Depression and Coronary Artery Atherosclerosis in Premenopausal Primates

绝经前灵长类动物的抑郁症和冠状动脉粥样硬化

• 批准号: 7317031
• 负责人: Carol A. Shively
• 金额: $ 68.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7317031
• 关键词: Antidepressive Agents; Appearance; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Behavior; Behavioral; Biopsy; Cardiovascular system; Characteristics; Clinical Trials; Coronary artery; Deltastab; Development; Elderly; Equilibrium; Event; Functional disorder; Future; Goals; Heart Rate; Individual; Inflammation; Inflammatory; Lesion; Life; Lipids; Macaca fascicularis; Malignant Neoplasms; Menopause; Mental Depression; Monkeys; Morbidity - disease rate; Outcome; Ovarian; Pathogenesis; Pathology; Placebos; Plasma; Platelet Activation; Postmenopause; Premenopause; Prevalence; Primates; Process; Public Health; Purpose; Relative (related person); Research; Research Personnel; Risk; Risk Factors; Selective Serotonin Reuptake Inhibitor; Serotonin; Shapes; Source; Staging; Study models; Symptoms; System; Time; Woman; atherogenesis; depressive symptoms; feeding; human study; improved; mortality; nonhuman primate; programs; prospective; relating to nervous system; research study; subclinical depression; treatment effect

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.

描述（由申请人提供）：CHD 是美国女性发病和死亡的主要原因，超过了所有癌症的总和。绝经时冠状动脉粥样硬化（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期 CAA 程度的绝经前属性。该应用的重点是确定抑郁症对绝经前 CAA 的相对影响，以及它是否是“可逆”风险的来源。尽管冠心病的出现早于抑郁症，这表明抑郁症可能是冠心病的独立危险因素，但CAA在冠心病症状出现之前几十年就已经发生，并且抑郁症和CAA之间的时间关系尚不清楚。抑郁症和冠心病病理学中涉及的一种常见的潜在机制是血清素能系统。重要的是，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（SSRI）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。我们利用绝经前食蟹猴（Macaca fasciculis）这一研究冠状动脉粥样硬化和抑郁行为的既定模型，首次确定抑郁症与亚临床 CAA 进展之间的时间关系。此外，我们将研究用 SSRI 控制神经血清素功能对心血管和行为的影响。猴子将被喂食致动脉粥样硬化的饮食，并在 18 个月的预处理期间记录抑郁行为。动脉粥样硬化程度将通过髂活检确定。然后，猴子将接受 SSRI 或安慰剂治疗，平衡治疗前的抑郁行为，并在 18 个月后评估动脉粥样硬化进展。具体目标是确定： 抑郁行为与动脉粥样硬化之间关系的大小；针对神经血清素系统的治疗或减少抑郁行为或两者同时进行，是否可以减缓动脉粥样硬化的进展；与早期动脉粥样硬化形成和抑郁行为相关的病理生理特征（例如血小板活化、炎症过程、心率变异性、卵巢功能障碍、血浆脂质）；以及治疗对这些特征的影响。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，以及该风险是否可逆，确定抗抑郁治疗的时机和积极性，并提供支持前瞻性临床试验需求的证据能够检测 SSRI 治疗后心血管结局的变化。