Evid Based Mental Health: first published as 10.1136/ebmh.4.3.77 on 1 August 2001. Downloaded from Review: the benefit of atypical antipsychotics over standard drugs disappears after controlling for comparator dose Geddes J, Freemantle N, Harrison P,et al, for the National Schizophrenia Guideline Development Group. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000 Dec 2;321:1371–6. QUESTION: In patients with schizophrenia, are atypical antipsychotic drugs effective and tolerable for controlling symptoms? Data sources advantage for atypicalantipsychotic drugs as the dose of Studies were identified by searching Medline, EMBASE/ haloperidol increased; the benefit disappeared when Source of funding: UK Excerpta Medica, PsycLIT, and the Cochrane Controlled the haloperidol dose decreased. A similar effect was Department of Health. Trials Register. Additional trials were found by seen for chlorpromazine. For correspondence: contacting pharmaceutical companies and consulting Dr J Geddes, Cochrane group members. Conclusion Department of In patients with schizophrenia, atypical antipsychotic Psychiatry, University of Oxford, Warneford Study selection drugs reduce symptoms and dropout rates, but the Hospital, Oxford Studies were selected if they were randomised con- benefits do not remain after controlling for the dose of OX3 7JX, UK. Fax trolled trials (RCTs) comparing the effectiveness of conventional antipsychotic comparator drugs. +44 (0)1865 793 101. atypical and conventional antipsychotic drugs (restricted to compounds licensed in the UK) for treating schizophrenia and related disorders. Atypical v conventional antipsychotic drugs for schizophrenia and related disorders* Outcomes at Atypical Number Standardised mean Controls with Data extraction median 6.5 weeks antipsychotic of RCTs difference (95% CI) worse outcome† Data were extracted on patient inclusion and exclusion Overall symptom criteria, length of follow up, main outcome measures, reduction Amisulpride 4 −0.35 (−0.52 to −0.18) 64% (57 to 70) patient characteristics, overall symptom scores, quality of Clozapine 12 −0.68 (−0.82 to −0.55) 75% (71 to 79) life, dropout rates, side effects, and costs. Olanzapine 4 −0.22 (−0.30 to −0.14) 59% (56 to 62) Quetiapine 2 −0.03 (−0.23 to 0.18) Not significant Main results Risperidone 6 −0.15 (−0.27 to −0.04) 56% (52 to 61) 52 RCTs (12 649 patients) met the selection criteria. OR (CI) NNT (CI) Median follow up was 6.5 weeks. Most RCTs compared atypical antipsychotic drugs with haloperidol. Chlo- Dropout rate Amisulpride 4 0.6 (0.4 to 0.8) 9 (5 to 22) rpromazine was used in 7 RCTs; flupenthixol, per- Clozapine 20 0.5 (0.4 to 0.7) ST 31 (14 to 200) phenazine, and zuclopenthixol were used in 1 RCT LT4(2to5) each. Substantial heterogeneity existed among the Olanzapine 4 0.5 (0.4 to 0.6) 7 (6 to 9) http://ebmh.bmj.com/ RCTs, including those that compared the same atypical Quetiapine 2 0.7 (0.5 to 1.1) Not significant antipsychotic and comparator drugs. The table shows Risperidone 10 0.6 (0.5 to 0.7) 11 (7 to 19) the results. The dose of the comparator drug affected *LT=long term; OR=odds ratio; RCTs=randomised controlled trials; ST=short term. Other abbreviations defined in glossary. the outcome: in the 23 RCTs using haloperidol as †Proportion of patients in the control group with a worse outcome than the average patient in the experimental the comparator drug, meta-regression showed an group; see glossary. COMMENTARY on September 23, 2021 by guest. Protected copyright. This important review by Geddes et al will be of great interest to psychiatrists and service users alike. The review shows that the overall superior tolerability and effectiveness of atypical antipsychotics over standard antipsychotics disappear when the comparator dose is taken into account. Nevertheless, atypical antipsychotics maintain the benefit of fewer extrapyramidal side effects (EPS) after controlling for the effect of dose. The review uses a relatively new technique (meta-regression) to pool the results. Tolerability was measured using dropout rates as a proxy but patients may discontinue medication for many other reasons (eg, lack of efficacy or protocol violation). The authors also recommend that atypical antipsychotics should be reserved for second line use. Implicit in this judgement is that any advantage of atypicals over standard drugs with respect to EPS is small compared with a considerably greater cost. (The authors point out that data were not available for analysing EPS rates after controlling for dose by meta-regression, but they indicate that the EPS difference seemed relatively small.) Certainly, if EPS were shown to be the most common complaint of patients and the most important determinant of future compliance (or the atypicals were likely to lower rates of tardive dyskinesia in the future), then perhaps an atypical should have been recommended as first line. These issues are far from clear, however, and their recommendations seem reasonable given our current knowledge. Finally, given the median RCT duration of 6.5 weeks, the long term adverse effects of atypical antipsychotics, including substantial weight gain, are unknown.1 Although the review has certain limitations, it has some impressive strengths. Firstly, it is one of the first studies to systematically examine the effect of dose on the relative benefits of atypicals and standard drugs. Secondly, it avoids some of the problems associated with sensitivity analysis that examines the effect of dose by simply excluding those studies with higher doses of standard drug.2 Finally, it uses a set protocol and avoids the pitfalls of other more subjective material and the inherent biases of drug company sponsored information. Overall, the weaknesses of this review do not seriously undermine the findings, and it is currently the best available evidence addressing this important issue, although unlikely to be the final word. Andrew McIntosh, MB, ChB, MRCPsych Royal Edinburgh Hospital Edinburgh, UK 1 Duggan L, Fenton M, Dardennes RM, et al. Olanzapine for schizophrenia. Cochrane Database Syst Rev 2000;(2):CD001359. 2 Kennedy E, Song F, Hunter R, et al. Risperidone versus typical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev 2000;(2):CD000440. Therapeutics www.ebmentalhealth.com EBMH Volume 4 August 2001 77.