Depression, Epinephrine, Serotonin, & Platelet Function

几项研究表明，严重的抑郁和相关症状，如绝望，是发展为缺血性心脏病(IHD)的主要独立危险因素，也是指标性心肌梗死后死亡的主要独立危险因素。不仅血小板在止血、动脉粥样硬化和急性冠脉综合征中发挥中心作用，而且重度抑郁症患者的血小板GPIIb/IIIa受体数量增加，这是纤维蛋白原和其他配体的受体，也是血小板聚集和粘连发生的最终共同途径。总体目标是确定在重度抑郁症患者中，特定的分子通路，以及这些通路的相对贡献，通过这些通路，血小板GPIIb/IIIa受体从低亲和力构象转变为高亲和力构象。为了实现这一目标，我们将仔细研究单相、反复发作、重度抑郁症患者，不仅包括抑郁严重程度和血小板GPIIb/IIIa受体，还包括通过以下途径表征血小板自分泌“前馈”途径的：血小板5-羟色胺(5HT)和5HT2受体、血小板腺苷三磷酸(ATP)释放和尿11-脱氢血栓素Beta2的排泄：(1)在受控的基础条件下，(2)Trier社会应激试验(一种持续的精神应激源，通过外周释放血小板激动剂肾上腺素来刺激血小板功能)。此外，我们将使用帕罗西汀(一种选择性的5-羟色胺再摄取抑制剂)与地塞帕明(一种去甲肾上腺素能三环)进行随机、双盲治疗，以确定抗抑郁治疗减少高亲和力GPIIb/IIIa受体数量的分子机制。将使用最先进的技术，包括荧光激活的流式细胞术(FAFC)，血小板钙动员，以及评估体外抗抑郁药物对血小板功能的直接“药物效果”。将收集新的信息，不仅关于抑郁症患者对IHD易感性增加的生物学基础，还包括潜在的血栓血管靶点，通过这些靶点，精神药物干预可能会降低重度抑郁症患者未来心脏病发作和猝死的风险。

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.