Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania

Objective: Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania. Method: Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N=19) or treatment as usual (no clozapine) (N=19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study. Results: Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder. Conclusions: The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.