Depression, Epinephrine, Serotonin, & Platelet Function

几项研究表明，重度抑郁及其相关症状，如绝望，是缺血性心脏病（IHD）发展和指数心肌梗死后死亡的主要独立危险因素。血小板不仅在止血、动脉粥样硬化和急性冠状动脉综合征中发挥核心作用，而且重度抑郁症患者的功能性血小板GPIIb/IIIa受体数量增加，GPIIb/IIIa受体是纤维蛋白原和其他配体的受体，也是血小板聚集和粘附的最终共同途径。总体目标是确定重度抑郁症患者的特定分子途径，以及这些途径的相对贡献，血小板GPIIb/IIIa受体从低亲和力转化为高亲和力构象。为了实现这一目标，我们将仔细研究患有单极、复发性、重度抑郁症的男性，不仅研究抑郁症的严重程度和血小板GPIIb/IIIa受体，还将通过血小板5 -羟色胺（5HT）和5HT2受体、血小板三磷酸腺苷（ATP）释放和尿中11-脱氢血栓素β 2的排泄来表征血小板自分泌“前驱”途径。(1)在受控基础条件下，(2)在特里尔社会压力测试（一种持续的精神压力源，通过血小板激动剂肾上腺素的外周释放刺激血小板功能）之后。此外，我们将确定抗抑郁药物治疗减少高亲和力GPIIb/IIIa受体数量的分子机制，采用随机，双盲，帕罗西汀（一种选择性5HT再摄取抑制剂）与地西帕明（一种去肾上腺素能三环）治疗。将使用最先进的技术，包括荧光活化流式细胞术（FAFC），血小板钙动员，以及评估体外抗抑郁药对血小板功能的直接“药物效应”。新的信息不仅将收集到抑郁症患者对IHD易感性增加的生物学基础，而且还将收集到潜在的血栓血管靶点，即精神药理学干预可能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.