Antidepressants for bipolar disorder: A meta-analysis of randomized, double-blind, controlled trials

OBJECTIVE: To examine the efficacy and safety of short-term and long-term use of antidepressants in the treatment of bipolar disorder. DATA SOURCES: A literature search of randomized, double-blind, controlled trials published until December 2012 was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central Register of Controlled Trials databases. The keywords “bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia, mixed mania and depression, rapid cycling and bipolar disorder”, AND “antidepressant agent, antidepressive agents second- generation, antidepressive agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake inhibitor, serotonin uptake inhibitor, and tricyclic antidepressant agent” were used. The studies that were listed in the reference list of the published papers but were not retrieved in the above-mentioned databases were supplemented. STUDY SELECTION: Studies selected were double-blind randomized controlled trials assessing the efficacy and safety of antidepressants in patients with bipolar disorder. All participants were aged 18 years or older, and were diagnosed as having primary bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers were used in experimental interventions. Placebos, mood stabilizers, antipsychotics and other antide pressants were used in the control interventions. Studies that were quasi-randomized studies, or used antidepressants in combination with antipsychotics in the experimental group were excluded. All analyses were conducted using Review Manager 5.1 provided by the Cochrane Collaboration. MAIN OUTCOME MEASURES: The primary outcome was the response and switching to mania. The secondary outcomes included remission, discontinuation rate, and suicidality. RESULTS: Among 5 001 treatment studies published, 14 double-blind randomized controlled trials involving 1 244 patients were included in the meta-analysis. Eleven short-term studies and three maintenance studies were included. Studies suggested that patients treated with antidepressants were not significantly more likely to achieve higher response and remission rates in the short-term or long-term treatment than patients treated with placebo and other medications. Antidepressants were not associated with an increased risk of discontinuation, relapse or suicidality. When one antidepressant was compared with another, no significant difference in efficacy and tolerability was found. CONCLUSION: Existing evidence of efficacy does not support the short-term or long-term application of antidepressant therapy in patients with bipolar disorder, although the tolerability and safety of antidepressants have been generally acknowledged. There is a need for large-sample, double-blind, randomized controlled trials to elucidate the role of antidepressants in patients with different subcategories of bipolar disorder.