Antidepressant combination for major depression in incomplete responders--a systematic review

J Affect Disord. 2013 Jan 10;144(1-2):1-6. doi: 10.1016/j.jad.2012.04.048. Epub 2012 Jul 24.


Background: Antidepressant combination has been suggested as a strategy to increase treatment efficacy. The objective of this study was to perform a systematic review and meta-analysis of studies that assessed the effect of antidepressant combination for major depression in patients with incomplete response to an initial antidepressant.

Methods: Studies were retrieved from PubMed (1966-February, 2012), Cochrane Library (-February, 2012), Embase (1980-February, 2012), PsycINFO (1980-February, 2012), Lilacs (1982-February, 2012), clinical trials registry, thesis database (, and secondary references. Included studies had an open label phase in which an initial antidepressant was used for the treatment of major depression and a double blind phase for the incomplete responders that compared monotherapy with the first antidepressant versus the association of a second antidepressant to the first one.

Results: Out of the 4,884 studies retrieved, only five satisfied the inclusion criteria. The total number of patients included was 483. Only two small trials reported benefits of adding a second antidepressant to the initial antidepressant. Dropouts due to side effects were not reported in three studies. Meta-analysis was not performed due to the small number of studies, the inconsistency in the direction of effect and the possible instability of effect size. Only limited kinds of combination, involving mianserin, mirtazapine and desipramine were studied. Some properties of the first two drugs such as the anxiolytic, sedative, and orexigenic effects, can mimic depression improvement.

Limitations: Publication bias cannot be ruled out. Only one study included a monotherapy arm with the antidepressant used for augmentation of the first antidepressant.

Conclusions: The practice of using a combination of antidepressants for major depression in incomplete responders is not warranted by the literature.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Desipramine / therapeutic use*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Mianserin / analogs & derivatives*
  • Mianserin / therapeutic use*
  • Middle Aged
  • Mirtazapine
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


  • Antidepressive Agents
  • Mianserin
  • Mirtazapine
  • Desipramine