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

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


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.


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.


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

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