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Onset of antidepressant effect of olanzapine and olanzapine/fluoxetine combination in bipolar depression


  • SD, GDT, SDB, LEVanC, MC, and MT are employees and/or shareholders of Eli Lilly & Co. MET has served as a consultant to Eli Lilly & Co., as well as to AstraZeneca, Bristol-Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Novartis, Organon, Pfizer, and Wyeth. This work was sponsored by Lilly Research Laboratories, Eli Lilly & Co., study protocol F1D-MC-HGGY.

Sanjay Dubé, MD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Fax: +1 317 277 6286; e-mail:


Objectives:  The current analysis investigated the onset of antidepressant effect of olanzapine/fluoxetine combination.

Methods:  Data for these post hoc analyses were obtained from a clinical trial comparing olanzapine, placebo, and olanzapine/fluoxetine combination in bipolar depression (BD). Subjects were 833 patients with a DSM-IV diagnosis of bipolar I disorder, depressed. The Montgomery–Åsberg Depression Rating Scale measured depressive symptoms. Multiple analytic methods were applied, including traditional (mean differences) analysis, pattern analysis, survival analysis of sustained response, mixed-effects regression, and area-under-the-curve analysis.

Results:  Traditional analysis showed significantly greater improvement in depression scores at week 1 for olanzapine/fluoxetine combination versus placebo (−9.55 versus −5.08, p < 0.001) and for olanzapine versus placebo (−8.31 versus −5.08, p < 0.001). Pattern analysis revealed olanzapine/fluoxetine combination had a significantly greater percentage of early persistent responders than placebo or olanzapine (32.4% versus 12.7%, p < 0.001; and 18.3%, p < 0.05, respectively). Survival analysis showed a significantly shorter time to sustained response for the combination versus placebo (p < 0.001), for olanzapine versus placebo (p = 0.04), and for the combination versus olanzapine (p = 0.03). Mixed-effects regression analysis revealed a significant therapy-by-time interaction (p < 0.001). Early area-under-the-curve analysis revealed a significantly greater percentage of improvement for the combination versus placebo (26.7% versus 13.9%, p < 0.001) and for olanzapine versus placebo (22.0% versus 13.9%, p < 0.001).

Conclusions:  Based on consistent results from related methods of measuring onset, olanzapine/fluoxetine combination demonstrated rapid onset of antidepressant effect (within 7 days) compared to placebo that was sustained over 8 weeks of treatment in a sample of BD patients. Using multiple statistical techniques may help profile a drug's onset of effect.