Platelet inhibition by sertraline and N-desmethylsertraline: A possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors

Recently, clinical depression has been identified as an independent risk fa ctor for increased mortality in patients following acute coronary events. A lthough the underlying mechanisms of this link remain uncertain, increased platelet activity has been suggested but never proven as the mechanism resp onsible for this association. Sertraline hydrochloride is a selective serot onin reuptake inhibitor (SSRI), and is an effective antidepressant agent. I ts major liver metabolite, N-desmethylsertraline (NDMS), is known to be neu rologically inactive. We assessed the in vitro effects of escalating concentrations of sertraline and NDMS on human platelets by aggregometry in plasma and whole blood, by expression of major surface receptors with flow cytometry in washed cells a nd in the whole blood, and quantitatively by various platelet function anal ysers in healthy volunteers and patients with coronary artery disease. Pret reatment of blood samples with sertraline and NDMS resulted in a dose-depen dent inhibition of platelet-rich plasma aggregation induced by 5 muM ADP (P = 0.002), by 10 muM ADP (P = 0.0017), by collagen (P = 0.008), and by thro mbin(P = 0.026). Whole blood platelet aggregability was also significantly reduced when induced by 20 muM ADP(P = 0.006), and by collagen (P = 0.01). Surface expression of CD9 (P = 0.004), GP Ib (P = 0.0001), GP IIb/llla (P = 0.007), VLA-2 (P = 0.01), P-selectin (P = 0.02), and PECAM-1 (P = 0.01), b ut not the vitronectin receptor, was also reduced in sertraline and NDMS pr etreated washed platelets. Whole blood flow cytometry revealed significant inhibition of GP IIb/IIla(P = 0.008), and P-selectin expression (P = 0.0001 ) in NDMS treated samples. Closure time was delayed for the collagen-ADP ca rtridge (P = 0.009), and for the collagen-epinephrin cartridge (P = 0.01), indicating platelet inhibition in whole blood under high shear conditions. Rapid platelet-function assay revealed a decreased (P = 0.002) ability of p latelets to agglutinate fibrinogen-coated beads, suggesting GP IIb/IIIa inh ibition. Both sertraline, and its neurologically inactive metabolite NDMS, exhibited significant dose-dependent inhibition of human platelets. The documented a nti-platelet effects of sertraline and NDMS may be directly related to the mortality benefits of SSRIs after ischemic events including myocardial infa rction and stroke. (C) 2001 Academic Press.