OBJECTIVE: Evaluate efficacy of standard and higher doses of venlafaxine extended release (ER) in depressed outpatients who had either not responded to or could not tolerate an adequate trial of therapy with a selective serotonin reuptake ihibitor (SSRI). METHODS: Outpatients (n = 232) with major depressive disorder were randomly assigned to 8 weeks of treatment with either "standard" (n = 119; mean dose ≤ 148 mg/d) or "hirher" (n = 113; mean dose = 309 mg/d) dosage therapies. Between weeks 8 and 12, nonresponders in the standard dose group could receive higher dose therapy. RESULTS: Response rates in the higher dose group were significantly greater at week 8 on the Clinical Global Impressions-Improvement scale (68% vs 52%; P < 0.001) and Patient Global Impressions scale (intent-to- treat; 68% vs 52%; P < 0.001). The dosing strategies did not, however, differ significantly in change in HAM-D21 total score or HAM-D21 responnse or remission rates. At week 12, there were no significant efficacy differences between the two groups in the intent-to-treat sample. Five side effects (costipation, sweating, hypertension, agitation, and urinary frequency) were more common in the high-dose group. CONCLUSIONS: Higher dose therapy with venlafaxine ER (ie, 300-375 mg/d) resulted in a more rapid response on some measures, but was not as well tolerated as therapy at standard doses. Although these data provide further evidence of a dose-response relationship for venlafaxine therapy results suggest that slower titration to higher doses of venlafaxine ER may improve tolerability without greatly diminishing the probability of sucess. Copyright © 2006 by Lippincott Williams & Wilkins.