As many as 45% of patients with major depression also meet diagnostic criteria for bipolar (BP) II disorder.Although the use of a concurrent mood-stabilizing drug has been suggested in treating BP II depression, antidepressant monotherapy has received less attention. The efficacy and safety of venlafaxine were examined in 17 BP II (mean +/- SD; age, 41 +/- 14 years) versus 31 unipolar (UP) (45 +/- 14 years) patients with major depression. Minimum pretreatment Hamilton Rating Scale for Depression (HAM-D21) score was >or=to 20. After a 1-week placebo lead-in, patients were randomly assigned to receive double-blind treatment with once- versus twice-daily venlafaxine dosing starting at 37.5 mg daily and increasing up to 225 mg daily. Patients were evaluated weekly for efficacy using the HAM-D21, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression (CGI) Scale. We observed a similar overall efficacy in BP and UP patients by 6 weeks of treatment (p = not significant). However, we also observed a more rapid reduction of HAM-D (21) (p < 0.03) and MADRS (p < 0.02) scores by week 2 of treatment in BP patients who completed the entire trial. No episodes of venlafaxine-induced "manic switch" were observed in either patient group. In conclusion, our preliminary findings suggest that short-term, 6-week venlafaxine treatment may be a safe and effective antidepressant monotherapy for BP II major depression. (J Clin Psychopharmacol 1998; 18:414-417)