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Loss of Antidepressant Efficacy During Maintenance Therapy: Possible Mechanisms and Treatments

Sarah E. Byrne, M.D.; and Anthony J. Rothschild, M.D.


Background: Many patients with unipolar depression experience a return of depressive symptoms while taking a constant maintenance dose of an antidepressant.

Method: All cited studies were found using computerized literature searches of the MEDLINE database since 1966.

Results: The return of depressive symptoms during maintenance antidepressant treatment has occurred in 9% to 57% of patients in published trials. Possible explanations include loss of placebo effect, pharmacologic tolerance, increase in disease severity, change in disease pathogenesis, the accumulation of a detrimental metabolite, unrecognized rapid cycling, and prophylactic inefficacy.

Conclusion: Although several strategies have been proposed to overcome the loss of antidepressant efficacy, double-blind controlled studies are needed to ascertain the optimal strategy for this perplexing clinical problem.

(J Clin Psychiatry 1998;59:279-288)


Received June 28, 1997; accepted Jan. 26, 1998. From the Department of Internal Medicine, Cambridge Hospital, Cambridge, Mass. (Dr. Byrne), and the Department of Psychiatry, University of Massachusetts Medical School, Worcester (Dr. Rothschild).

Supported in part by grants from the Harvard Medical School Student Research Fellowship (Dr. Byrne) and National Institute of Mental Health grant MH-47457, the Betty and Irving Brudnick Fund for Researchin Affective Disorders, and the Poitras Charitable Foundation (Dr. Rothschild).

Reprint requests to: Anthony J. Rothschild, M.D., Department of Psychiatry, University of Massachusetts Medical Center, 55 Lake Ave. N., Worcester, MA 01655.