BackgroundThe evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear.MethodsOur objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, ‘active’ placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library’s CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life.ResultsA total of 131 randomised placebo-controlled trials enrolling a total of 27,422 participants were included. None of the trials used ‘active’ placebo or no intervention as control intervention. All trials had high risk of bias. SSRIs significantly reduced the Hamilton Depression Rating Scale (HDRS) at end of treatment (mean difference −1.94 HDRS points; 95% CI −2.50 to −1.37; P < 0.00001; 49 trials; Trial Sequential Analysis-adjusted CI −2.70 to −1.18); Bayes factor below predefined threshold (2.01*10−23). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious adverse events (OR 1.37; 95% CI 1.08 to 1.75; P = 0.009; 44 trials; Trial Sequential Analysis-adjusted CI 1.03 to 1.89). This corresponds to 31/1000 SSRI participants will experience a serious adverse event compared with 22/1000 control participants. SSRIs also significantly increased the number of non-serious adverse events. There were almost no data on suicidal behaviour, quality of life, and long-term effects.ConclusionsSSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.Systematic review registrationPROSPERO CRD42013004420.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-1173-2) contains supplementary material, which is available to authorized users.

The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.