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The Use of Antidepressants in Bipolar Disorder

Virginio Salvi, M.D.; Andrea Fagiolini, M.D.; Holly A. Swartz, M.D.; Giuseppe Maina, M.D.; and Ellen Frank, Ph.D.

Background: Whether or not to use antidepressants in patients with bipolar disorder is a matter of debate. Antidepressant treatment of bipolar depression has been associated with manic switch and cycle acceleration. Furthermore, recent studies have argued against the efficacy of antidepressants in the treatment of bipolar depression. Nevertheless, many clinicians continue to employ antidepressants, especially in the management of severe depression that is unresponsive to mood stabilizers alone.

Objective: Because of the unclear risk-to-benefit ratio of antidepressants in bipolar disorder, we have performed an updated review of the relevant literature. In this article we examine (1) all randomized controlled trials (RCTs) evaluating the use of antidepressants in the treatment of acute bipolar depression and assessing the risk of antidepressant-induced manic switch and (2) non-RCT trials that evaluate the impact of antidepressant discontinuation after acute antidepressant response.

Data Sources: A MEDLINE search of journals, covering the period from January 1966 to July 2007 and supplemented by bibliographic cross-referencing, was performed to identify the relevant studies. The keywords used were antidepressant, bipolar depression, bipolar disorder, switch, manic switch, antidepressant-induced mania, predictors, and antidepressant discontinuation. Criteria used to select studies included (1) English language and (2) studies published in peer-reviewed journals.

Data Synthesis: Randomized, double-blind, placebo-controlled studies have demonstrated that antidepressants exert some efficacy in the treatment of bipolar depression in some populations of patients. Moreover, the risk of manic switch, although not totally countered, appears to be strongly reduced when antidepressants are given in combination with a mood stabilizer and when new-generation antidepressants are preferred over old tricyclic antidepressants. Finally, some studies have proven that the continuous use of antidepressants after the remission of a major depressive episode helps to prevent further depressive relapses without causing a significant increase in manic relapses.

Conclusion: Clearly, there is a place for antidepressants in bipolar disorder; however, it is important to be cautious and evaluate their use on a case-by-case basis. Looking at specific depressive symptoms might help physicians in making the choice of whether to prescribe or not prescribe antidepressants.

(J Clin Psychiatry 2008;69:1307-1318. Online Ahead of Print July 29, 2008.)

Received Oct. 30, 2007; accepted Jan. 27, 2008. From the Department of Neuroscience, University of Turin, Italy (Drs. Salvi and Maina); and the Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pa. (Drs. Salvi, Fagiolini, Swartz, and Frank).

We acknowledge Taryn Belmonte, B.A., of the University of Pittsburgh, for her thorough editing of the manuscript. Ms. Belmonte reports no relevant financial disclosure.

Dr. Fagiolini is a consultant for Bristol-Myers Squibb, Novartis, and Pfizer and is a member of the speakers/advisory boards for Bristol-Myers Squibb and Pfizer. Dr. Swartz has received grant/research support from and is a member of the speakers/advisory board for Bristol-Myers Squibb and has received honoraria from Bristol-Myers Squibb and AstraZeneca. Drs. Salvi, Maina, and Frank report no financial affiliations or other relationships relevant to the subject of this article.

Corresponding author and reprints: Virginio Salvi, M.D., Department of Neuroscience, University of Turin, Via Cherasco 11, 10126 Turin, Italy (e-mail: