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

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.