Randomised, controlled trials have been completed in the study of the response of bipolar depression to lithium, antiepileptic drugs, antidepressants (particularly the selective serotonin re-uptake inhibitors) and a few miscellaneous agents including pramipexole. In most cases, only one randomised, controlled trial has been completed, perhaps because that can be sufficient to gain US FDA approval for an additional approved use for a medication already approved for another use (usually mania). Despite numerous early studies of lithium, only one recent study was completed with sufficient controls. In virtually all trials, the controlled comparison has been with placebo. A review of risk factors, as well as adverse events and kinetics based on these studies, focuses on net benefits, in particular for quetiapine and lamotrigine. All antidepressants present with some risk for induction of mania and/or cycle acceleration and are best used in combination with mood stablisers; greatest risk for destabilisation seems to be with venlafaxine.