Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies

Acta Psychiatr Scand. 2017 Feb;135(2):106-116. doi: 10.1111/acps.12672. Epub 2016 Nov 23.


Objective: We aimed to explore whether the prevalence of manic switch was underestimated in randomized controlled trials (RCTs) compared to observational studies (OSs).

Method: Meta-analyses and simple and systematic reviews were identified by two reviewers in a blinded, standardized manner. All relevant references were extracted to include RCTs and OSs that provided data about manic switch prevalence after antidepressant treatment for a major depressive episode. The primary outcome was manic switch prevalence in the different arms of each study. A meta-regression was conducted to quantify the impact of certain variables on manic switch prevalence.

Results: A total of 57 papers (35 RCTs and 22 OSs) were included in the main analysis. RCTs underestimated the rate of manic switch [0.53 (0.32-0.87)]. Overestimated prevalence was related to imipraminics [1.85 (1.22-2.79)]; to serotonin-norepinephrine reuptake inhibitors [1.74 (1.06-2.86)]; and to other classes of drugs [1.58 (1.08-2.31)], compared to placebo treatment. The prevalence of manic switch was lower among adults than among children [0.2 (0.07-0.59)]; and higher [20.58 (8.41-50.31)] in case of bipolar disorder.

Conclusion: Our results highlight an underestimation of the rates of manic switch under antidepressants in RCTs compared to the rates observed in observational studies.

Keywords: affective disorders; depression; meta-analysis; randomized controlled trial.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Review

MeSH terms

  • Adult
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / classification*
  • Antidepressive Agents / therapeutic use
  • Bipolar Disorder / epidemiology*
  • Child
  • Child, Preschool
  • Depressive Disorder, Major / drug therapy*
  • Female
  • Humans
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Observational Studies as Topic
  • Prevalence
  • Randomized Controlled Trials as Topic
  • Regression Analysis


  • Antidepressive Agents