This report describes the first evaluation in humans of DOV 216,303, a putative antidepressive that inhibits the reuptake of norepinephrine, serotonin, and dopamine. Subjects received single oral doses of 5 to 150 mg of DOV 216,303 or placebo. At 150 mg, 4 of 7 subjects reported gastrointestinal disturbances. In the multiple-dose phase of the evaluation, subjects received total daily doses of 50, 75, or 100 mg of DOV 216,303 or placebo for 10 days. At a total daily dose of 100 mg, gastrointestinal disturbances were reported in 4 of 6 volunteers. In both the single- and multiple-dose evaluations, no significant changes were noted in vital signs, electrocardiogram, hematology, or clinical chemistry. DOV 216,303 was rapidly absorbed (plasma t(max) of 0.7-1.2 hours and t(1/2) of 3.3-4.4 hours), with dose-proportional C(max) and AUC values. Furthermore, no remarkable difference was apparent in either the C(max) or AUC(tau) of DOV 216,303 following 1 and 10 days of dosing. The present results demonstrate that DOV 216,303 is safe and well tolerated both at single doses of up to 100 mg and multiple doses of up to 100 mg/day for 10 days. Plasma concentrations of DOV 216,303 after doses > 10 mg exceed its reported IC(50) values for inhibition of biogenic amine reuptake.