This NIMH-Stanley Foundation Bipolar Network (the "Network") study will be the first systematic assessment in bipolar depression of the comparative efficacy of bupropion (Wellbutrin), sertraline (Zoloft), and venlafaxine (Effexor), three newer antidepressants which have very different mechanisms of action. Bupropion is largely dopaminergic while sertraline is a serotonin selective reuptake inhibitor (SSRI) and venlafaxine is a mixed serotonin, norepinephrine, and to a lesser extent dopamine reuptake inhibitor. Subjects enrolled in this study will be bipolar patients on prophylactic treatment who experience a breakthrough major depressive episode. Subjects will be assigned in a double-blind manner using a three-arm forced randomization procedure to antidepressant therapy with either bupropion, sertraline, or venlafaxine for a ten-week acute response trial. The study medications will be assigned as adjuvant treatment to mood stabilizing medication(s) which have proven unsatisfactorily effective within therapeutic range(s) or at maximum tolerated dose(s). All subjects will receive active drug at dosages established as clinically relevant for unipolar major depressive disorder. Subjects and research personnel conducting cross-sectional and longitudinal rating assessments of mood and functioning will be blinded to treatment group assignment. The primary outcome measures will be the Inventory for Depressive Symptoms - Clinician form (IDS-C), the Clinical Global Impression (CGI-BP) scale, and the Life Charting Methodology (LCM). Subjects who worsen from baseline to week four of treatment will be considered non-responders to the initially assigned medication, and will be offered re-randomization to either of the two drugs to which the subject was not originally randomized (e.g., for bupropion non-response, to either sertraline or venlafaxine) for an additional ten-week acute response trial. Responders to the acute trial enter a 12 month trial of continuation therapy to assess long term effects on prophylaxis of depression and possible induction of mania or cycle acceleration. We also wish to explore possible clinical and biological correlates of acute and long term response to these antidepressants which have received almost no systematic study in bipolar illness. One hypothesis of this study is that the acute efficacy for the three antidepressants would be the same. Another hypothesis is that because of the potent noradrenergic (NE) effects, venlafaxine would have a higher rate of inducing mania compared with bupropion or sertraline.