Antidepressant Combinations: Cutting Edge Psychopharmacology or Passing Fad?

Michael E. Thase

This article reviews the rationale for and history of combining antidepressants, as well as the current state of the evidence, in the treatment of major depression. Although it has long been suggested that some individuals may benefit from regimens that combine two dissimilar antidepressants, enthusiasm for this practice has waxed and waned and there was never a strong empirical foundation to support this practice. The tangibly better safety profiles of the newer generation antidepressants, both singly and in combination, have permitted greater use of such combinations in contemporary practice than ever before. Combinations that pair a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) with a dissimilar antidepressant, such as bupropion or mirtazapine, are now widely used for patients who have not responded to trials of first- or second-line antidepressant monotherapies and have been tested as a potential way of speeding the benefits of treatment. However, there still is no strong evidence that even the most widely used combinations have particular merit and clinicians should be mindful that alternatives exist with more established efficacy. Moreover, aside from selected cases of drug-drug interactions, it may take full therapeutic doses of both drugs across a typically adequate duration of exposure to achieve the desired effects of combined treatment.