Methods We searched Cochrane CENTRAL, CINAHL, EMBASE, LiLACS, MEDLINE, PSYCINFO, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to January 8th 2016, for the acute treatment of major depressive disorder diagnosed according to standard operationalised criteria. We included placebo-controlled and head-to-head trials of 21 antidepressants in adults. We assessed the certainty of evidence using GRADE. Primary outcomes were efficacy (response rate) and acceptability (discontinuations due to any cause). Secondary outcomes included symptom severity, remission rate and discontinuations due to adverse events. We estimated summary odds ratios (OR) and standardised mean differences using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO (CRD42012002291).
Findings. We included 522 trials with 116,477 participants. The certainty of evidence was moderate to very low. In terms of efficacy, all antidepressants were more effective than placebo, with OR ranging between 2.13 for amitriptyline and 1.38 for reboxetine. For acceptability, agomelatine and fluoxetine were associated with fewer dropouts than placebo (OR 0.84 and 0.88, respectively), while clomipramine was worse than placebo (OR 1.31). When all trials were considered, differences in OR between antidepressants ranged from 1.15 to 1.55 for efficacy and from 0.64 to 0.88 for acceptability, with wide confidence intervals on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, sertraline, venlafaxine and vortioxetine were more effective than other antidepressants (OR range: 1.12-2.00), while fluoxetine, reboxetine and trazodone were the least efficacious drugs (OR range: 0.50-0.89). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were the best drugs (OR range: 0.42-0.81), while amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine had the highest dropout rates (OR range: 1.31-2.38).
Interpretation. All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, while there was more variability in efficacy and rate of drop out in head-to-head trials. These results are very important in term of evidence-based practice and should inform patients, physicians, guideline developers and policy-makers on the relative merits of the different antidepressants.