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

Background—Depression after acute coronary syndromes (ACSs) has been identified as an independent risk factor for subsequent cardiac death. Enhanced platelet activation has been hypothesized to represent 1 of the mechanisms underlying this association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelet activity. Whether treatment of depressed post-ACS patients with SSRIs alters platelet function was not known. Accordingly, we serially assessed the release of established platelet/endothelial biomarkers in patients treated with sertraline vs placebo in the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART). Methods and Results—Plasma samples (baseline, week 6, and week 16) were collected from patients randomized to sertraline (n=28) or placebo (n=36). Anticoagulants, aspirin, and ADP-receptor inhibitors were permitted in this study. Platelet factor 4, &bgr;-thromboglobulin (&bgr;TG), platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane B2, 6-ketoprostaglandin F1a, vascular cell adhesion molecule-1, and E-selectin were measured by ELISA. Treatment with sertraline was associated with substantially less release of platelet/endothelial biomarkers than was treatment with placebo. These differences attained statistical significance for &bgr;TG (P =0.03) at weeks 6 and 16 and for P-selectin (P =0.04) at week 16. Repeated-measures ANOVA revealed a significant advantage for sertraline vs placebo for diminishing E-selectin and &bgr;TG concentrations across the entire treatment period. Conclusions—Treatment with sertraline in depressed post-ACS patients is associated with reductions in platelet/endothelial activation despite coadministration of widespread antiplatelet regimens including aspirin and clopidogrel. The antiplatelet and endothelium-protective properties of SSRIs might represent an attractive additional advantage in patients with depression and comorbid coronary artery and/or cerebrovascular disease.

[1]  R. Pakala,et al.  Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation. , 1997, Circulation.

[2]  N. Frasure-smith,et al.  Depression following myocardial infarction. Impact on 6-month survival. , 1993, JAMA.

[3]  P. Gurbel,et al.  Effect of thrombolytic therapy on platelet expression and plasma concentration of PECAM-1 (CD31) in patients with acute myocardial infarction. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[4]  M. Alderman,et al.  Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents. , 2000, The American journal of medicine.

[5]  J. Azorin,et al.  Evidence for an increase in functional platelet 5-HT2A receptors in depressed patients using the new ligand [125I]-DOI , 1999, European Psychiatry.

[6]  V. Caillard,et al.  Sertraline: a new antidepressant. , 1988, The Journal of clinical psychiatry.

[7]  D. Ahern,et al.  Biobehavioral variables and mortality or cardiac arrest in the Cardiac Arrhythmia Pilot Study (CAPS). , 1990, The American journal of cardiology.

[8]  G. Elsasser,et al.  Assessment and treatment of depression following myocardial infarction. , 2001, American family physician.

[9]  J. Butler,et al.  The Platelet Serotonergic System in Depression and Following Sertraline Treatment , 1988, International clinical psychopharmacology.

[10]  J. Sääf,et al.  Classification of patients with affective disorders using platelet monoamine oxidase activity, serum melatonin and post‐dexamethasone Cortisol , 1995, Acta psychiatrica Scandinavica.

[11]  J. Eidt,et al.  Role of thromboxane and serotonin as mediators in the development of spontaneous alterations in coronary blood flow and neointimal proliferation in canine models with chronic coronary artery stenoses and endothelial injury. , 1991, Journal of the American College of Cardiology.

[12]  J. Shuster,et al.  Platelet activation in depression and effects of sertraline treatment: An open-label study. , 2000, The American journal of psychiatry.

[13]  C. Nemeroff,et al.  Exaggerated platelet reactivity in major depression. , 1996, The American journal of psychiatry.

[14]  G. Morgan,et al.  Single-factor repeated-measures designs: analysis and interpretation. , 2002, Journal of the American Academy of Child and Adolescent Psychiatry.

[15]  J. Piletz,et al.  Elevated P-selectin on platelets in depression: response to bupropion. , 2000, Journal of psychiatric research.

[16]  R. Schlienger,et al.  Use of selective serotonin reuptake inhibitors and risk of developing first-time acute myocardial infarction. , 2001, British journal of clinical pharmacology.

[17]  M. Briley,et al.  [3H]-Imipramine binding in human platelets: A new biochemical parameter in depression , 1980, Neuropharmacology.

[18]  Sertraline Treatment of Major Depression in Patients With Acute MI or Unstable Angina , 2002 .

[19]  B. Pollock,et al.  Elevated platelet factor 4 and β-thromboglobulin plasma levels in depressed patients with ischemic heart disease , 1997, Biological Psychiatry.

[20]  J. Bigger,et al.  Cardiovascular effects of fluoxetine in depressed patients with heart disease. , 1998, The American journal of psychiatry.

[21]  C. Benedict,et al.  Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. , 1986, Circulation.

[22]  E. Tukiainen,et al.  Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients , 1976, Nature.

[23]  M. Keller,et al.  Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. , 2000, The Journal of clinical psychiatry.

[24]  C. O'connor,et al.  Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. , 2001, Pharmacological research.

[25]  L. Oreland,et al.  Platelet monoamine oxidase activity in patients with winter seasonal affective disorder , 1996, Psychiatry Research.

[26]  C. O'connor,et al.  Effect of selective serotonin reuptake inhibitors on platelets in patients with coronary artery disease. , 2001, The American journal of cardiology.

[27]  R. Carney,et al.  Major depressive disorder in coronary artery disease. , 1987, The American journal of cardiology.

[28]  Five-Year Risk of Cardiac Mortality in Relation to Initial Severity and One-Year Changes in Depression Symptoms After Myocardial Infarction , 2002 .

[29]  C. Nemeroff,et al.  Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression. , 1988, Archives of general psychiatry.

[30]  L. Schneider,et al.  Platelet monoamine oxidase activity in elderly depressed outpatients , 1986, Biological Psychiatry.

[31]  H. Wellens,et al.  Beta-thromboglobulin and platelet factor 4 levels in post-myocardial infarction patients with major depression , 2002, Psychiatry Research.

[32]  A. Ravindran,et al.  Platelet serotonergic indices in major depression: up-regulation of 5-HT2A receptors unchanged by antidepressant treatment , 1997, Psychiatry Research.

[33]  L. Konopka,et al.  Platelet cytosolic calcium hyperresponsivity to serotonin in patients with hypertension and depressive symptoms , 1999, Biological Psychiatry.

[34]  J. Bigger,et al.  The safety of tricyclic antidepressants in cardiac patients. Risk-benefit reconsidered. , 1993, JAMA.

[35]  C. Nemeroff,et al.  Platelet reactivity in depressed patients treated with paroxetine: preliminary findings. , 2000, Archives of general psychiatry.

[36]  H. Vetter,et al.  Elevated serum concentrations of soluble adhesion molecules in coronary artery disease and acute myocardial infarction. , 1997, European journal of medical research.

[37]  M. Bourassa,et al.  Five-Year Risk of Cardiac Mortality in Relation to Initial Severity and One-Year Changes in Depression Symptoms After Myocardial Infarction , 2002, Circulation.

[38]  A. Wear.  CIRCULATION , 1964, The Lancet.

[39]  J. Nordrehaug,et al.  Serotonin is associated with coronary artery disease and cardiac events. , 1999, Circulation.

[40]  B. Pollock,et al.  Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. , 1998, JAMA.

[41]  S. Kimmel,et al.  Selective Serotonin Reuptake Inhibitors and Myocardial Infarction , 2001, Circulation.

[42]  D. Hedeker,et al.  A RANDOM-EFFECTS MIXTURE MODEL FOR CLASSIFYING TREATMENT RESPONSE IN LONGITUDINAL CLINICAL TRIALS , 2001, Journal of biopharmaceutical statistics.

[43]  P. Shapiro,et al.  Depression and the course of coronary artery disease. , 1998, The American journal of psychiatry.

[44]  A. Yeung,et al.  Comparison of Coronary Thermodilution and Doppler Velocity for Assessing Coronary Flow Reserve , 2003, Circulation.

[45]  M. Furman,et al.  Circulating Monocyte-Platelet Aggregates Are a More Sensitive Marker of In Vivo Platelet Activation Than Platelet Surface P-Selectin: Studies in Baboons, Human Coronary Intervention, and Human Acute Myocardial Infarction , 2001, Circulation.

[46]  C. Nemeroff,et al.  The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. , 1998, Archives of general psychiatry.

[47]  N. Frasure-smith,et al.  Depression and 1-year prognosis in unstable angina. , 2000, Archives of internal medicine.

[48]  A. Ravindran,et al.  Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder , 1997, Biological Psychiatry.

[49]  M. Goberna,et al.  Elevated Thrombotic Activity after Myocardial Infarction: A 2-Year Follow-Up Study , 1998, Pathophysiology of Haemostasis and Thrombosis.

[50]  Y. Koga,et al.  Soluble form of P-selectin in patients with acute myocardial infarction. , 1994, Coronary artery disease.

[51]  D. Helmeste,et al.  Serotonin uptake inhibitors modulate intracellular Ca2+ mobilization in platelets. , 1995, European journal of pharmacology.