Translational Studies of Depression, Platelets, & CAD

描述(由申请人提供)：抑郁症状显著增加急性冠脉综合征复发(ACS)的风险。在破裂的动脉粥样硬化斑块上形成的血小板血栓是急性冠脉综合征复发的基础。5-羟色胺(5-羟色胺)是一种重要的血小板反应性刺激物。由于血小板5-HT2a受体的上调，5-羟色胺介导的血小板反应性增加，增加了血栓的形成，并被认为是将抑郁与ACS复发联系起来的主要机制。 目前尚不清楚抑郁症干预是否能逆转抑郁症患者发生急性冠脉综合征的风险增加。选择性5-羟色胺再摄取抑制剂(SSRIs)和5-HT2A受体抗抑郁药改善抑郁症状的效率相同。这两种类型的抗抑郁药都可以通过改善抑郁症状(中枢神经系统介导的间接效应)来减弱血小板的反应性。然而，SSRIs和5-HT2A受体拮抗剂可能对血小板反应性有额外但不同的药理作用(直接的血小板作用)。鉴于抑郁、血小板血栓形成与急性冠脉综合征的关系，那些既能改善抑郁症状又能直接抑制血小板反应性的抗抑郁药物在抑制血小板血栓形成和预防急性冠脉综合征事件方面可能具有最大的净(直接+间接)影响。 一项横断面病例对照研究将比较有冠心病病史的抑郁和非抑郁患者的5-NT介导的血小板反应性和血栓形成。SSRIs和5-HT2A受体拮抗剂的直接体外效应也将被评估。一项随机、3个有效组、1个对照组的抑郁干预试验将比较药物治疗(SSRIs和5-HT2A受体拮抗剂)和非药物治疗(认知行为治疗)对抑郁冠心病患者的血小板反应性和血栓形成的间接影响。通过确定直接作用于血小板、中枢神经系统介导的间接作用和净作用对血小板反应性和血栓形成的不同，最能抑制血小板反应性和血栓形成的抑郁干预措施可以被测试以降低心血管发病率和死亡率。

DESCRIPTION (provided by applicant): Depressive symptoms significantly increase the risk of acute coronary syndromes recurrence (ACS). Platelet-thrombus formation over a disrupted atherosclerotic plaque is fundamental for ACS recurrence.Serotonin (5-HT) is an important stimulant of platelet reactivity. Increased 5-HT-mediated platelet reactivity due to upregulation of the platelet 5-HT2A receptor, increases thrombosis formation and has been postulated to a major mechanism linking depression to ACS recurrence. It is not known at this time if depression interventions reverse the increased risk of ACS events in depressed patients. The selective serotonin reuptake inhibitors (SSRIs) and the 5-HT2A receptor antidepressants improve depressive symptoms at equal rates. Both types of antidepressants may attenuate platelet reactivity by improving depressive symptoms (CNS mediated indirect effects). However, the SSRIs and the 5-HT2A receptor antagonists may have additional but divergent pharmacologic effects on platelet reactivity (direct platelet effects). Given the relationship between depression, platelet-thrombus formation, and the ACS, those antidepressants capable not only of improving depression symptoms but also of inhibiting platelet reactivity directly, may have the greatest net (direct + indirect) impact in inhibiting platelet-thrombus formation and preventing ACS events. A cross-sectional, case-control study will be conducted to compare 5-NT-mediated platelet reactivity and thrombosis between depressed and non-depressed patients with coronary artery disease (CAD) history. The direct in vitro effects of the SSRIs and 5-HT2A receptor antagonists will also be assessed. A randomized, 3 active arm, 1 control arm, depression intervention trial will be conducted to compare the in vivo net effects of pharmacologic (the SSRIs and 5-HT2A receptor antagonists) treatment and the indirect effects of a non-pharmacologic (cognitive behavioral therapy) treatment on platelet reactivity and thrombosis in depressed CAD patients. By defining differences in direct-platelet, CNS-mediated indirect, and net effects on platelet reactivity and thrombus formation, depression interventions that are best at inhibiting platelet reactivity and thrombogenicity can then be tested for reducing cardiovascular morbidity and mortality.