Antipsychotic augmentation for clozapine resistance

A European team published a meta-analysis of combining clozapine with another antipsychotic in 2007 which was not encouraging for this strategy. Nonetheless, clinicians have persisted in combining clozapine with either first or second-generation antipsychotics. Is this entirely irrational or do practicing psychiatrists know something that researchers don’t?

The same team has published an updated meta-analysis comprising a total of 14 studies, including some unpublished data, with 734 subjects. All the studies were randomized, blinded, placebo-controlled, and a minimum of six weeks in duration. The coadminstered antipsychotics included amisulpride, aripirprazole, chlorpromazine, haloperidol, pimozide, risperidone, sertindole, and sulpiride.

The combined reduction in symptom scores favored combined therapy with an effect size of -0.239 (P = 0.028) and 95% confidence intervals of -0.452 to -0.026. The investigators examined the duration of cotherapy and found no advantage for treatment lasting ten or more weeks compared with less than ten weeks.

The researchers concluded that combining clozapine with another antipsychotic may offer on average “a small benefit.” Although this is the largest such meta-analysis to date, it offers only limited clinical guidance. Determining which patients may benefit from addition of which antipsychotic remains the practitioners’ quandary.

Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic – a meta-analysis. Acta Psychiatr Scand. 2012;125:15–24.

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