Serotonin‐Affecting Antidepressant Use in Relation to Platelet Reactivity

Abstract

Depression is an independent risk factor of cardiovascular disease morbidity. 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 (n = 3,140), and AD use (n = 563) and aspirin use (n = 681) were noted. Depression was measured using the Center for Epidemiological Studies-Depression (CES-D) 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-affecting ADs, and norepinephrine-affecting ADs, respectively. There were strong associations with reduced platelet function and AD use, particularly with serotonin-affecting medications. This included lower Optimul epinephrine maximal aggregation (P = 4.87E-13), higher U46619 half maximal effective concentration (P = 9.09E-11), lower light transmission aggregometry (LTA) adenosine diphosphate (ADP) final aggregation (P = 1.03E-05), and higher LTA ADP disaggregation (P = 2.28E-05). We found similar associations with serotonin-affecting ADs in an aspirin-taking 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-affecting 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.

Bleeding in patients on concurrent treatment with a selective serotonin reuptake inhibitor (SSRI) and low‐dose acetylsalicylic acid (ASA) compared with SSRI or low‐dose ASA alone—A systematic review and meta‐analysis

“…It may be tempting to interpret available indirect evidence to evaluate a potential interaction between SSRIs and ASA. However, in vitro data on established primary haemostasis/bleeding-related platelet markers and function parameters are disparate, many supporting the presence, [49][50][51][52][53] but some the absence, 54 of an SSRI + ASA bleeding interaction. In addition, apart from intracellular serotonin depletion, further mechanisms/molecular routes whereby SSRIs may affect the risk of bleeding have been discussed in the literature.…”

Trends among platelet function, arterial calcium, and vascular function measures

“…Phlebotomists used a 21 gauge safety lock blood collection system (BD Biosciences; San Jose, CA). 34 …”

“…In addition, three 4.5 mL sodium citrate (3.2%) tubes (BD; San Jose, CA) were collected for PRP assays. 34 …”

“…These preparations were made in accordance with the International Society on Thrombosis and Hemostasis guidelines. 34 …”

Heterogeneity of platelets and their responses

“…We know that activated platelets are required to stimulate the innate immune system [ 67 ], while platelet subpopulations have been shown to respond differentially to antiplatelet therapy [ 68 , 69 ]. Effects on platelet function are also seen in medications prescribed for other indications, including antidepressants [ 70 ] and antiretrovirals [ 71 ]. Likewise, lifestyle factors such as diet, smoking, and alcohol affect platelet function, but at what scale they become relevant is an ongoing study [ 72 , 73 ].…”