OBJECTIVES: To assess the beneficial and harmful effects of duloxetine versus 'active placebo', placebo or no intervention for adults with major depressive disorder. DESIGN: Systematic review with meta-analysis and trial sequential analysis of randomised trials. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and other relevant databases up until January 2023. We requested clinical study reports from 36 competent authorities. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: All randomised clinical trials comparing duloxetine versus placebo, 'active placebo' or no intervention, irrespective of publication type, publication status, publication year and language for treatment of major depressive disorder in adults. DATA EXTRACTION AND SYNTHESIS: Five authors in pairs extracted data using a standardised data extraction sheet. A third review author was consulted for disagreements. Intervention effects were assessed by both random-effects and fixed-effect model meta-analyses, risk of bias assessments were performed by two independent review authors using Cochrane's risk of bias tool V.2 and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. RESULTS: We included 28 trials randomising a total of 7872 participants. All results were at high risk of bias. The trials' assessment time points were between 6 and 16 weeks after randomisation. Meta-analyses showed evidence of a beneficial effect of duloxetine on depressive symptoms (mean difference -1.81, Hamilton Depression Rating Scale (HDRS-17) points
95% CI -2.34 to -1.28
heterogeneity I CONCLUSIONS: Duloxetine appears to reduce depressive symptom scores and improve quality of life scores in the short term, but the effect sizes are minimal and of questionable patient importance. The short- and long-term effects of duloxetine on risks of SAEs and suicidality are uncertain. Duloxetine increases the risks of several short-term adverse events. Systematic assessments of benefits and harms over longer periods are required. TRIAL REGISTRATION NUMBER: PROSPERO 2016 CRD42016053931.