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Serotonin is a key neurotransmitter in depressive pathology, contained within platelets, and is a weak activator of platelets. Our study assessed the link between platelet reactivity traits, depression, and antidepressant (AD) use in a large population sample. Our study was conducted in the Framingham Heart Study (<jats:italic>n\u00a0<\/jats:italic>=\u00a03,140), and AD use (<jats:italic>n\u00a0<\/jats:italic>=\u00a0563) and aspirin use (<jats:italic>n\u00a0<\/jats:italic>=\u00a0681) were noted. Depression was measured using the Center for Epidemiological Studies\u2010Depression (CES\u2010D) survey. Platelet reactivity traits were measured across multiple agonists using five distinct assays. We utilized a linear mixed effects model to test associations between platelet traits and depression, adjusting for age, sex, aspirin use, and AD use. Similarly, we analyzed trait associations with any AD use, serotonin\u2010affecting ADs, and norepinephrine\u2010affecting ADs, respectively. There were strong associations with reduced platelet function and AD use, particularly with serotonin\u2010affecting medications. This included lower Optimul epinephrine maximal aggregation (<jats:italic>P<\/jats:italic>\u00a0=\u00a04.87E\u201013), higher U46619 half maximal effective concentration (<jats:italic>P<\/jats:italic>\u00a0=\u00a09.09E\u201011), lower light transmission aggregometry (LTA) adenosine diphosphate (ADP) final aggregation (<jats:italic>P<\/jats:italic>\u00a0=\u00a01.03E\u201005), and higher LTA ADP disaggregation (<jats:italic>P<\/jats:italic>\u00a0=\u00a02.28E\u201005). We found similar associations with serotonin\u2010affecting ADs in an aspirin\u2010taking subset of our sample. There were no significant associations between platelet traits and depression. In the largest study yet of AD use and platelet function we show that antidepressants, particularly serotonin\u2010affecting ADs, inhibit platelets. We did not find evidence that depressive symptomatology in the absence of medication is associated with altered platelet function. Our results are consistent with AD use leading to platelet serotonin depletions, decreased stability of platelet aggregates, and overall decreased aggregation to multiple agonists, which may be a mechanism by which ADs increase risk of bleeding and decrease risk of thrombosis.<\/jats:p>","DOI":"10.1002\/cpt.2517","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T03:19:23Z","timestamp":1640229563000},"page":"909-918","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Serotonin\u2010Affecting Antidepressant Use in Relation to Platelet Reactivity"],"prefix":"10.1111","volume":"111","author":[{"given":"Joseph","family":"Grech","sequence":"first","affiliation":[{"name":"Population Sciences Branch National Heart, Lung, and Blood Institute Framingham Massachusetts 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