PHARMACOEPIDEMIOLOGY AND PRESCRIPTION Use of antidepressants and the risk of cardiovascular and cerebrovascular disease: a meta-analysis of observational studies A Biffi 1 & L Scotti 1 & G Corrao 1 Received: 7 November 2016 /Accepted: 19 December 2016 # Springer-Verlag Berlin Heidelberg 2017 Abstract Purpose This study aims to systematically review studies quantifying the associations between antidepressants (ADs) use and the risk of cardiovascular (CV) outcomes. Methods Medline was searched to October 2015 for full text articles in English. Prospective cohort and case-control studies were admitted if they investigated the relationship between current use of ADs as a whole, tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), and the onset CV events. Summary relative risks (RRs) with confidence intervals (CIs) were calculated using random- effects or fixed-effects models. Results A total of 99,367 incident cases of CV outcomes who met inclusion criteria were identified from 22 observational studies. Compared with no users of ADs, use of SSRIs was associated with an increased risk of cerebrovascular disease (RRs, 1.24; 95% CI, 1.15 to 1.34), while the use of TCA was associated with an increased risk of acute heart disease (RRs, 1.29; 95% CI, 1.09 to 1.54). Conclusions The results of this meta-analysis have to be taken with caution because even though an increased risk of cere- brovascular and acute heart disease was observed respectively in SSRIs and TCA users, the estimates are characterized by a high between study heterogeneity. Moreover, it was not pos- sible to distinguish between the effects of ADs and depression itself. Further well-designed studies are required to confirm this association. Keywords Depression . Antidepressants . Tricyclic antidepressants . Selective serotonin reuptake inhibitors . Stroke . Cardiovascular disease . Cerebrovascular disease Introduction Due to its high worldwide prevalence, depression is a serious public health concern. Currently, it is estimated to affect over 350 million people worldwide and a quarter of the European population [1]. Antidepressant drugs (ADs), developed since 1950s to treat depressive symptoms, are nowadays widely available with several treatment options tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs), are the most commonly prescribed ADs. Despite their similar effec- tiveness, however, SSRIs have in part replaced TCAs since their better tolerability [2]. Even though several studies showed the efficacy of these drugs in treating depression symptoms [3], conflicting results are available on their cardio- vascular safety. In particular, TCAs have shown to be related with systemic inflammation which may lead to an increased risk of cardio- vascular (CV) disease [4–12] and, in particular, myocardial infarction (MI) [4, 7, 11, 13], ventricular arrhythmia [4, 5, 14–16], and fatal cardiac events [17]. On the other hand, Electronic supplementary material The online version of this article (doi:10.1007/s00228-016-2187-x) contains supplementary material, which is available to authorized users. * A Biffi a.biffi14@campus.unimib.it L Scotti lorenza.scotti@unimib.it G Corrao giovanni.corrao@unimib.it 1 Laboratory of Healthcare Research and Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Via Bicocca degli Arcimboldi, 8, Edificio U7, 20126 Milan, Italy Eur J Clin Pharmacol DOI 10.1007/s00228-016-2187-x