Combining antidepressants for treatment-resistant depression: a review

Many patients with depression remain poorly responsive to antidepressant monotherapy. One approach for managing treatment-resistant depression is to combine antidepressants and to capitalize on multiple therapeutic mechanisms of action. This review critically evaluates the evidence for efficacy of combining antidepressants.

A MEDLINE search of the last 15 years (up to June 2001), supplemented by a review of bibliographies, was conducted to identify relevant studies. Criteria used to select studies included (1) published studies with original data in peer-reviewed journals, (2) diagnosis of depression with partial or no response to standard treatments, (3) any combination of 2 antidepressants with both agents used to enhance antidepressant response, (4) outcome measurement of clinical response, and (5) sample size of 4 or more subjects.

Twenty-seven studies (total N = 667) met the inclusion criteria, including 5 randomized controlled trials and 22 open-label trials. In the 24 studies (total N = 601) reporting response rates, the overall mean response rate was 62.2%. Methodological limitations included variability in definitions of treatment-resistant depression and response to treatment, dosing of medications, and reporting of adverse events.

There is limited evidence, mostly in uncontrolled studies, supporting the efficacy of combination antidepressant treatment. Further randomized controlled trials with larger sample sizes are required to demonstrate the efficacy of a combination antidepressant strategy for patients with treatment-resistant depression.