BackgroundFew studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression.AimsTo examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers.MethodIn a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers.ResultsA total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49–53%) and remission (34–41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline.ConclusionsMore caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.