Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause

描述（由申请人提供）：心血管疾病（CVD）是女性死亡的主要原因，目前在美国，由于绝经后心血管风险负担更大，导致女性死亡人数多于男性。抑郁症使患心血管疾病的风险增加两倍。了解抑郁症与心血管疾病之间的联系对女性尤其重要，因为女性患抑郁症的比例是男性的两倍。雌激素（E2）的减少不仅会增加女性患心血管疾病的风险，还会导致抑郁症。计划中的研究将在围绝经期E2停药的背景下，检查CVD和抑郁症（炎症、内皮功能障碍、心脏自主神经失调和代谢紊乱）中常见的风险生物介质。心血管、神经内分泌和炎症对压力的反应性升高也定义了风险的特征，并对上述风险介质产生不利影响。虽然E2对抑郁症和心血管疾病常见的风险介质和应激反应具有有益作用，并且对减轻抑郁症状也有效，但E2在心脏保护和抗抑郁反应方面存在实质性差异。计划中的研究旨在确定风险概况，以预测E2在预防围绝经期妇女心血管风险进展和抑郁症出现方面的最大益处。基于CVD和抑郁风险的共同介质，我们预测，与从未患过抑郁症的女性相比，有复发性抑郁症病史的围绝经期女性在12个月内心血管风险的进展更大，抑郁症的发生率更高，E2对心血管有益。共有320名围绝经期妇女（45-55岁；STRAW阶段1）符合E2的候选人将被研究。根据SCID访谈，其中一半（n=160）将有复发性抑郁症病史（2+抑郁发作，1+必须是重度抑郁症），但处于缓解期（>2年，目前的CES-D评分为d8）， 160名将被招募为从未抑郁的围绝经期妇女（也是CES-D d8）。在医学和精神病学评估后，包括终身创伤暴露评估，女性将接受基线心血管风险概况的测试，其中包括：1)心脏自主张力-由压力感受器敏感性定义，涉及无创测量HR和搏动血压变化；2)应激反应性-基于特里尔社会压力测试中心血管（血压和血管阻力）、神经内分泌（皮质醇）和炎症（IL-6）反应的综合评分；3)内皮功能——基于超声测量反应性充血时血流介导的肱动脉扩张；5)代谢风险-根据符合代谢综合征的标准标准或口服葡萄糖耐量试验表现出胰岛素抵抗来确定。使用双盲程序，受试者将被随机分配到172-E2透皮组（100微克/天）或安慰剂组，为期12个月，并且每3个月给活动性ERT组的女性服用微孕酮(P)(3个月中的2个月服用安慰剂P)，安慰剂组的女性每月服用安慰剂P。在干预期间，将定期评估受试者的抑郁、依从性、生命体征和副作用。在治疗期的第6个月和第12个月，将重复基线评估时进行的所有心血管程序。这是一项机制研究，旨在检测未经治疗的围绝经期妇女心血管风险进展的预测因素（复发性抑郁症病史）和调节因素（创伤暴露），以及E2治疗对抑郁和心血管风险有益作用的调节因素（应激反应谱）。这项研究的结果旨在确定行为或生物干预的潜在目标，并提供可以在生命其他阶段发生的抑郁症中进行测试的机制假设，以及帮助推进个体化医疗的目标。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in women, and currently kills more women than men in the U.S. due to the greater burden of cardiovascular risk after menopause. Depression increases risk for CVD by two-fold. Understanding the depression-CVD link has particular relevance for women since they suffer from depression at a rate twice that of men. Estrogen (E2) withdrawal not only increases cardiovascular risk in women, but is also involved in depression. The planned study will examine the biological mediators of risk that are common to both CVD and depression (inflammation, endothelial dysfunction, cardiac autonomic dysregulation, and metabolic disturbance) within the context of E2 withdrawal during the perimenopause. Heightened cardiovascular, neuroendocrine and inflammatory reactivity to stress also define a profile of risk and adversely impacts the mediators of risk described above. While E2 is associated with beneficial effects on the mediators of risk common to depression and CVD and on stress reactivity, and is also effective in reducing depressive symptoms, there is substantial variance in both the cardioprotective and antidepressant responses to E2. The planned research intends to identify a profile of risk that would predict the greatest benefits of E2 in the prophylaxis of the progression of cardiovascular risk and appearance of depression in perimenopausal women. Based on the shared mediators of risk for CVD and depression, we predict that perimenopausal women with histories of recurrent depression will show greater progression of cardiovascular risk and suffer from more depression over 12 months than never depressed women, and show cardiovascular benefit of E2. A total of 320 perimenopausal women (45-55 years of age; STRAW stage-1) who are eligible candidates for E2 will be studied. Based on SCID interview, one half (n=160) will have a history of recurrent depression (2+ depressive episodes, 1+ must be major depression), but in remission (>2 yrs and with current CES-D score d 8) and 160 will be recruited as never depressed perimenopausal women (also CES-D d 8). Following medical and psychiatric evaluation, including assessment of lifetime trauma exposure, women will be tested for baseline cardiovascular risk profiles which include: 1) Cardiac Autonomic Tone - defined by baroreceptor sensitivity involving the non-invasive measurement of HR and beat-to-beat change in BP; 2) Stress Reactivity - based on a composite score involving cardiovascular (blood pressure and vascular resistance), neuroendocrine (cortisol), and inflammatory (IL-6) responses to the Trier Social Stress Test; 3) Endothelial Function - based on ultrasound measurement of flow mediated dilatation of the brachial artery during reactivity hyperemia; and 5) Metabolic Risk - determined based on meeting standard criteria for the metabolic syndrome or exhibiting insulin resistance in response to the oral glucose tolerance test. Using double-blind procedures, subjects will then be randomized to either transdermal 172-E2 (100ug/day) or placebo for 12 months, and micronized progesterone (P) will be given every 3 months to women on active ERT (placebo P given on 2 out of 3 months) and placebo P will be given every month to women on placebo ERT. Subjects will be assessed at regular intervals during the intervention for depression, compliance, vitals, and side effects. At months 6 and 12 of the treatment period, all cardiovascular procedures conducted at the baseline assessment will be repeated. This is a mechanistic study designed to examine the predictors (history of recurrent depression) and moderators (trauma exposure) of cardiovascular risk progression in untreated perimenopausal women over 12 months, and the mediators (stress reactivity profile) of the beneficial effects of E2 treatment on depression and cardiovascular risk. The results of this study are intended to identify potential targets for behavioral or biological intervention and provide mechanistic hypotheses that can be tested in depressions that occur during other stages of life as well as help advance the goals of individualized medicine.