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

J Clin Psychiatry 1998;59(6):279-288

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.