Combining Antidepressants for Treatment-Resistant Depression: A Review.

Objective: 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.

Method: 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.

Results: 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.

Conclusion: 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.