Melatonin in Menopausal Depression

描述（由申请人提供）：现在一个明确的现象，一个严重的抑郁症发作在绝经期可导致广泛的发病率和死亡率。然而，其发病机制和治疗尚未得到系统研究。医学研究集中在心血管和生殖系统，相对较少关注中枢神经系统。我们已经观察到增加褪黑激素分泌和延迟早晨偏移更年期抑郁症患者（DP）与正常对照（NC）妇女相比。本修订申请的目的是检验以下假设：与NC女性相比，绝经期DP具有增加的褪黑激素幅度和延迟的早晨偏移，主要归因于a）亮/暗和睡眠/觉醒周期和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下丘脑对性腺类固醇的敏感性降低，这破坏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。夜间在昏暗的光线下觉醒增加，导致觉醒时间延迟，早晨明亮的光线暴露减少和延迟，白天睡眠增加或对光暴露的敏感性不足或降低，加剧了问题。让人想起仓鼠在冬季夜间长时间黑暗期间的发现，绝经期DP具有增加的褪黑激素持续时间，延长的睡眠时间，近期性腺功能减退，更高的卵泡刺激素（FSH）水平和体重指数（BMI），这些与抑郁评分相关。我们的目的是在这个建议是扩展和复制我们的初步研究结果异常褪黑激素分泌在绝经期DP和调查可能的影响因素的光，睡眠，活动和生殖内分泌功能，作为基础上开发针对特定的致病因素在未来的研究治疗。在50例符合DSM-IV标准的绝经前或绝经后DP和50例年龄和绝经状态匹配的NC妇女中，我们将测量血浆褪黑素24小时周期之间的相位、振幅、波形和时间关系（在昏暗的灯光下采样30分钟）、照明、睡眠和活动（通过多导睡眠图和Actillume），以及生殖内分泌功能（通过促性腺激素和类固醇水平）和BMI，与情绪有关。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。这些发现可能会影响对与女性生殖周期相关的其他抑郁症的理解。它还将证实和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.