Tachyphylaxis in Unipolar Major Depressive Disorder

David A. Solomon, M.D.; Andrew C. Leon, Ph.D.; Timothy I. Mueller, M.D.; William Coryell, M.D.; Jedediah J. Teres, B.S.; Michael A. Posternak, M.D.; Lewis L. Judd, M.D.; Jean Endicott, Ph.D.; and Martin B. Keller, M.D.

Background: Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis.

Method: The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis.

Results: For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval.

Conclusions: Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

(J Clin Psychiatry 2005;66:283-290)

Received Sept. 15, 2003; accepted Aug. 23, 2004. From the Department of Psychiatry and Human Behavior, Brown University, Providence, R.I. (Drs. Solomon, Mueller, Posternak, and Keller); the Department of Psychiatry, Cornell University, New York, N.Y. (Dr. Leon and Mr. Teres); the Department of Psychiatry, University of Iowa College of Medicine, Iowa City (Dr. Coryell); the Department of Psychiatry, University of California, La Jolla (Dr. Judd); and the Department of Research and Training, New York State Psychiatric Institute, New York (Dr. Endicott).

This study was supported by grant 2R10 MH25478-29A2 from the National Institute of Mental Health (NIMH).

This manuscript has been reviewed by the Publication Committee of the NIMH Collaborative Depression Study (CDS) and has its endorsement. Study participants and program information are provided at the end of the article.

Dr. Judd has been a consultant to and an advisory board member of Roche. Dr. Keller has been a consultant to and received honoraria from Bristol-Myers Squibb, Collegium, Cypress Bioscience, Cyberonics, Eli Lilly, Forest Laboratories, Janssen, Merck, Organon, Otsuka, Pfizer, Pharmacia, Pharmastar, Sepracor, Vela Pharmaceuticals, and Wyeth; has received grant/research support from Forest, Merck, Organon, Pfizer, and Wyeth; and has been on advisory boards of Bristol-Myers Squibb, Cephalon, Cyberonics, Cypress Bioscience, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Merck, Mitsubishi Pharma Corporation, Novartis, Organon, Pfizer, Pharmacia, Sanofi-Synthelabo, Scirex, Sepracor, Somerset, Vela Pharmaceuticals, and Wyeth.

Corresponding author and reprints: David A. Solomon, M.D., Mood Disorders Program, Department of Psychiatry, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903-4970 (e-mail: DASolomon@Lifespan.org).