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Atypical antipsychotics

Fulbourn Hospital, Cambridge CB1 5EF

Sir: Bebbington's conclusion that the new atypical antipsychotics are no more effective in reducing psychotic symptoms than their older counterparts (Psychiatric Bulletin, August 2001, 25, 284-286) may not apply to one of these drugs, clozapine.

Clozapine was re-introduced in 1989 on the basis of repeated indications of therapeutic superiority, which culminated in the Kane et al trial (McKenna & Bailey, 1993), not, as Bebbington suggests, as part of a strategy to develop drugs without extrapyramidal side-effects. Supporting this, the meta-analysis of Geddes et al (2000) found the effect size for clozapine's effectiveness over conventional neuroleptics to be 0.68, which falls between the values of 0.5 and 0.8 proposed by Cohen for ‘moderate’ and ‘large’, respectively. This is difficult to reconcile with Bebbington's statement that "the meta-analysis indicated that some of the atypical antipsychotics had slightly better efficacy". Geddes et al (2000) argued that the apparent superiority of atypical neuroleptics was owing to the high dose of comparison drug used in many of the studies. However, clozapine was the atypical neuroleptic in only 12 of the 30 studies included in their two meta-regressions. When the Cochrane Collaboration (Wahlbeck et al, 1999) compared clozapine trials using low doses and standard doses of the comparison drug, no difference in clinical improvement, relapse rate or drop-outs was found.

References

GEDDES, J., FREEMANTLE, N., HARRISON, P., et al (2000) Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ, 321, 1371-1376.[Abstract/Free Full Text]

McKENNA, P. J. & BAILEY, P. E. (1993) The strange story of clozapine. British Journal of Psychiatry, 162, 32-37.

WAHLBECK, K., CHEINE, M., ESSALI, A., et al (1999) Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. American Journal of Psychiatry, 156, 990-999.[Abstract/Free Full Text]

Authors' reply

McKenna criticises the basis on which Bebbington included clozapine in his conclusion that the newer neuroleptics had little therapeutic advantage over their older counterparts. While he may be right to conclude that clozapine is especially effective, our metaregression (Geddes et al, 2000) did appear to apply equally to all atypicals.

Part of the problem with a correct evaluation of the effectiveness of clozapine is that it is largely based on studies involving patients known to be resistant to treatment with conventional neuroleptics. Greater effectiveness in this context may merely be a reflection of effectiveness in a different client group. Equally, conventional neuroleptics would be almost bound to do better in a group of patients unresponsive to clozapine. Furthermore, there is now evidence that clozapine has no advantage over conventional neuroleptics in unselected patients with first episodes (Lieberman et al, 2001).

This is not to say that the clozapine lacks utility in people unresponsive to other medication, but it does bear on the claim that it should be a first-use drug.

References

LIEBERMAN, J. A., PHILLIPS, M., KONG, I. et al (2001) Efficacy and safety of clozapine versus chlorpromazine in first episode psychosis: results of a 52-week randomized double-blind trial. Abstracts of the VIIIth International Congress on Schizophrenia Research, April 2001. Schizophrenia Research, 49, special issue.

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