Melatonin in Menopausal Depression

描述（由申请人提供）：绝经期重度抑郁发作是一种明确的现象，可引起广泛的发病率和死亡率。然而，其发病机制和治疗尚未系统研究。医学研究主要集中在心血管系统和生殖系统，而对中枢神经系统的关注相对较少。我们观察到与正常对照（NC）女性相比，绝经期抑郁症患者（DP）褪黑激素分泌增加，晨间偏移延迟。本修订申请的目的是检验与NC妇女相比，绝经期DP的褪黑激素振幅增加和早晨偏移延迟的假设，主要归因于a)光/暗和睡眠/觉醒周期的改变以及b)生殖和其他内分泌功能的改变。根据我们的概念模型，绝经期DP患者下丘脑对性腺类固醇的敏感性降低，这扰乱了昼夜节律的正常调节，并表现为褪黑激素分泌增加，早晨偏移延迟。在夜间昏暗的光线下醒来次数增加，导致醒来时间延迟，暴露在早晨明亮的光线下的时间减少和延迟，白天睡眠增加或对光线暴露的敏感性不足或降低，使问题恶化。让人想起仓鼠在冬季夜间长时间黑暗中的发现，绝经期DP增加了褪黑激素持续时间，延长了睡眠时间，近期性腺功能减退，促卵泡激素（FSH）水平升高，体重指数（BMI）与抑郁等级相关。我们的目的是扩展和重复我们关于绝经期DP中褪黑激素分泌异常的初步发现，并探讨光照、睡眠、活动和生殖内分泌功能可能的影响因素，为未来研究开发针对特定致病因素的治疗方法奠定基础。在50名符合DSM-IV标准的绝经前后DP患者和50名年龄和绝经状态相匹配的NC女性中，我们将测量血浆褪黑激素（在昏暗光线下30分钟采样）、光照、睡眠和活动（通过多导睡眠仪和Actillume）、生殖内分泌功能（通过促性腺激素和类固醇水平）以及与情绪相关的BMI的24小时周期之间的相位、幅度、波形和时间关系。作为我们正在进行的经前、妊娠和产后抑郁症的时间生物学研究的延伸，这项研究有可能导致新的假设和治疗策略的发展。这一发现可能会影响人们对其他与女性生殖周期有关的抑郁症的理解。它还将确认并扩展我们对抑郁症女性时间生物学异常的理解，作为开发创新治疗方法的基础。

DESCRIPTION (provided by applicant): Now a clearly identified phenomenon, a major depressive episode at menopause can cause extensive morbidity and mortality. Its pathogenesis and treatment, however, have not been systematically investigated. Medical studies have focused on the cardiovascular and reproductive systems, with relatively little attention being paid to the central nervous system. We have observed increased melatonin secretion and delayed morning offset in menopausal depressed patients (DP) compared with normal control (NC) women. The aim of this revised application is to test the hypothesis that compared with NC women, menopausal DP have increased melatonin amplitude and delayed morning offset, attributable primarily to alterations in a) light/dark and sleep/wake cycles and b) reproductive and other endocrine functions. According to our conceptual model, menopausal DP have a decreased hypothalamic sensitivity to gonadal steroids, which disrupts the normal regulation of circadian rhythms, and is manifested in increased melatonin secretion with delayed morning offset. Increased arousals in dim light at night, resulting in delayed wake time with decreased and delayed exposure to morning bright light, increased daytime sleep or insufficient or decreased sensitivity to light exposure, exacerbate the problem. Reminiscent of the findings in hamsters during extended dark periods at night in winter, menopausal DP have increased melatonin duration, extended sleep time, recent hypogonadism, higher Follicle Stimulating Hormone (FSH) levels and Body Mass Index (BMI) that correlate with depression ratings. Our aim in this proposal is to extend and replicate our preliminary findings of abnormal melatonin secretion in menopausal DP and investigate the likely contributing factors of light, sleep, activity and reproductive endocrine function, as a basis for developing treatments targeted to specific pathogenic factors in future studies. In 50 peri- or post-menopausal DP by DSM-IV criteria, and in 50 NC women, matched for age and menopausal status, we will measure the phase, amplitude, waveform and temporal relations among 24-hour cycles of plasma melatonin (30 minute sampling in dim light), illumination, sleep and activity (by polysomnography and Actillume), as well as reproductive endocrine function (by gonadotropin and steroid levels) and BMI, in relation to mood. As an extension of our ongoing investigation of the chronobiology of premenstrual, pregnancy and postpartum depression, this study has the potential to lead to the development of new hypotheses and treatment strategies. The findings may impact the understanding of other depressive disorders related to the reproductive cycle in women. It also will confirm and extend our understanding of chronobiological abnormalities in depressed women as the basis for developing innovative treatments.