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Review: the benefit of atypical antipsychotics over standard drugs disappears after controlling for comparator dose
  1. Andrew McIntosh, MB, ChB, MRCPsych
  1. Royal Edinburgh Hospital Edinburgh, UK

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QUESTION: In patients with schizophrenia, are atypical antipsychotic drugs effective and tolerable for controlling symptoms?

Data sources

Studies were identified by searching Medline, EMBASE/Excerpta Medica, PsycLIT, and the Cochrane Controlled Trials Register. Additional trials were found by contacting pharmaceutical companies and consulting Cochrane group members.

Study selection

Studies were selected if they were randomised controlled trials (RCTs) comparing the effectiveness of atypical and conventional antipsychotic drugs (restricted to compounds licensed in the UK) for treating schizophrenia and related disorders.

Data extraction

Data were extracted on patient inclusion and exclusion criteria, length of follow up, main outcome measures, patient characteristics, overall symptom scores, quality of life, dropout rates, side effects, and costs.

Main results

52 RCTs (12 649 patients) met the selection criteria. Median follow up was 6.5 weeks. Most RCTs compared atypical antipsychotic drugs with haloperidol. Chlorpromazine was used in 7 RCTs; flupenthixol, perphenazine, and zuclopenthixol were used in 1 RCT each. Substantial heterogeneity existed among the RCTs, including those that compared the same atypical antipsychotic and comparator drugs. The table shows the results. The dose of the comparator drug affected the outcome: in the 23 RCTs using haloperidol as the comparator drug, meta-regression showed an advantage for atypicalantipsychotic drugs as the dose of haloperidol increased; the benefit disappeared when the haloperidol dose decreased. A similar effect was seen for chlorpromazine.

Atypical v conventional antipsychotic drugs for schizophrenia and related disorders*


In patients with schizophrenia, atypical antipsychotic drugs reduce symptoms and dropout rates, but the benefits do not remain after controlling for the dose of conventional antipsychotic comparator drugs.


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.


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  • Source of funding: UK Department of Health.

  • For correspondence: Dr J Geddes, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK. Fax +44 (0)1865 793 101.

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