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Monotherapy with a selective serotonin reuptake inhibitor (SSRI) is the most common initial treatment for major depressive disorder (MDD), but this monotherapy leads to remission in fewer than a third of patients. The combination of the SSRI escitalopram and bupropion-SR is commonly used for treating patients with MDD who have had an inadequate response to antidepressant monotherapy. This pilot study was conducted to evaluate this combination in the treatment of MDD in patients with chronic or recurrent MDD to estimate safety, tolerability, and remission rates.In this study, 51 outpatients with chronic or recurrent non-psychotic MDD were treated with a combination of escitalopram and bupropion-SR for up to 12 weeks. Participants were started on escitalopram at 10 mg/day, and bupropion-SR was then added at week 1, starting at 150 mg/day. The maximum dose of escitalopram was 20 mg/day and the maximum dose of bupropion-SR was 400 mg/day.Rates of response (62%) and remission (50%) at study exit (based on participants for whom at least one post-baseline measure was collected) were significantly higher than is typical for SSRI monotherapy. The level of treatment emergent adverse events was low, and only 3 participants (6%) discontinued treatment due to side effects. The mean maximum dose of escitalopram was 18 mg/day, which was achieved by week 6, and the mean dose at study exit was also 18 mg/day. The mean maximum dose of bupropion-SR was 329 mg/day, which was achieved by week 8, and the mean dose at study exit was 327 mg/day.These results suggest that the combination of escitalopram and bupropion-SR is effective and well tolerated. Further controlled trials comparing this combination with monotherapy are needed.