Defining the Mechanisms of Menopause-Associated Sleep and Mood Disturbances

定义更年期相关睡眠和情绪障碍的机制

• 批准号: 7735854
• 负责人: HADINE JOFFE
• 金额: $ 40.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7735854
• 关键词: Address; Adverse effects; Antidepressive Agents; Biological; Brain; Clinical; Comorbidity; Complex; Consult; Development; Disease; Estradiol; Estrogens; Etiology; Experimental Models; Exposure to; Goals; Gonadal Hormones; Hormones; Hot flushes; Intervention Studies; Lead; Link; Major Depressive Disorder; Measurement; Measures; Medical; Menopausal Symptom; Menopause; Modeling; Moods; Observational Study; Pathway interactions; Perception; Perimenopause; Physiological; Postmenopause; Premenopause; Productivity; Public Health; Relative (related person); Research; Risk; Sleep; Sleep disturbances; Sleeplessness; Symptoms; Testing; Therapeutic; Therapeutic Effect; Time; Woman; Women' s Health; Work; base; burden of illness; depression; disturbance in affect; evidence base; health care service utilization; hormone therapy; improved; inhibitor/antagonist; insight; middle age; negative mood; novel; public health relevance; reuptake; suicidal risk; theories; therapeutic target; vehicular accident

DESCRIPTION (provided by applicant): The broad goal of this project is to define the mechanisms of menopause-associated insomnia and depression in order to improve therapeutic approaches to these common and debilitating disorders. Women are at increased risk for insomnia and depression during the perimenopause and early postmenopause. Hot flashes have been linked to menopause-associated insomnia and depression, but the biological basis of these associations is poorly understood. This proposal will explore the basis for the association between hot flashes and depression to determine if hot flashes are associated with depression: (1) because hot flashes are merely a marker for menopause-associated alterations in gonadal hormones, and/or (2) because hot flashes exert their effects on depression through their sleep-disrupting effects. In this proposal, we will dissect the complex interactions among gonadal hormones and menopausal symptoms in women using an experimental model of hot flashes in premenopausal women (Aims 1 and 2) and a clinical intervention study in postmenopausal women (Aim 3). Aim 1 will determine the effect of hot flashes on sleep to test the hypotheses that hot flashes worsen objectively measured sleep and lead to the perception of poor sleep quality over time. Aim 2 will identify the relative effects of hot flashes and sleep disruption on mood. This will test the hypotheses that objectively measured sleep disturbance has a greater effect than hot flashes on mood and that perception of poor sleep correlates with negative mood. Aim 3 will define the relative effects of hot flashes and changes in estradiol on mood. This will test the hypotheses that estrogen treatment has a similar therapeutic effect on mood in women with and without hot flashes and that increasing levels of estradiol correlate with improvement in mood. The significance of these findings lies in their ability to define the causal contributions of gonadal hormone changes, hot flashes and sleep disruption to menopause-associated mood disturbance. Since the results of the Women's Health Initiative described important risks of hormone therapy, fewer women are being treated with hormone therapy. Similarly, although serotonergic reuptake inhibitors are effective antidepressants and suppress hot flashes in some women, their side effect profiles may limit their acceptability. Novel treatment approaches are needed. Understanding the causal pathways between alterations in gonadal hormones, hot flashes, sleep disruption, and mood disturbance will inform the development of rational and targeted therapeutic strategies for management of menopause-associated depression. PUBLIC HEALTH RELEVANCE: This study will identify the mechanisms of menopause-associated insomnia and depression, common and debilitating disorders for which women are at increased risk during midlife. The proposed mechanistic studies will define the impact of hot flashes on sleep and the relative effects of gonadal hormones, hot flashes, and sleep disruption on mood disturbance. This work has important public health relevance because it will inform the development of rational therapeutic strategies and lead to novel treatment paradigms for menopause- associated depression.

描述（由申请人提供）：该项目的总体目标是确定更年期相关失眠和抑郁的机制，以改进这些常见和衰弱性疾病的治疗方法。女性在围绝经期和绝经后早期失眠和抑郁的风险增加。潮热与更年期相关的失眠和抑郁有关，但人们对这些关联的生物学基础知之甚少。该提案将探讨潮热与抑郁症之间关联的基础，以确定潮热是否与抑郁症相关：（1）因为潮热仅仅是绝经期相关性腺激素变化的标志，和/或（2）因为潮热通过扰乱睡眠的方式对抑郁症产生影响。在本提案中，我们将使用绝经前女性潮热实验模型（目标 1 和 2）和绝经后女性临床干预研究（目标 3）来剖析女性性腺激素和更年期症状之间复杂的相互作用。目标 1 将确定潮热对睡眠的影响，以测试以下假设：潮热会恶化客观测量的睡眠，并随着时间的推移导致睡眠质量较差的感觉。目标 2 将确定潮热和睡眠中断对情绪的相对影响。这将检验以下假设：客观测量的睡眠障碍比潮热对情绪的影响更大，并且睡眠不佳的感觉与消极情绪相关。目标 3 将定义潮热和雌二醇变化对情绪的相对影响。这将检验以下假设：雌激素治疗对患有或不患有潮热的女性的情绪具有相似的治疗效果，并且雌二醇水平的增加与情绪的改善相关。这些发现的重要性在于它们能够确定性腺激素变化、潮热和睡眠中断与更年期相关情绪障碍的因果关系。由于妇女健康倡议的结果描述了激素治疗的重要风险，因此接受激素治疗的女性越来越少。同样，尽管血清素再摄取抑制剂是有效的抗抑郁药并可抑制某些女性的潮热，但其副作用可能会限制其可接受性。需要新的治疗方法。了解性激素变化、潮热、睡眠中断和情绪障碍之间的因果关系，将为制定合理且有针对性的治疗策略来管理更年期相关抑郁症提供信息。公共健康相关性：这项研究将确定与更年期相关的失眠和抑郁症的机制，这些常见的和使人衰弱的疾病是女性在中年时面临更高风险的疾病。拟议的机制研究将定义潮热对睡眠的影响以及性激素、潮热和睡眠中断对情绪障碍的相对影响。这项工作具有重要的公共卫生意义，因为它将为合理治疗策略的制定提供信息，并为更年期相关抑郁症带来新的治疗范例。