Schizophrenia Bulletin vol. 36 no. 3 pp. 448–449, 2010 doi:10.1093/schbul/sbq030 Advance Access publication on April 5, 2010
COCHRANE CORNER
Risperidone Versus Placebo for Schizophrenia
Ranganath D. Rattehalli*,1, Mahesh B. Jayaram2, and Michael Smith2 1
North Yorkshire and York NHS Trust, York, UK; 2Leeds Partnerships NHS Foundation Trust, Leeds, UK
*To whom correspondence should be addressed; Assertive Outreach Team, 22 The Avenue, York YO30 6AS, UK; tel: 01904-553170, fax: 01904-553172, e-mail:
[email protected].
Key words: systematic review/meta-analysis/randomized clinical trials
Main Results We found 815 citations but were only able to include 10 studies (42 reports). One study (n = 599) compared risperidone with placebo but the attrition rate was 60% over a period of 6 weeks rendering most of the efficacy and global improvement data unusable. Overall, attrition rate was higher for placebo compared with risperidone (n = 1363, 10 randomized clinical trials (RCTs); RR 0.70, CI 0.57–0.86; NNT 13, CI 9–29) and less people left trials in the risperidone arm due to lack of efficacy (n = 888, 5 RCTs; RR 0.38, CI 0.20–0.73; NNT 7, CI 5–15). Risperidone was no better than placebo on Clinical Global Impression (CGI)-severity (n = 397, 3 RCTs; RR 0.80, CI 0.55–1.15) but significantly more participants in risperidone arms had more than 20% reduction in their Brief Psychiatric Rating Scale (BPRS)/Positive and Negative Syndrome Scale score (n = 856, 7 RCTs; RR 0.43, CI 0.32–0.58; NNT 7, CI 6–10) (figure 1). Data became considerably more homogeneous (and positive) when the one study independent of industry funding was removed (I2 75%–55%). Despite poor reporting, it is clear that around 24% of all participants receiving either risperidone or placebo developed some form of extrapyramidal effect (n = 723, 5 RCTs; RR 1.40, CI 0.93–2.10). Three people on risperidone had prolonged QTc (n = 198, 1 RCT; RR 7.5, CI 0.4–144), more on risperidone gained weight (n = 303, 2 RCTs; RR 5.14, CI 1.79–14.73; NNH 10, CI 3–51), and had raised prolactin levels (n = 323, 2 RCTs; RR 12.54, CI 5.11–30.79; NNH 3, CI 2–5). Fewer in the risperidone arm needed an additional psychotropic during the trial period (n = 186, 1 RCT; RR 0.62, CI 0.45–0.85; NNT 10, CI 7–28) (figure 2). Full version of this review is published on the Cochrane Library.1
Background Risperidone is the first new generation antipsychotic drug made available in the market in its generic form. Objectives To examine the clinical effects and safety of oral risperidone for people with schizophrenia and schizophrenialike psychoses in comparison with placebo. Search Strategy We searched the Cochrane Schizophrenia Group’s Register (February 2008), inspected references of all included studies, contacted industry, and authors of included studies for relevant studies and data. Selection Criteria We included all the randomized clinical trials comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia-like psychoses. Data Collection and Analysis Two reviewers independently inspected citations and/or abstracts, ordered papers, reinspected, and assessed the quality of results and extracted data. For dichotomous data, we calculated the relative risk (RR), the 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT), on an intention-to-treat basis. For continuous data, we calculated weighted mean differences.
Authors’ Conclusions Risperidone appears to have a marginal benefit in terms of clinical improvement compared with placebo in the
Ó The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email:
[email protected].
448
Risperidone Versus Placebo for Schizophrenia
Study or Subgroup Borison 1992 Marder 1994a Marder 1994b NCT00272584 Potkin 1997 Potkin 2003 Potkin 2006 Total (95% CI)
Risperidone Placebo Events Total Events Total Weight 5 27 6 28 30 60 48
12 63 22 34 85 99 152
12 50 19 25 44 79 29
467
Risk Ratio M-H, Fixed, 95% CI
4.7% 18.5% 7.1% 9.3% 16.6% 28.9% 14.8%
0.44 [0.23, 0.84] 0.55 [0.40, 0.75] 0.32 [0.16, 0.64] 1.12 [0.87, 1.44] 0.67 [0.47, 0.95] 0.79 [0.65, 0.96] 0.77 [0.54, 1.11]
389 100.0%
0..70 [0.62, 0.79]
12 64 22 34 83 103 71
Risk Ratio M-H, Fixed, 95% CI
258 Total events 204 Heterogeneity: Chi² = 24.06, df = 6 (P = 0.0005); I² = 75% Test for overall effect: Z = 5.62 (P < 0.00001)
0.1 0.2
0.5
1
Favours risperidone
2
5
10
Favours placebo
Fig. 1. Mental State; At Least 20% Reduction on BPRS/Positive and Negative Syndrome Scale Total Score. Risperidone Placebo Events Total Events Total Weight Study or Subgroup 1.2.1 no clinically significant improvement (CGI-S)
Risk Ratio M-H, Random, 95% CI
Marder 1994a 24 63 45 64 29.6% 28 NCT00272584 34 25 34 33.9% 60 Potkin 2003 99 79 103 36.5% Subtotal (95% CI) 196 201 100.0% 112 Total events 149 Heterogeneity: Tau² = 0.09; Chi² = 12.17, df = 2 (P = 0.002); I² = 84% Test for overall effect: Z = 1.21 (P = 0.23)
Risk Ratio M-H, Random, 95% CI
0.54 [0.38, 0.77] 1.12 [0.87, 1.44] 0.79 [0.65, 0.96] 0.80 [0.55, 1.15]
1.2.2 needing additional antipsychotic medicaitons 48 Potkin 2006 133 Subtotal (95% CI) 133 48 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.95 (P = 0.003)
31
53 100.0% 53 100.0%
0.62 [0.45, 0.85] 0.62 [0.45, 0.85]
15 100.0% 15 100.0%
0.92 [0.53, 1.61] 0.92 [0.53, 1.61]
31
1.2.3 needing concomitant sedative/hypnotic 8 Marder 1994b 13 10 Subtotal (95% CI) 13 Total events 8 10 Heterogeneity: Not applicable Test for overall effect: Z = 0.28 (P = 0.78)
0.01
0.1
1
10
100
Favours risperidone Favours placebo
Fig. 2. Global State.
first few weeks of treatment but data are surprisingly limited, poorly reported, and probably biased in favor of risperidone. The margin of improvement chosen by most researchers may not be clinically meaningful. There was very little to choose between risperidone and placebo for outcomes of global state, some efficacy measures and adverse events especially relating to cardiovascular and neurological effects. Although
risperidone is widely used, further independent trials can be justified. Reference 1. Rattehalli RD, Jayaram MB, Smith M. Risperidone versus placebo for schizophrenia. Cochrane Database Syst Rev. 2010;(1); Art. No.: CD006918. doi: 10.1002/14651858. CD006918.pub2.
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