Olanzapine/Fluoxetine Combination for Treatment-Resistant Depression: A Controlled Study of SSRI and Nortriptyline Resistance

Richard C. Shelton, M.D.; Douglas J. Williamson, M.B.Ch.B., M.R.C.Psych.; Sara A. Corya, M.D.; Todd M. Sanger, Ph.D.; Luann E. Van Campen, Ph.D.; Michael Case, M.S.; Susan D. Briggs, Ph.D.; and Gary D. Tollefson, M.D., Ph.D.

Background: This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination.

Method: The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS).

Results: At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p <= .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies.

Conclusions: The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.

(J Clin Psychiatry 2005;66:1289-1297)

Received Jan. 17, 2005; accepted July 6, 2005. From the Department of Psychiatry, Vanderbilt University, Nashville, Tenn. (Dr. Shelton); and Lilly Research Laboratories, Indianapolis, Ind. (Drs. Williamson, Corya, Sanger, Van Campen, Briggs, and Tollefson and Mr. Case).

This work was sponsored by Eli Lilly and Company.

Portions of these data were presented at the 42nd annual meeting of the American College of Neuropsychopharmacology, December 2001, Waikaloa, Hawaii; the Association of European Psychiatrists 11th Congress, May 2002, Stockholm, Sweden; and the XII World Congress of Psychiatry, August 2002, Yokohama, Japan.

Dr. Shelton has received grant/research support from Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, Wyeth-Ayerst, AstraZeneca, and Abbott; has been a paid consultant for Pfizer and Janssen; and has participated on speakers bureaus for Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, GlaxoSmithKline, Wyeth-Ayerst, and Abbott. Drs. Williamson, Corya, Sanger, Van Campen, Briggs, and Tollefson and Mr. Case are employees of Eli Lilly and Company.

Acknowledgments are listed at the end of the article.

Corresponding author and reprints: Richard C. Shelton, M.D., Department of Psychiatry, Vanderbilt University, 1500 21st Ave. S., Nashville, TN 37212 (e-mail: richard.shelton@vanderbilt.edu).