A Randomized, Double-Blind Comparison of Olanzapine/Fluoxetine Combination, Olanzapine, and Fluoxetine in Treatment-Resistant Major Depressive Disorder

Michael E. Thase, M.D.; Sara A. Corya, M.D.; Olawale Osuntokun, M.D.; Michael Case, M.S.; David B. Henley, M.D.; Todd M. Sanger, Ph.D.; Susan B. Watson, Ph.D.; and Sanjay Dubé, M.D.

Objective: Two parallel, 8-week double-blind studies compared olanzapine/fluoxetine combination, olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD).

Method: Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to olanzapine/fluoxetine combination, olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005.

Results: After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, olanzapine: -10.5). In Study 2, olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for olanzapine/fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and olanzapine (-8.8, p < .001). Pooled remission rates were 27% for olanzapine/fluoxetine combination, 17% for fluoxetine, and 15% for olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for olanzapine/fluoxetine combination, +0.8 for fluoxetine, and +2.7 for olanzapine. Mean weight change (kg) was +4.9 for olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for olanzapine.

Conclusion: Patients with TRD (defined as treatment failure on 2 antidepressants) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD.

Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00035321.

(J Clin Psychiatry 2007;68:224-236)

Received May 30, 2006; accepted Sept. 21, 2006. From the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pa. (Drs. Thase and Dubé); and Lilly Research Laboratories, Indianapolis, Ind. (Drs. Corya, Osuntokun, Henley, Sanger, Watson, and Dubé and Mr. Case).

This work was sponsored by Eli Lilly and Co., Indianapolis, Ind.

Dr. Thase is an advisor/consultant for AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, Neuronetics, Novartis, Organon, Sepracor, Shire US, and Wyeth and is a member of the speakers' bureaus for AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, Sanofi, and Wyeth. Drs. Corya, Osuntokun, Henley, Sanger, Watson, and Dubé and Mr. Case are employees of Eli Lilly.

Acknowledgments are listed at the end of this article.

Corresponding author and reprints: Michael E. Thase, M.D., University of Pittsburgh Medical Center, 3811 O'Hara St., Pittsburgh, PA 15213 (e-mail: thaseme@upmc.edu).