A double-blind multicenter evaluation compared the antidepressant efficacy of bupropion (Wellbutrin) to both placebo and amitriptyline (Elavil, Endep) in adult patients who met DSM-III criteria for major depressive disorder. Steady-state plasma samples were obtained 11-12 hours and 4 hours after the last dose in 50 and 44 patients, respectively, who were treated for 6 weeks with bupropion. There was a curvilinear relationship between antidepressant efficacy and trough plasma bupropion concentrations, with maximum response observed at 5-100 ng/ml and virtually none below 25 ng/ml. The increase in plasma bupropion concentration from the trough level to the 4 hour postdose peak level was also positively related to antidepressant response.