Depression and Coronary Artery Atherosclerosis in Premenopausal

描述(申请人提供)：冠心病是美国女性发病率和死亡率的主要原因，超过了所有癌症的总和。绝经后冠状动脉粥样硬化(CAA)的程度是绝经后冠心病风险的重要决定因素。一个主要的挑战是确定在绝经时影响CAA程度的绝经前属性。这项应用侧重于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。虽然抑郁症的出现早于冠心病的出现，提示抑郁症可能是冠心病的独立危险因素，但在出现冠心病症状之前，CAA已经发展了几十年，抑郁症与CAA之间的时间关系尚不清楚。抑郁症和冠心病的一个共同的潜在机制是5-羟色胺能系统。重要的是，有初步证据表明，选择性5-羟色胺再摄取抑制剂(SSRI)，通常用于治疗抑郁症，在促进动脉粥样硬化形成(血小板激活、炎症、低心率变异性)的过程中具有有益效果。利用绝经前食蟹猴(猕猴)，一种已建立的研究冠状动脉动脉粥样硬化形成和抑郁行为的模型，我们建议首次确定抑郁和亚临床CAA进展之间的时间关系。此外，我们还将研究SSRI对调节神经5-羟色胺能功能的心血管和行为的影响。猴子将被喂食18个月预处理期间记录的致动脉粥样硬化饮食和抑郁行为。动脉粥样硬化程度将通过髂骨活检来确定。然后，猴子将接受SSRI或安慰剂治疗，平衡治疗前的抑郁行为，18个月后将评估动脉粥样硬化的进展。其具体目的是确定：抑郁行为和动脉粥样硬化之间的关系的大小；动脉粥样硬化的进展是通过针对神经5-羟色胺系统的治疗，还是通过减少抑郁行为，或者两者兼而有之；与早期动脉粥样硬化形成和抑郁行为有关的病理生理特征(例如，血小板激活、炎症过程、心率变异性、卵巢功能障碍、血脂)；以及治疗对这些特征的影响。这些结果将与公共健康相关，因为它们将确定绝经前抑郁与后来患CHD的风险的相对重要性，以及这种风险是否可逆，塑造抗抑郁药物治疗的时机和力度，并提供证据支持需要进行前瞻性临床试验，以检测SSRI治疗后心血管结果的变化。

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.