Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: post hoc analyses of 47-week data

Abstract

Background: Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania.

Methods: A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5-20 mg/day) to divalproex sodium (500-2500 mg/day) for bipolar manic or mixed episodes (N=251). Young Mania Rating Scale (YMRS) scores > or = 20 were required for inclusion. Patients were classified at study entry as "rapid cyclers" if they experienced > or = 4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline.

Results: A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p=0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p<0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific.

Limitations: Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account.

Conclusions: Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment.