ABT-200 is a novel potential antidepressant which antagonizes both norepi-nephrine uptake and noradrenergic a2 receptors. This single-site study conducted over 5 months compared the safely and efficacy of ABT-200 (titrated up to 280 mg/day) to a fixed dose offluoxetine (20 mg/day) and placebo in 216 patients meeting DSM-III-R criteria for major depressive disorder. Following a 1-week placebo lead-in phase, patients were randomized to receive ABT-200 (n = 72), fluoxetine (n = 72), or placebo (n = 72) for 9 weeks of double-blind treatment. At the end of the study there were no differences (P > 0.05) in HAM-D total score changes from baseline between ABT-200-treated and placebo-treated patients, whose mean scores were reduced by 4.6 points (16.8%) and 6.4 points (23.3%), respectively. Patients on fluoxetine, however, showed statistically significant improvement over placebo on total HAM-D scores with a decrease of 8.6 points (30.5%,P < 0.05). While there were no serious adverse events thought to be related to the study drug, 36.1% of ABT-200 patients discontinued the study due to adverse events, compared to only 5.6% of placebo patients and 4.2% offluoxetine patients. If ABT-200 produced the spectrum of biochemical effects in humans predicted from preclinical studies, our results suggest that these actions do not lead to antidepressant effects in general depressed outpatient populations. Depression 3:199–203 (1995). © 1995 Wiley-Liss, Inc.