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

Publication ,  Journal Article
Serebruany, VL; Gurbel, PA; O'Connor, CM
Published in: Pharmacol Res
May 2001

Recently, clinical depression has been identified as an independent risk factor for increased mortality in patients following acute coronary events. Although the underlying mechanisms of this link remain uncertain, increased platelet activity has been suggested but never proven as the mechanism responsible for this association. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI), and is an effective antidepressant agent. Its major liver metabolite, N-desmethylsertraline (NDMS), is known to be neurologically 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 and in the whole blood, and quantitatively by various platelet function analysers in healthy volunteers and patients with coronary artery disease. Pretreatment of blood samples with sertraline and NDMS resulted in a dose-dependent inhibition of platelet-rich plasma aggregation induced by 5 microM ADP (P =, 0.002), by 10 microM ADP (P = 0.0017), by collagen (P = 0.008), and by thrombin (P = 0.026). Whole blood platelet aggregability was also significantly reduced when induced by 20 microM ADP (P = 0.006), and by collagen (P = 0.01). Surface expression of CD9 (P = 0.004), GP Ib (P = 0.0001), GP IIb/IIIa (P = 0.007), VLA-2 (P = 0.01), P-selectin (P = 0.02), and PECAM-1 (P = 0.01), but not the vitronectin receptor, was also reduced in sertraline and NDMS pretreated washed platelets. Whole blood flow cytometry revealed significant inhibition of GP IIb/IIIa (P = 0.008), and P-selectin expression (P = 0.0001) in NDMS treated samples. Closure time was delayed for the collagen-ADP cartridge (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 platelets to agglutinate fibrinogen-coated beads, suggesting GP IIb/IIIa inhibition. Both sertraline, and its neurologically inactive metabolite NDMS, exhibited significant dose-dependent inhibition of human platelets. The documented anti-platelet effects of sertraline and NDMS may be directly related to the mortality benefits of SSRIs after ischemic events including myocardial infarction and stroke.

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Published In

Pharmacol Res

DOI

ISSN

1043-6618

Publication Date

May 2001

Volume

43

Issue

5

Start / End Page

453 / 462

Location

Netherlands

Related Subject Headings

  • Sertraline
  • Selective Serotonin Reuptake Inhibitors
  • Receptors, Cell Surface
  • Platelet Function Tests
  • Platelet Aggregation Inhibitors
  • Platelet Aggregation
  • Pharmacology & Pharmacy
  • In Vitro Techniques
  • Humans
  • Flow Cytometry
 

Citation

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Serebruany, V. L., Gurbel, P. A., & O’Connor, C. M. (2001). Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharmacol Res, 43(5), 453–462. https://doi.org/10.1006/phrs.2001.0817
Serebruany, V. L., P. A. Gurbel, and C. M. O’Connor. “Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors.Pharmacol Res 43, no. 5 (May 2001): 453–62. https://doi.org/10.1006/phrs.2001.0817.
Journal cover image

Published In

Pharmacol Res

DOI

ISSN

1043-6618

Publication Date

May 2001

Volume

43

Issue

5

Start / End Page

453 / 462

Location

Netherlands

Related Subject Headings

  • Sertraline
  • Selective Serotonin Reuptake Inhibitors
  • Receptors, Cell Surface
  • Platelet Function Tests
  • Platelet Aggregation Inhibitors
  • Platelet Aggregation
  • Pharmacology & Pharmacy
  • In Vitro Techniques
  • Humans
  • Flow Cytometry