Author's reply

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.