Antidepressants for Bipolar Depression: A Systematic Review of Randomized, Controlled Trials
Harm J. Gijsman, Ph.D., M.R.C.Psych. John R. Geddes, M.D., F.R.C.Psych. Jennifer M. Rendell, M.A. Willem A. Nolen, Ph.D. Guy M. Goodwin, D.Phil., F.R.C.Psych.
Objective: This study reviewed the evidence from randomized, controlled trials on the efficacy and safety ofantidepressants in the short-term treatment of bipolar depression. Method: The authors performed a systematic review and meta-analysis of randomized, controlled trials. They searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The main outcome measures were the proportionof patients who clinically responded to treatment and the rate of switching to mania. Results: Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. Antidepressants were more effective than placebo.Antidepressants did not induce more switching to mania (the event rate for antidepressants was 3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two antidepressants. The rate of switching for tricyclic antidepressants was 10%, and for all other antidepressants combined, it was 3.2%. Conclusions: Antidepressants are effective in the short-term treatment of bipolar depression. Thetrial data do not suggest that switching is a common early complication of treatment with antidepressants. It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment. Given the limited evidence, there is a compelling need for further studies with longer follow-up periods and careful definition andfollow-up of emerging mania and partial remission. (Am J Psychiatry 2004; 161:1537–1547)
he treatment of depressive episodes in patients with bipolar disorder presents a puzzling paradox. In perhaps most countries in the world where treatment is available, patients are offered antidepressants with little deliberation. By contrast, in all treatment guidelines, experts appear to agonizeover whether antidepressants should be offered at all, at least as monotherapy. This division of opinion between the real world of treatment and the more refined world of evidence is one of the major current challenges in psychiatric management. It reflects genuine uncertainty about the benefit and harm of antidepressants in treating the 50 million people who may have bipolar disorder worldwide. Thisis a substantial therapeutic challenge because in bipolar disorder, depression—either recurrent or chronic—causes more disability than any other manifestation of the illness (1–3). Clinically, the issue is an apparently straightforward balance between benefit and risk. Do antidepressants work in acute bipolar depression as well as they do in unipolar depression? If they do, is the potentialcost—the risk of induction of a manic episode or mood instability—too high to justify their use? And should they be prescribed only in combination with mood stabilizers? These questions clearly concern both the short-term use of antidepresAm J Psychiatry 161:9, September 2004
sants and also the longer-term use for relapse prevention. Depression is often chronic and highly recurrent in bipolarpatients, and it carries a significant risk of suicide (4, 5). In unipolar patients, there is strong evidence that longterm treatment with antidepressants prevents relapse of depression for at least 3 years and perhaps indefinitely (6). By contrast, the long-term use of antidepressants in bipolar patients may be associated with manic relapse (7, 8) and sometimes an increased frequency of bipolar...