Bupropion, a specific dopamine reuptake inhibitor, was compared to amitriptyline in two multicenter studies involving 183 depressed outpatients and inpatients. Initial results from these ongoing studies provide additional evidence of the antidepressant activity of bupropion. At the end of the treatment periods (6 weeks for inpatients and 13 weeks for outpatients), bupropion appeared to be at least as effective as amitriptyline. However, bupropion exerted a slightly but nonsignificantly smaller overall therapeutic effect than amitriptyline during the first 4 weeks of drug treatment. Slight weight loss and dopaminergic side effects, such as insomnia, nausea/vomiting, and anorexia, were somewhat more common among bupropion-treated patients. Compared to bupropion, amitriptyline induced more weight gain and had more anticholinergic, antihistaminic, and antiadrenergic side effects. In view of its numerous sites of action, amitriptyline does not appear to be the ideal antidepressant. It remains to be demonstrated whether bupropion has any advantage over secondary amine tricyclic antidepressants, such as nortriptyline and desipramine.