Antidepressant combinations: widely used, but far from empirically validated.

This paper reviews the evidence on combining antidepressants (ADs) for treatment of major depressive disorder. Although widely used and usually safe, the efficacy of even the most widely prescribed combinations of ADs has not been established by properly controlled, adequately powered, clinical trials. This stands in contrast to several adjunctive strategies for AD nonresponders, including adjunctive lithium, thyroid hormone, or newer-generation antipsychotics. The wide use of AD combinations no doubt reflects the limited efficacy of commonly used ADs and the unmet need for effective strategies for patients with treatment-resistant depression. Although of unproven efficacy, potential merits of combining selected ADs include: (1) avoiding discontinuation-emergent symptoms and cross-titration schedules, (2) at worst, the second AD should be as effective in combination as it would be as a monotherapy following a switch, and (3) the possibility of complementary neuropharmacologic effects that may enhance efficacy or improve tolerability. The dearth of controlled studies of such a commonly used strategy for such a highly prevalent condition is symptomatic of shortcomings in the way clinically relevant research is funded, points to the need for industry-academic-federal collaborations, and underscores the need for large, practice-based, research groups that can efficiently complete publicly funded studies of high public health impact.