Several studies have shown that major depression and associated symptoms, such as hopelessness, are a major independent risk factor in development of ischemic heart disease (IHD), and for death after an index myocardial infarction. Not only do platelets play a central role in hemostasis, atherosclerosis, and acute coronary syndromes, but patients with major depression exhibit increased numbers of the functional platelet GPIIb/IIIa receptor, the receptor for fibrinogen and other ligands, and the final common pathway by which platelet aggregation and adhesion occurs. The overall goal is to determine in patients with major depression, the specific molecular pathways, and relative contributions of these pathways, whereby the platelet GPIIb/IIIa receptor is converted from a low- affinity to high-affinity conformation. To accomplish this goal, we will scrutinize in men with unipolar, recurrent, major depression, not only depression severity and platelet GPIIb/IIIa receptors, but characterize platelet autocrine """"""""feed forward"""""""" pathways via: platelet serotonin (5HT) and 5HT2 receptors, platelet adenosine triphosphate (ATP) release, and urinary excretion of 11-dehydrothromboxane beta2: (1) under controlled basal conditions, (2) after the Trier Social Stress Test (a sustained mental stressor which will stimulate platelet function via peripheral release of the platelet agonist epinephrine). Moreover we will determine the molecular mechanisms whereby antidepressant treatment reduces numbers of high-affinity GPIIb/IIIa receptors, using randomized, double-blind, treatment with paroxetine (a selective 5HT reuptake inhibitor) in comparison to desipramine (a noradrenergic tricyclic). State-of- the-art techniques will be used, including fluorescence activated flow cytometry (FAFC), platelet calcium mobilization, and evaluation of in vitro antidepressant direct """"""""drug effects"""""""" of upon platelet function. Novel information will be gleaned regarding not only the biological basis for the increased vulnerability of depressed patients to IHD, but also potential thrombovascular targets whereby psychopharmacologic interventions might reduce the future risk of heart attack and sudden death in patients with major depression.
| Wulsin, Lawson R; Musselman, Dominique; Otte, Christian et al. (2009) Depression and whole blood serotonin in patients with coronary heart disease from the Heart and Soul Study. Psychosom Med 71:260-5 |
| Bruce, Erica C; Guo, Ying; Lawson, Kathryn C et al. (2008) Platelet thromboxane A2 secretion in patients with major depression responsive to electroconvulsive therapy. Psychosom Med 70:319-27 |
| Pace, Thaddeus W W; Mletzko, Tanja C; Alagbe, Oyetunde et al. (2006) Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 163:1630-3 |
| Bruce, Erica C; Musselman, Dominique L (2005) Depression, alterations in platelet function, and ischemic heart disease. Psychosom Med 67 Suppl 1:S34-6 |
