Olanzapine/Fluoxetine Combination for the Treatment of Mixed Depression in Bipolar I Disorder: A Post Hoc Analysis

Objective: Mixed depression (ie, co-occurrence of syndromal depression and subsyndromal mania/hypomania) is a common variant of bipolar depression. However, its treatment is much understudied. The aim of the study was to assess the efficacy of the antipsychotic and mood-stabilizing agent olanzapine and the efficacy of the combination of an antidepressant (fluoxetine) and olanzapine (olanzapine/fluoxetine combination; OFC) for the treatment of bipolar I mixed depression.

Method: We carried out a post hoc analysis of an 8-week, double-blind trial of adult bipolar I depression treated with placebo (n‘ ‰=‘ ‰355), olanzapine (5-20 mg/d; n‘ ‰=‘ ‰351), or OFC (olanzapine/fluoxetine doses: 6/25, 6/50, 12/50 mg/d; n‘ ‰=‘ ‰82). Studying mixed depression was not a previous goal of the double-blind trial. Subjects in the trial were diagnosed according to DSM-IV and were randomly assigned to treatment during the period June 2000 to December 2001. Mixed depression was defined as the co-occurrence of a major depressive episode and‘ ‰ ≥‘ ‰2 manic/hypomanic symptoms (ie,‘ ‰≥‘ ‰2 Young Mania Rating Scale [YMRS] items scoring‘ ‰ ≥‘ ‰2). Response was defined as a‘ ‰ ≥‘ ‰50% reduction in Montgomery-Asberg Depression Rating Scale score and‘ ‰<‘ ‰2 concurrent manic/hypomanic symptoms. Switching to mania/hypomania was definedas a YMRS score‘ ‰ ≥‘ ‰15.

Results: Frequency of mixed depression was 45.1% in the OFC arm, 49.3% in the olanzapine arm, and 46.8% in the placebo arm (P‘ ‰=‘ ‰.705). The most frequent manic/ hypomanic symptoms of mixed depression were irritability, reduced need for sleep, talkativeness, and racing thoughts. Response rates in patients with nonmixeddepression versus patients with mixed depression were the following: in the OFC arm, 48.9% versus 43.2% (OR‘ ‰=‘ ‰1.24; 95% CI, 0.51-2.98); in the olanzapine arm, 39.9% versus 26.6% (OR‘ ‰=‘ ‰1.84; 95% CI, 1.17-2.90); in the placebo arm, 27.5% versus 16.3% (OR‘ ‰=‘ ‰1.94; 95% CI, 1.15-3.28). Response rates in the samples of patientswith mixed depression were the following: OFC versus olanzapine, OR‘ ‰=‘ ‰2.00 (95% CI, 0.96-4.19); OFC versus placebo, OR‘ ‰=‘ ‰3.91 (95% CI, 1.80-8.49); olanzapine versus placebo, OR‘ ‰=‘ ‰1.95 (95% CI, 1.14-3.34). It was found that no baseline manic/hypomanic symptom of mixed depression predicted treatment response. A higher number of baseline concurrent manic/hypomanic symptoms predicted a lower response rate in the olanzapine and placebo arms, but not in the OFC arm. The rates of switching were the following: in the OFC arm, 8.5%; in the olanzapine arm, 6.8%; and in the placebo arm, 7.9% (P‘ ‰=‘ ‰.808). The rates of dropouts in patients with mixed depression versus patients with nonmixed depression were not significantly different within any of the treatment arms. The rates of dropouts in the samples of patients with mixed depression were the following: in the OFC arm, 29.7%; in the olanzapine arm, 53.8%; and in the placebo arm, 59.6% (olanzapine vs OFC: OR‘ ‰=‘ ‰2.66; 95% CI, 1.23-5.75; placebo vs OFC: OR‘ ‰=‘ ‰3.48; 95% CI, 1.61-7.54; placebo vs olanzapine: OR‘ ‰=‘ ‰1.30; 95% CI, 0.84-2.01).

Conclusion: Olanzapine/fluoxetine combination may be an effective treatment for bipolar I mixed depression. Statistically, the efficacy of OFC was not significantly different from that of olanzapine, but inspection of the 95% CI showed a trend in favor of a possible superiority of OFC. Supporting the study findings are the similar efficacy of OFC in bipolar mixed depression independent of the number of concurrent manic/hypomanic symptoms, a lower dropout rate, and a similarly low switching rate compared to olanzapine. Contrary to other current limited evidence, an antidepressant (fluoxetine) showed efficacy and did not worsen bipolar mixed depression if combined with a mood-stabilizing agent (olanzapine).

Submitted: October 3, 2008; accepted January 2, 2009.

‘  Deceased.

Corresponding author: Franco Benazzi, MD, Via Pozzetto 17, 48015 Castiglione Cervia RA, Italy ([email protected]).