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PATHOPHYSIOLOGY |
From the Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
Address correspondence and reprint requests to Dominique Musselman, MD, MS, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322. E-mail: dmussel{at}emory.edu
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ABSTRACT |
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Key Words: depression • platelet dysfunction • ischemic heart disease
Abbreviations: IHD = ischemic heart disease; SSRI = selective serotonin reuptake inhibitor.
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INTRODUCTION |
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The basic platelet response begins with binding of agonists such as collagen or thrombin to receptors on the platelet surface. Platelets then become activated, converting platelet membrane GPIIb/IIIa complexes into functional receptors for fibrinogen, increasing so-called "platelet stickiness." Activation is accompanied by change in platelet shape, degranulation, secretion of intraplatelet contents, and aggregation. Platelet aggregation occurs when activated platelets bind together. Early platelet events that occur after platelet activation by primary agonists and prior to platelet aggregation can be detected by fluorescence-activated flow cytometry (FAFC). Changes at the activated platelet surface, which occur before platelet aggregation, may be detected with murine monoclonal antibodies (mAbs) as the platelet proceeds from activation to aggregation (2). Enzyme-linked immunosorbent assay (ELISA) may be used to measure plasma concentrations of the platelet-specific proteins secreted from storage granules during degranulation in vivo, i.e., beta-thromboglobulin (ß-TG) and platelet factor 4 (PF4) (3). Dose–response platelet aggregation is induced by platelet agonists such as adenosine diphosphate (ADP) and collagen. Aggregation results are expressed as the agonist concentration producing half-maximal aggregation (AC50).
As summarized in Table 1, studies with differing methodologies have shown that depressed patients with risk factors for IHD or clinically evident IHD exhibit evidence showing circulating platelets that have proceeded through the platelet response cascade to irreversible secretion. The extent of the increased platelet "stickiness," increased numbers of functional GPIIb/IIIa receptor, or platelet degranulation (as reflected by increased plasma concentrations of ß-thromboglobulin [ß-TG] and platelet factor 4 [PF4]) appears to be as great (4), or greater (5,6), than comparison groups of patients with atherosclerotic thrombovascular disease, respectively.
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More recently, interest has been growing about whether treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants exerts beneficial effects on platelet reactivity. Significantly decreased platelet secretion in response to collagen stimulation has been reported after 6 weeks of open-label treatment with sertraline.6a In patients with major depression, significant reduction in the number of functional GPIIb/IIIa receptors and diminished secretion of PF4 has been observed after short-term, open-label treatment with the SSRI paroxetine (7). In a double-blind, randomized trial of depressed IHD patients comparing paroxetine with the nonselective tricyclic antidepressant (TCA) nortriptyline, paroxetine, but not nortriptyline, significantly decreased PF4 and ß-TG plasma concentrations after 6 weeks of treatment (8). Inhibition of serotonin transport into the platelet by SSRI antidepressants, with subsequent depletion of intraplatelet serotonin, may impair platelet activation, thereby imparting potentially therapeutic benefit to depressed patients with atherosclerotic heart disease. For example, in the SADHART study, plasma samples were collected from patients randomized to sertraline (n = 28) or placebo (n = 36). In comparison to the placebo, treatment with sertraline was associated with substantially less release of ß-TG, as well as significantly diminished plasma concentrations of E-selectin, which is a component of the inflammatory response that can be released from both platelets and vascular endothelium. That is, sertraline treatment of these depressed patients was associated with greater reductions in platelet/endothelial activation even with the presence of traditional cardiac antiplatelet regimens such as aspirin and clopidogrel (9). Congruent with the SADHART platelet substudy results are reports of the "antiplatelet" effects of SSRI treatment. Indeed, retrospective examinations of large-scale prescription medication databases reveal an increased risk of upper gastrointestinal bleeding with SSRI antidepressants (10,11), especially when coprescribed with nonsteroidal antiinflammatory drugs (10,12), although discordant reports exist (13). In a related, double-blind, placebo-controlled, randomized trial, prophylactic administration of sertraline to poststroke survivors significantly reduced the incidence of poststroke depression; serious adverse events and hospital admissions related to cardiovascular causes were significantly reduced in sertraline-treated patients (14).
Although SSRIs are potentially cardioprotective in patients who exhibit increased platelet activation, e.g., smokers (15), a critical question is whether antidepressant-induced inhibition of platelet function contributes to IHD-related morbidity and/or mortality, e.g., bleeding. Certainly, future prospective, double-blind trials using "antiplatelet" SSRIs will reveal whether these agents confer an added advantage in patients with depression and comorbid coronary artery disease.
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NOTES |
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In accordance with CME accreditation guidelines, Dominique L. Musselman disclosed that she has received research support from and/or served on the speakers’ bureau for GlaxoSmithKline, Schering-Plough, Janssen, Forest Pharmaceuticals, Pfizer, Organon, and the Dana Foundation. Erica C. Bruce disclosed no real or potential conflicts of interest.
DOI:10.1097/01.psy.0000164227.63647.d9
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