OBJECTIVE: This trial was conducted to compare the efficacy and tolerability of a fixed dose of escitalopram 10 mg/day with sertraline optimally dosed within its recommended dose range (50-200 mg/day) for the treatment of major depressive disorder. METHODS: In this multicenter trial, depressed patients (DSM-IV defined; baseline Montgomery-Asberg Depression Rating Scale [MADRS] 22) aged 18-80 years were randomly assigned to 8 weeks of double-blind treatment with escitalopram (10 mg/day) or sertraline (50-200 mg/day) following a 1-week single-blind placebo lead-in period. There was no placebo comparison arm. Sertraline was initiated at 50 mg/day, and could be increased by 50 mg/day at weekly intervals based on clinical need and tolerability at the lower dose level. The blind was maintained with matching double-blind placebo capsules for the escitalopram group. Change from baseline to endpoint in MADRS total score (last observation carried forward) was the primary efficacy measure. RESULTS: A total of 212 patients received double-blind medication. At week 8, the mean sertraline dosage was 144 mg/day (median = 150 mg/day). Mean changes from baseline to endpoint in MADRS scores were -19.1 and -18.4 for the escitalopram and sertraline groups, respectively. At endpoint, 75% and 70% of escitalopram- and sertraline-treated patients, respectively, were responders (> or =50% improvement from baseline in mean MADRS scores). Both treatments were generally well tolerated; only 2% and 4% of patients prematurely discontinued escitalopram and sertraline treatment, respectively, due to adverse events. CONCLUSION: No differences in efficacy were observed for fixed-dose escitalopram 10 mg/day and sertraline flexibly dosed from 50-200 mg/day. At these doses, both escitalopram and sertraline were generally well tolerated.