Analyses of Treatment-Emergent Mania With Olanzapine/Fluoxetine Combination in the Treatment of Bipolar Depression

Paul E. Keck, Jr., M.D.; Sara A. Corya, M.D.; Lori L. Altshuler, M.D.; Terence A. Ketter, M.D.; Susan L. McElroy, M.D.; Michael Case, M.S.; Susan D. Briggs, Ph.D.; and Mauricio Tohen, M.D., Dr.P.H.

Background: Treatment-emergent mania is a potential risk when patients with bipolar disorder are treated with antidepressant agents. These subanalyses compare treatment-emergent mania rates in bipolar I depressed patients treated with olanzapine, placebo, or olanzapine/fluoxetine combination.

Method: In this 8-week, double-blind investigation, patients with bipolar I depression (DSM-IV criteria) (N = 833, baseline Montgomery-Asberg Depression Rating Scale total score > = 20) were randomly assigned to olanzapine (5-20 mg/day, N = 370), placebo (N = 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50 mg/day; N = 86). Treatment-emergent mania was evaluated with the Young Mania Rating Scale (YMRS), the Clinical Global Impressions-Bipolar Edition (CGI-BP) Severity of Mania scale, and adverse events records.

Results: Overall rates of study discontinuation due to mania were low and not significantly different among the therapy groups (p = .358). Incidence of treatment-emergent mania (defined as a YMRS score < 15 at baseline and > = 15 at any subsequent visit) did not differ significantly among therapy groups (olanzapine 5.7%, placebo 6.7%, olanzapine/fluoxetine combination 6.4%; p = .861). Subjects receiving olanzapine or olanzapine/fluoxetine combination had greater mean decreases in YMRS scores than those receiving placebo (p < .001 for both). Subjects receiving olanzapine or olanzapine/fluoxetine combination also had greater mean decreases in CGI-BP scores than those receiving placebo (p = .040 and p = .003, respectively).

Conclusion: These results suggest that olanzapine/fluoxetine combination does not present a greater risk of treatment-emergent mania compared to olanzapine or placebo over 8 weeks of acute treatment for bipolar I depression. Due to the cyclical nature of bipolar disorder, patients taking olanzapine/fluoxetine combination for bipolar depression should still be monitored for signs or symptoms of emerging mania.

(J Clin Psychiatry 2005;66:611-616)

Received June 7, 2004; accepted Nov. 2, 2004. From the Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine; Mental Health Service Line and General Clinical Research Center, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (Drs. Keck and McElroy); Lilly Research Laboratories, Indianapolis, Ind. (Drs. Corya, Briggs, and Tohen and Mr. Case); Department of Psychiatry, UCLA School of Medicine, Los Angeles, Calif. (Dr. Altshuler); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif. (Dr. Ketter); and the Department of Psychiatry, Harvard Medical School/McLean Hospital, Belmont, Mass. (Dr. Tohen).

This work was sponsored by Lilly Research Laboratories, study protocol F1D-MC-HGGY.

Portions of these data were presented at the following meetings: Society of Biological Psychiatry Annual Meeting, May 2003, San Francisco, Calif.; American Psychiatric Association Annual Meeting, May 2003, San Francisco, Calif.; New Clinical Drug Evaluation Unit Annual Meeting, May 2003, Boca Raton, Fla.; International Conference on Bipolar Disorder, June 2003, Pittsburgh, Pa.; European College of Neuropsychopharmacology Congress, September 2003, Prague, Czech Republic; Institute on Psychiatric Services, October 2003, Boston, Mass.; U.S. Psychiatric and Mental Health Congress, November 2003, Orlando, Fla.; International Forum on Mood and Anxiety Disorders, November 2003, Monte Carlo, Monaco.

Financial disclosure appears at the end of this article.

Corresponding author and reprints: Paul E. Keck, Jr., M.D., 7005 MSB, Cincinnati, OH 45267 (e-mail: paul.keck@uc.edu).