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状动脉综合征（ACS）复发的风险。动脉粥样硬化斑块破裂后血小板血栓形成是ACS复发的基础，5-羟色胺（5-HT）是血小板反应性的重要刺激物。由于血小板5-HT 2A受体的上调，5-HT介导的血小板反应性增加，增加血栓形成，并已被假定为联系抑郁症与ACS复发的主要机制。 目前尚不清楚抑郁症干预是否能逆转抑郁症患者ACS事件风险的增加。选择性5-羟色胺再摄取抑制剂（SSRIs）和5-HT 2A受体抗抑郁药以相同的速度改善抑郁症状。这两种类型的抗抑郁药都可以通过改善抑郁症状（CNS介导的间接作用）来减弱血小板反应性。然而，SSRI和5-HT 2A受体拮抗剂可能对血小板反应性具有额外但不同的药理学作用（直接血小板作用）。考虑到抑郁、血小板血栓形成和ACS之间的关系，那些不仅能够改善抑郁症状而且能够直接抑制血小板反应性的抗抑郁药可能在抑制血小板血栓形成和预防ACS事件方面具有最大的净（直接+间接）影响。 将进行一项横断面病例对照研究，比较有冠心病（CAD）病史的抑郁症和非抑郁症患者之间5-NT介导的血小板反应性和血栓形成。还将评估SSRI和5-HT 2A受体拮抗剂的直接体外作用。将进行一项随机、3个活性组、1个对照组的抑郁干预试验，以比较药物（SSRI和5-HT 2A受体拮抗剂）治疗和非药物（认知行为治疗）治疗对抑郁CAD患者血小板反应性和血栓形成的体内净效应。通过定义直接血小板、CNS介导的间接和净效应对血小板反应性和血栓形成的差异，可以测试最能抑制血小板反应性和血栓形成的抑郁干预措施是否能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.