine compared with the all-doses analyses Acknowledgements This study was supported by a grant from Eli Lilly Australia Pty Ltd. Editorial assistance was provided by Frank Pilling, BSc (Hons), Elixir Healthcare Education Pty Ltd. Statement of interest At no time did the authors agree with the sponsor that the publications of the results of this study would be contingent on the sponsor’s approval or censorship of the manuscript.
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