Direct Comparison of Tricyclic and Serotonin-Reuptake Inhibitor Antidepressants in Randomized Head-To-Head Trials in Acute Major Depression: Systematic Review and Meta-Analysis

J Psychopharmacol. 2017 Sep;31(9):1184-1189. doi: 10.1177/0269881117711709. Epub 2017 Jun 21.


Background: A comparison across trials conducted over several decades suggested superior efficacy of tricyclic antidepressants (TCAs) over selective serotonin-reuptake inhibitors (SSRIs). However, this outcome may reflect a selective secular decline of responses after randomization to placebo. Remaining uncertainty encouraged direct comparison of the drug-types in trials involving randomized, head-to-head comparisons.

Methods: We systematically identified reports of randomized trials of TCAs versus SSRIs for major depression in several digital databases, and applied standard meta-analytic and multiple-factor regression methods to analyze and pool the findings.

Results: In 89 head-to-head trials, there was no detectable overall difference in responder rates or percent-improvement between TCAs and SSRIs. In addition to non-difference between drug-types, outcomes were unrelated to reporting-year, trial-size or nominal duration, proportion of women participants, initial depression ratings, rating scales, subjects/arm, imipramine-equivalent mg/day drug dose, or dropout rate. Trial size and duration increased significantly over the years 1980-2016.

Conclusions: Previous evidence suggesting superior benefits of TCAs over SSRIs for the treatment of acute major depression is probably an artifact of a selective secular decline in responses to placebo, as no difference was found in a large series of direct comparisons of these antidepressant-types.

Keywords: Antidepressants; head-to-head; randomized trials; serotonin-reuptake inhibitor; tricyclic.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antidepressive Agents, Tricyclic / therapeutic use*
  • Depression / drug therapy*
  • Depression / metabolism
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Double-Blind Method
  • Humans
  • Imipramine / therapeutic use
  • Serotonin / metabolism*
  • Serotonin Uptake Inhibitors / therapeutic use*


  • Antidepressive Agents, Tricyclic
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Imipramine