W C Wirshing

BACKGROUND: We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain. METHOD: Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated. RESULTS: Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04). CONCLUSION: Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings.

The pharmacologic treatment of the schizophrenic patient has remained substantively unchanged during the last 35 years. It is evident that as our knowledge of neuropharmacology has grown--the notion of schizophrenia being merely caused by a hyperdopaminergic state may be too simplistic. Multiple neurotransmitter systems may be involved in the manifestations of this illness. Conventional neuroleptics--the mainstay of antipsychotic treatment--have proved to be only partially effective and their untoward side effects have led to notorious patient noncompliance and iatrogenic morbidity. The demonstration that clozapine possesses both increased efficacy and reduced neurotoxicity, however, has forever altered the conventional wisdom that held all antipsychotics to be equally efficacious and uniformly neurotoxic. The pharmacologic legacy of clozapine promises to provide clinicians with biologic therapies that are at once safe, effective, and easy to administer.