Abstract
There is an increasing body of evidence suggesting that selective serotonin reuptake inhibitors exhibit clinical benefit beyond treating depression, by simultaneously inhibiting platelet activity. We recently demonstrated that escitalopram (ESC), but not its major metabolites, inhibits multiple platelet biomarkers in healthy volunteers. Considering that the metabolic syndrome represents one of the major risk factors for vascular disease, we here determined how ESC affects platelet activity in such patients. We assessed the in vitro effects of preincubation with escalating (50–200 nM/l) concentrations of ESC on platelet aggregation, expression of major surface receptors by flow cytometry, and quantitatively by platelet function analyzers. Blood samples were obtained from 20 aspirin-naïve patients with documented metabolic syndrome. Pretreatment of blood samples with medium (150 nM/l), or high (200 nM/l) doses of ESC resulted in a significant inhibition of platelet aggregation induced by ADP (p=0.007) and by collagen (p=0.004). Surface platelet expression of GPIb (CD42, p=0.03), LAMP-3 (CD63, p=0.04), and GP37 (CD165, p=0.03) was decreased in the ESC-pretreated samples. Closure time by the PFA-100 analyzer was prolonged after the 200 nM/l dose (p=0.02), indicating platelet inhibition under high shear conditions. On the other hand, the lowest tested concentration of ESC (50 nM/l) did not affect platelet activity in these patients. The in vitro antiplatelet characteristics of ESC in patients with the metabolic syndrome are similar to those in healthy volunteers. However, higher ESC doses are required to induce equally potent platelet inhibition. These data justify prospective ex vivo studies with the highest therapeutic dose to determine the potential clinical advantage of ESC in high-risk patients with vascular disease.
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References
Anfossi G, Russo I, Massucco P, Mattiello L, Doronzo G, De Salve A et al (2004). Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity. Eur J Clin Invest 34: 482–489.
Anfossi G, Russo I, Massucco P, Mattiello L, Trovati M (2003). Platelet resistance to the antiaggregating effect of N-acetyl-L-cysteine in obese, insulin-resistant subjects. Thromb Res 110: 39–46.
Antithrombotic Trialists' Collaboration (2002). Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high-risk patients. BMJ 324: 71–86.
Arruzazabala ML, Molina V, Mas R, Fernandez L, Carbajal D, Valdes S et al (2002). Antiplatelet effects of policosanol (20 and 40 mg/day) in healthy volunteers and dyslipidaemic patients. Clin Exp Pharmacol Physiol 29: 891–897.
Arteaga RB, Chirinos JA, Soriano AO, Jy W, Horstman L, Jimenez JJ et al (2006). Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 98: 70–74.
Atar D, Malinin AI, Takserman A, Pokov A, Van Zyl L, Tanguay J-F et al (2006). Escitalopram, but not its major metabolites, exhibits antiplatelet activity in humans. J Clin Psychopharmacol 26: 172–177.
Ault KA (1993). Flow cytometric measurement of platelet function and reticulated platelets. Ann New York Acad Sci 677: 293–308.
Bonnet F, Irving K, Terra JL, Nony P, Berthezene F, Moulin P (2005). Depressive symptoms are associated with unhealthy lifestyles in hypertensive patients with the metabolic syndrome. J Hypertens 23: 611–617.
Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G et al (2004). Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 292: 1440–1446.
Gil K, Radzillowicz P, Zdrojewski T, Pakalska-Korcala A, Chwojnicki K, Piwonski J et al (2006). Relationship between the prevalence of depressive symptoms and metabolic syndrome. Results of the SOPKARD Project. Kardiol Pol 64: 464–469.
Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger Jr JT et al (2002). Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288: 701–709.
Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C, American Heart Association; National Heart Lung Blood Institute (2004). Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation 109: 433–438.
Herva A, Rasanen P, Miettunen J, Timonen M, Laksy K, Veijola J et al (2006). Co-occurrence of metabolic syndrome with depression and anxiety in young adults: the Northern Finland 1966 Birth Cohort Study. Psychosom Med 68: 213–216.
Javors MA, Houston JP, Tekell JL, Brannan SK, Frazer A (2000). Reduction of platelet serotonin content in depressed patients treated with either paroxetine or desipramine. Int J Neuropsychopharmacol 3: 229–235.
Jesri A, Okonofua EC, Egan BM (2005). Platelet and white blood cell counts are elevated in patients with the metabolic syndrome. J Clin Hypertens 7: 705–711.
Kahl KG, Bester M, Greggersen W, Rudolf S, Dibbelt L, Stoeckelhuber BM et al (2005). Visceral fat deposition and insulin sensitivity in depressed women with and without comorbid borderline personality disorder. Psychosom Med 67: 407–412.
Kahn SE, Zinman B, Haffner SM, O'neill MC, Kravitz BG, Yu D et al (2006). Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes 55: 2357–2364.
Kinder LS, Carnethon MR, Palaniappan LP, King AC, Fortmann SP (2004). Depression and the metabolic syndrome in young adults: findings from the Third National Health and Nutrition Examination Survey. Psychosom Med 66: 316–322.
Lett HS, Blumenthal JA, Babyak MA, Sherwood A, Strauman T, Robins C et al (2004). Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 66: 305–315.
Mammen EF, Comp PC, Gosselin R, Greenberg C, Hoots WK, Kessler CM et al (1998). PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 24: 195–202.
McCaffery JM, Niaura R, Todaro JF, Swan GE, Carmelli D (2003). Depressive symptoms and metabolic risk in adult male twins enrolled in the National Heart, Lung, and Blood Institute twin study. Psychosom Med 65: 490–497.
Nieuwdorp M, Stroes ES, Meijers JC, Buller H (2005). Hypercoagulability in the metabolic syndrome. Curr Opin Pharmacol 5: 155–159.
Ovbiagele B, Saver JL, Lynn MJ, Chimowitz M, WASID Study Group (2006). Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 66: 1344–1349.
Plenge P, Mellerup ET, Laursen H (1991). Affinity modulation of [3H]imipramine, [3H]paroxetine and [3H]citalopram binding to the 5-HT transporter from brain and platelets. Eur J Pharmacol 206: 243–250.
Ruggeri ZM (1994). New insights into the mechanisms of platelet adhesion and aggregation. Semin Hematol 31: 229–239.
Serebruany VL, Glassman AH, Malinin AI, Nemeroff CB, Musselman DL, van Zyl LT et al (2003). Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 108: 939–944.
Serebruany VL, Gurbel PA, O'Connor CM (2001). Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharm Res 43: 453–462.
Serebruany VL, Pokov AN, Malinin AI, O'Connor C, Bhatt DL, Tanguay JF et al (2006). Valsartan inhibits platelet activity at different doses in mild to moderate hypertensives: Valsartan Inhibits Platelets (VIP) trial. Am Heart J 151: 92–99.
Shaw LJ, Berman DS, Hendel RC, Alazraki N, Krawczynska E, Borges-Neto S et al (2006). Cardiovascular disease risk stratification with stress single-photon emission computed tomography technetium-99m tetrofosmin imaging in patients with the metabolic syndrome and diabetes mellitus. Am J Cardiol 97: 1538–1544.
Shoelson SE, Lee J, Goldfine AB (2006). Inflammation and insulin resistance. J Clin Invest 116: 1793–1801.
Smith JW, Steinhubl SR, Lincoff AM, Coleman JC, Lee TT, Hillman RS et al (1999). Rapid platelet-function assay. An automated and quantitative cartridge-based method. Circulation 99: 620–625.
Soro-Paavonen A, Westerbacka J, Ehnholm C, Taskinen MR (2006). Metabolic syndrome aggravates the increased endothelial activation and low-grade inflammation in subjects with familial low HDL. Ann Med 38: 229–238.
Tassini M, Vivi A, Gaggelli E, Valensin G, Laghi Pasini F, Puccetti L et al (2002). Effects of fluoxetine treatment on carbohydrate metabolism in human blood platelets: a 1H-NMR study. Arch Biochem Biophys 404: 163–165.
Thase ME (2006). Managing depressive and anxiety disorders with escitalopram. Exp Opin Pharmacother 7: 429–440.
The ENRICHD Trial Investigators (2003). Effects of treating depression and low perceived social support on clinical events after myocardial infarction. The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 289: 3106–3116.
NCEP (2002). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. Circulation 106: 3143–3421.
Trost S, Pratley R, Sobel B (2006). Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. Curr Diab Rep 6: 47–54.
Acknowledgements
We thank all the nurses and laboratory personnel for their technical excellence and outstanding effort in this study. The study was supported in part by a grant from H Lundbeck A/S, Copenhagen Valby, Denmark.
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Atar, D., Malinin, A., Pokov, A. et al. Antiplatelet Properties of Escitalopram in Patients with the Metabolic Syndrome: A Dose-Ranging In Vitro Study. Neuropsychopharmacol 32, 2369–2374 (2007). https://doi.org/10.1038/sj.npp.1301355
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DOI: https://doi.org/10.1038/sj.npp.1301355
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