Depression and Coronary Artery Atherosclerosis in Premenopausal

描述（由申请人提供）：CHD是美国女性发病率和死亡率的主要原因，超过所有癌症的总和。绝经期冠状动脉粥样硬化（CAA）的程度是绝经后CHD风险的重要决定因素。一个主要的挑战是确定绝经前的属性，影响CAA的程度在绝经期。本申请的重点是确定抑郁症对绝经前CAA的相对贡献，以及它是否是“可逆”风险的来源。尽管CHD的出现早于抑郁，表明抑郁可能是CHD的独立危险因素，但CAA在CHD症状出现之前数十年就已发展，抑郁与CAA之间的时间关系尚不清楚。在抑郁症和CHD的病理学中涉及的一个共同的潜在机制是多巴胺能系统。重要的是，有初步证据表明，通常用于治疗抑郁症的选择性5-羟色胺再摄取抑制剂（SSRIs）对促进动脉粥样硬化形成的过程（血小板活化，炎症，低心率变异性）具有有益作用。使用绝经前食蟹猴（食蟹猴），冠状动脉粥样硬化和抑郁行为的研究模型，我们建议首次确定抑郁症和亚临床CAA进展之间的时间关系。此外，我们将研究用SSRI操纵神经递质功能的心血管和行为效应。在18个月的预处理期间，将对猴喂食致动脉粥样硬化饮食并记录抑郁行为。将通过髂动脉活检确定动脉粥样硬化程度。然后用SSRI或安慰剂治疗猴子，平衡治疗前的抑郁行为，并在18个月后评估动脉粥样硬化进展。具体目的是确定：抑郁行为和动脉粥样硬化之间的关系的程度;是否动脉粥样硬化的进展是通过靶向神经5-羟色胺系统的治疗，或通过减少抑郁行为，或两者兼而有之;病理生理特点（例如血小板活化、炎症过程、心率变异性、卵巢功能障碍，与早期动脉粥样硬化形成和抑郁行为相关的血浆脂质）;以及治疗对这些特征的影响。这些结果将与公共卫生相关，因为它们将确定绝经前抑郁症对以后冠心病风险的相对重要性以及这种风险是否可逆，塑造抗抑郁药治疗的时机和积极性，并提供证据支持需要一项前瞻性临床试验来检测SSRI治疗的心血管结局变化。

DESCRIPTION (provided by applicant): CHD is the leading cause of morbidity and mortality of women in the US, exceeding that of all cancers combined. The extent of coronary artery atherosclerosis (CAA) at menopause is an important determinant of postmenopausal CHD risk. A major challenge is to identify premenopausal attributes which influence CAA extent at the menopause. This application is focused on determining the relative contribution of depression to premenopausal CAA, and whether it is a source of "reversible" risk. Although the appearance of CHD is predated by depression, suggesting that depression may be an independent risk factor for CHD, CAA develops for decades before the appearance of CHD symptoms, and the temporal relationship between depression and CAA is unclear. One common underlying mechanism implicated in both the pathology of depression and CHD is the serotonergic system. Importantly, there is initial evidence that selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, have beneficial effects on processes that promotes atherogenesis (platelet activation, inflammation, low heart rate variability). Using premenopausal cynomolgus monkeys (Macaca fascicularis), an established model for the study of both coronary artery atherogenesis and depressive behavior, we propose to determine for the first time the temporal relationship between depression and subclinical CAA progression. Furthermore, we will examine the cardiovascular and behavioral effects of manipulating neural serotonergic function with SSRI's. Monkeys will be fed an atherogenic diet and depressive behavior recorded during an 18-month pretreatment period. Atherosclerosis extent will be determined by iliac biopsy. The monkeys then will be treated with an SSRI or placebo, balanced on pretreatment depressive behavior, and atherosclerosis progression will be assessed after 18 months. The specific aims are to determine: the magnitude of the relationship between depressive behavior and atherosclerosis; whether atherosclerosis progression is slowed by treatment targeting the neural serotonin system, or by reductions in depressive behavior, or both; pathophysiologic characteristics (e.g. platelet activation, inflammatory processes, heart rate variability, ovarian dysfunction, plasma lipids) associated with both early atherogenesis and depressive behavior; and the effects of treatment on these characteristics. The results will be relevant to public health as they will determine the relative importance of premenopausal depression to later risk for CHD and whether that risk is reversible, shape the timing and aggressiveness of antidepressant therapy, and provide evidence supporting the need for a prospective clinical trial powered to detect changes in cardiovascular outcomes with SSRI treatment.