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A major meta-analysis comparing 21 commonly used antidepressants, published in The Lancet, concluded that all are more effective than placebo for the short term treatment of acute depression in adults, with effectiveness ranging from small to moderate for different drugs. Overall, 522 double-blind randomised controlled trials (RCTs) between 1979 and 2016, with a total of 116 477 participants, were included in the meta-analysis, the most comprehensive analysis of a psychiatric treatment ever undertaken. The authors identified all RCTs that compared antidepressants with placebo or another antidepressant for the acute treatment (over 8 weeks) of major depression in adults aged 18 years or more. The authors then contacted pharmaceutical companies, original study authors, and regulatory agencies to supplement incomplete reports in the original articles or to provide data from unpublished studies. The primary outcomes were efficacy (number of patients who responded to treatment; ie, depressive symptoms, as measured on a validated rating scale, were reduced by at least 50% over 8 weeks) and acceptability (proportion of patients who withdrew from the study for any reason by week 8). A total of 87 052 participants had been randomly assigned to receive an antidepressant, and 29 425 to receive a placebo. Most patients had moderate to severe depression. All 21 antidepressants were more effective than placebo, with odds ratios (ORs) ranging between 2.13 (95% credible interval [CrI], 1.89–2.41) for amitriptyline and 1.37 (95% CrI, 1.16–1.63) for reboxetine. Only agomelatine (OR, 0.84; 95% CrI, 0.72–0.97) and fluoxetine (OR, 0.88; 95% CrI, 0.80–0.96) were associated with fewer dropouts than placebo, whereas clomipramine was the only antidepressant that was less acceptable than placebo (OR, 1.30; 95% CrI, 1.01–1.68). Based on studies that compared different antidepressants, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were found to be the most effective, and fluoxetine, fluvoxamine, reboxetine and trazodone the least effective. The majority of the most effective antidepressants are now off-patent and available in generic form. Antidepressants also differed in terms of acceptability, with agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine proving most tolerable, and amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine the least tolerable.