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.