Melatonin in Menopausal Depression

描述(由申请者提供)：现在，更年期的主要抑郁发作是一种明确识别的现象，可导致广泛的发病率和死亡率。然而，其发病机制和治疗方法尚未得到系统的研究。医学研究的重点是心血管和生殖系统，而对中枢神经系统的关注相对较少。我们观察到绝经期抑郁症患者(DP)与正常对照组(NC)女性相比，褪黑激素分泌增加和晨间抵销延迟。这项修订应用的目的是检验这一假设，即与正常对照组女性相比，绝经期糖尿病患者褪黑激素幅度增加，早晨抵消延迟，这主要归因于a)明/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的下丘脑对性腺类固醇的敏感性降低，这扰乱了正常的昼夜节律调节，表现为褪黑激素分泌增加，早晨抵消延迟。夜间在昏暗光线下的唤醒增加，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，或者对光线暴露的敏感度不足或降低，加剧了问题。这让人想起在冬季夜间延长黑暗时期对仓鼠的研究结果，更年期DP的褪黑素持续时间延长，睡眠时间延长，近期性腺功能减退，卵泡刺激素(FSH)水平和身体质量指数(BMI)升高，这些都与抑郁症分级有关。我们在这项建议中的目的是扩展和复制我们关于更年期糖尿病患者褪黑素分泌异常的初步发现，并探讨光线、睡眠、活动和生殖内分泌功能可能的影响因素，作为未来研究中针对特定致病因素的治疗基础。根据DSM-IV标准，50例围绝经期或绝经后DP患者，以及年龄和绝经状况相匹配的50例正常对照妇女，我们将测量24小时血浆褪黑素(在暗光下采样30分钟)、光照、睡眠和活动(多导睡眠图和振动仪)、生殖内分泌功能(促性腺激素和类固醇水平)和体重指数(BMI)与情绪的相位、幅度、波形和时间关系。作为我们正在进行的月经前、妊娠和产后抑郁的时间生物学研究的延伸，这项研究有可能导致新的假说和治疗策略的发展。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障碍的理解。它还将证实和扩大我们对抑郁症女性的时间生物学异常的理解，作为开发创新治疗的基础。

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.