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Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: A re-examination

  • Joanna Moncrieff (a1)
Abstract
Background

Although there is a consensus that clozapine is more effective than conventional antipsychotic drugs for treatment-resistant schizophrenia, there is great heterogeneity among results of relevant trials.

Aims

To re-evaluate the evidence comparing clozapine with conventional antipsychotics and to investigate sources of heterogeneity.

Method

Individual studies were inspected with assessment of clinical relevance of results. Meta-regression analysis was performed to investigate sources of heterogeneity.

Results

Ten trials were examined. Recent large-scale studies have not found a substantial advantage for clozapine, especially in terms of a clinically relevant effect. Meta-regression showed that shorter study duration, financial support from a drug company and higher baseline symptom score consistently predicted greater advantage of clozapine.

Conclusions

It may be inappropriate to combine studies in meta-analysis, given the degree of heterogeneity between their findings. The benefits of clozapine compared with conventional treatment may not be substantial.

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References
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The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
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Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: A re-examination

  • Joanna Moncrieff (a1)
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eLetters

A significant effect for clozapine despite variation between included studies

Michael D Hunter, Wellcome Training Fellow in Psychiatry
12 August 2003

The EditorBritish Journal of Psychiatry17, Belgrave SquareLondonSW1X 8PG

11th August 2003

Dear Sir

It was with great interest that I read Moncrieff’s (2003) re-examination of published evidence for the efficacy of clozapine, versus conventional antipsychotic drugs, in treatment-resistant schizophrenia. In that paper, particular emphasis was given to heterogeneity in results between studies included in the analyses; the author warned of ‘potential danger inherent in combining results from different studies while overlooking important variations between them’.

In calculating the overall effect size for clozapine, Moncrieff employed both fixed and random effects analyses. In the former the effectsize was 0.38 (95% confidence intervals 0.27-0.50) standard deviations andin the latter the effect size was 0.44 (0.15-0.73) standard deviations. Either method demonstrated a significant effect in favour of clozapine.

In contrast to fixed effects approaches, random effects analyses model both the variance within and between individuals (Bland, 2000). Random effects models can be statistically conservative (evidenced in Moncrieff’s paper by widening of the confidence intervals which, nonetheless, do not cross the point of equivalence) and allow inferences to be drawn regarding the effect of interest that are not confounded by the variance between individuals (or, in this case, individual studies).

Therefore, a parsimonious interpretation of Moncrieff’s analyses is that the current data sets demonstrate a significant effect for clozapine,in the pharmacotherapy of treatment-resistant schizophrenia, despite variation in results of individual studies.

Declaration of interestMDH has attended educational meetings sponsored by Novartis, the manufacturers of clozapine in the UK.

Bland, M. (2000) An Introduction to Medical Statistics. Oxford: Oxford University Press.

Moncrieff, J. (2003) Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. British Journal of Psychiatry, 183, 161-166.

Michael D HunterWellcome Training Fellow in PsychiatrySheffield Cognition and Neuroimaging Laboratory (SCANLab)Academic Clinical PsychiatryUniversity of SheffieldThe Longley CentreNorwood Grange DriveSheffield S5 7JT, UK.

T: +44 114 226 1514F: +44 114 226 1522
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Conflict of interest: None Declared

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