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Correspondence |
GGZ Delfland, St Jorisweg 2, 2612 GA Delft, The Netherlands
Dr Moncrieff (2003) re-analysed the data of a Cochrane meta-analysis by Wahlbeck et al (2000) on the comparison between clozapine and conventional antipsychotic drugs for treatment-resistant schizophrenia. After selecting nine randomised controlled trials and analysis she concluded that the Cochrane review might have overestimated the effects of clozapine as she found a lower overall effect. This was explained by the use of data from intention-to-treat analysis in the largest included study by Rosenheck et al (1997) and inclusion of the large study by Essock et al (1996), which was excluded in the Cochrane review.
There are good reasons for reporting the results from the studies by Rosenheck et al (1997) and Essock et al (1996) separately from the other seven studies rather than giving the overall results. These two studies are long-term studies with durations of 1 and 2 years, respectively. The study populations were much larger than most of the other studies, which were short-term studies lasting 6–29 weeks. The two long-term studies found a small to no difference in treatment effect between clozapine and the conventional antipsychotic. These results have a large negative impact on the overall effect because of the large study populations. However, the use of intention-to-treat analysis will result in smaller differences between the clozapine and control group the longer the study lasts, because drop-outs are classified as relapses irrespective of the reason for discontinuation. Longer studies tend to have larger drop-out rates, as is also apparent in this meta-analysis, resulting in smaller differences between study groups.
Reporting the results from the short-term and long-term studies separately will probably show that clozapine has a higher treatment effect than that reported by Moncrieff. Short-term studies explore the pharmacological efficacy of a medicine whereas long-term studies explore the treatment effect in daily practice and can be influenced by the patient’s willingness to continue treatment. These results should be reported separately.
REFERENCES
Essock, S. M., Hargreaves, W. A., Covell, N. H., et al (1996) Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacology Bulletin, 32, 683 -697.[Medline]
Moncrieff, J. (2003) Clozapine v.
conventional antipsychotic drugs for treatment-resistant schizophrenia: a
re-examination. British Journal of Psychiatry,
183, 161
-166.
Rosenheck, R., Cramer, J., Xu, W., et al
(1997) A comparison of clozapine and haloperidol in
hospitalized patients with refractory schizophrenia. Department of Veterans
Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.
New England Journal of Medicine,
337, 809
-815.
Wahlbeck, K., Cheine, M., Essali, M. A., et al (2000) Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Library, issue 3. Oxford:Update Software.
Mascalls Park, Rehabilitation Unit, Mascalls Lane, Brentwood, Essex CM14 5HQ, UK
Dr Karunakaran rightly points out some problems with the interpretation of the Essock et al (1996) naturalistic study of clozapine. However, despite its imperfections, that study deserves some attention, both because it was a large study and because its naturalistic design attempted to replicate the conditions in which clozapine would be given in real clinical practice. The randomisation was not imperfect but unbalanced. The study was indeed not blinded, but this usually favours the experimental treatment, in this case clozapine. Application of the Structured Clinical Interview for DSM–IV confirmed that 95% of cases had a diagnosis of schizophrenia or schizoaffective disorder. It is indeed difficult to decide what outcome data to use, as I mention in my paper. However, despite the number of crossovers, an intention-to-treat analysis in such a large sample would be expected to show some difference if the effect of clozapine is substantial. In the Kane et al (2001) study I did use intention-to-treat data, but also repeated the analysis with non-intention-to-treat data, because of the curiously high drop-out rate in the comparison group.
My analysis was meant to draw attention to the fact that results of different studies are quite discrepant. The largest study to date, and one that appears to be methodologically robust, found only slight differences between clozapine and haloperidol, which are of doubtful clinical relevance (Rosenheck et al, 1997). In this situation simply quoting the results of a meta-analysis may be misleading.
Dr Kho is right to point out that long-term studies find smaller effects. This cannot be attributed to drop-out rates in the Rosenheck et al (1997) study, at least, where the higher drop-out rate in the haloperidol group would tend to produce an inflated difference between clozapine and the comparator drug. We also cannot assume that short-term studies simply measure pharmacological effects and long-term studies are confounded by non-compliance. Drugs may have different short- and long-term pharmacological effects. Short-term studies might be more likely to be confounded by non-specific factors such as differential expectations of treatments.
REFERENCES
Essock, S. M., Hargreaves, W. A., Covell, N. H., et al (1996) Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacology Bulletin, 32, 683 -697.[Medline]
Kane, J., Marder, S. R., Schooler, N. R., et al
(2001) Clozapine and haloperidol in moderately refractory
schizophrenia: a 6-month randomized and double-blind comparison.
Archives of General Psychiatry,
58, 965
-972.
Rosenheck, R., Cramer, J., Xu, W., et al
(1997) A comparison of clozapine and haloperidol in
hospitalized patients with refractory schizophrenia. Department of Veterans
Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.
New England Journal of Medicine,
337, 809
-815.
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