INTRODUCTION: During the last decade, a number of meta-analyses questioned the clinically relevant efficacy of antidepressants. Part of the debate concerned the method used in each of these meta-analyses as well as the quality of the data set.MATERIALS AND METHODS: The Kirsch data set was analysed with a number of different methods, and eight key questions were tackled. We fit random effects models in both Bayesian and frequentist statistical frameworks using raw mean difference and standardised mean difference scales. We also compare between-study heterogeneity estimates and produce treatment rank probabilities for all antidepressants. The role of the initial severity is further examined using meta-regression methods.RESULTS: The results suggest that antidepressants have a standardised effect size equal to 0.34 which is lower but comparable to the effect of antipsychotics in schizophrenia and acute mania. The raw HDRS difference from placebo is 2.82 with the value of 3 included in the confidence interval (2.21-3.44). No role of initial severity was found after partially controlling for the effect of structural (mathematical) coupling. Although data are not definite, even after controlling for baseline severity, there is a strong possibility that venlafaxine is superior to fluoxetine, with the other two agents positioned in the middle. The decrease in the difference between the agent and placebo in more recent studies in comparison to older ones is attributed to baseline severity alone.DISCUSSION: The results reported here conclude the debate on the efficacy of antidepressants and suggest that antidepressants are clearly superior to placebo. They also suggest that baseline severity cannot be utilized to dictate whether the treatment should include medication or not. Suggestions like this, proposed by guidelines or institutions (e.g. the NICE), should be considered mistaken.