BackgroundAntidepressant Drugs (ADs) are among the most commonly prescribed medications in developed countries. The available epidemiological evidence suggests an association between AD use and higher risk of developing type 2 diabetes mellitus. However, some methodological issues make the interpretation of these results difficult. Moreover, very recent studies provided conflicting results. Given the high prevalence of both diabetes and AD use in many countries, clarifying whether this association is causal is of extreme relevance for the public health. The aim of the present study is to provide an up-to-date evaluation of the evidence in support of a causal role of ADs in inducing diabetes.Methods and findingsA systematic literature search was conducted to identify relevant studies in MEDLINE (PubMed), PsycINFO, and International Pharmaceutical Abstracts (IPA) through 31st December 2016. Only studies assessing the incidence of new-onset diabetes in subjects treated with ADs were included. Results were pooled using a random-effects meta-analysis. Moreover, we extensively reviewed the role of the different sources of bias that have been proposed to explain the association between AD and diabetes. Twenty studies met the inclusion criteria. In the meta-analysis, the association between AD use and diabetes was still evident after the inclusion of the recent negative studies [pooled relative risk = 1.27, 95% confidence interval (CI), 1.19–1.35; p<0.001]. None of the biases proposed by previous authors seemed able to fully explain the observed association.ConclusionsThis updated meta-analysis confirms the association between AD use and incident diabetes. It still remains a matter of debate whether single ADs exert a different effect on the risk of diabetes. Given the possible heterogeneity, we suggest that a classification of ADs according to their pharmacological profiles could be useful in better elucidating the nature of this association.