Depression and Coronary Artery Atherosclerosis in Premenopausal

描述（由申请人提供）：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。绝经期冠状动脉粥样硬化（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影响绝经时CAA程度的绝经前属性。本应用程序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。虽然冠心病的出现早于抑郁，提示抑郁可能是冠心病的独立危险因素，但CAA在冠心病症状出现前已发展数十年，抑郁与CAA之间的时间关系尚不清楚。在抑郁症和冠心病的病理中，一个共同的潜在机制是血清素能系统。重要的是，有初步证据表明，通常用于治疗抑郁症的选择性血清素再摄取抑制剂（SSRIs）对促进动脉粥样硬化（血小板活化、炎症、低心率变异性）的过程有有益作用。绝经前食蟹猴（Macaca fascicularis）是研究冠状动脉粥样硬化和抑郁行为的既定模型，我们首次提出确定抑郁与亚临床CAA进展之间的时间关系。此外，我们将研究用SSRI操纵神经血清素能功能对心血管和行为的影响。研究人员将给猴子喂食致动脉粥样硬化的食物，并在18个月的预处理期间记录它们的抑郁行为。动脉粥样硬化程度将通过髂活检确定。然后，这些猴子将接受SSRI或安慰剂治疗，平衡预处理的抑郁行为，并在18个月后评估动脉粥样硬化的进展。具体目的是确定：抑郁行为与动脉粥样硬化之间关系的大小；是否通过针对神经血清素系统的治疗，或通过减少抑郁行为，或两者兼而有之来减缓动脉粥样硬化的进展；与早期动脉粥样硬化和抑郁行为相关的病理生理特征（如血小板活化、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。这些结果将与公共卫生相关，因为它们将确定绝经前抑郁症对后期冠心病风险的相对重要性，以及这种风险是否可逆，塑造抗抑郁治疗的时机和侵略性，并提供证据支持前瞻性临床试验的需要，以检测SSRI治疗对心血管结果的改变。

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.