Pharmaceutical Therapy for Seasonal Affective Disorder

描述（由申请人提供）：季节性情感障碍（SAD）是最常见的情绪障碍之一，影响温带气候中1-3%的人口，主要是女性。目前，还没有针对SAD的特异性药物治疗方法。医生给病人开一般的抗抑郁药或强光疗法。SAD的症状包括情绪低落、兴趣丧失、注意力难以集中、精力丧失和疲劳。此外，SAD患者往往在下午或晚上食欲增加，伴有体重增加和对碳水化合物（尤其是甜食）的渴望。尽管睡眠时间增加了，但白天常常有强烈的睡意。SAD是一种未得到满足的医疗需求。SAD的流行和缺乏特异性、有效和安全的药物治疗需要启动一个项目，以发现一种基于疾病生物学的治疗方法。这项工作的最终目标是通过在哺乳动物视网膜中发现的表达黑视素的内在光敏视网膜神经节细胞（ipRGC）来开发一种治疗SAD的药物。该途径在生物学上得到了验证，即刺激ipRGCs的强光疗法对SAD患者有效，并且发现具有特定黑视素突变的患者患SAD的可能性要高6倍。该通路的顶端是黑视素，这是一种只在靶细胞中表达的g蛋白偶联受体（GPCR）。一种激活黑视素的药物应该能够控制并改变视交叉上核的昼夜节律起搏器，因此作为一种治疗SAD、时差反应、与倒班工作有关的失眠和睡眠时间障碍的药物，它将是无价的。提出的具体目标是(1)验证293T细胞中人类黑视素激活的发光报告分析读数；(2)优化几种细胞类型的报告系统；(3)通过微阵列分析鉴定其他可能更好的基因，并评估其在发光实验中的表现；(4)调整和验证Aims 1-3中优化的检测方法，用于黑视素激动剂的高通量筛选。据我们所知，这种方法在制药领域尚无先例。

DESCRIPTION (provided by applicant): Seasonal Affective Disorder (SAD) is one of the most common mood disorders, affecting 1-3% of the population in temperate climates, predominantly women. Currently, there are no specific drug therapies for SAD. Patients are prescribed general anti-depressants or bright light therapy. SAD symptoms include low mood, loss of interest, difficulty concentrating, loss of energy and fatigue. In addition, SAD patients tend to have an increased appetite with associated weight gain and carbohydrate cravings, sweets in particular, in the afternoon or evening. There is often an intense daytime drowsiness in spite of increased sleep duration. SAD constitutes an unmet medical need. The prevalence of SAD and the absence of specific, efficacious and safe pharmacotherapy warrant initiation of a project to discover a therapeutic based in the biology the disease. The end goal of the proposed work is the development a pharmaceutical treatment for SAD by targeting the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGC) found in the mammalian retina. The pathway is biologically validated in that bright light therapy, which stimulates the ipRGCs, is efficacious in patients with SAD, and patients having a particular melanopsin mutation have been found to be ~6x more likely to have SAD. The pathway has at its apex, melanopsin, a G-protein coupled receptor (GPCR) that is only expressed in the target cells. A drug activating melanopsin should be able to entrain and shift the circadian pacemaker in the suprachiasmatic nucleus and thus would be invaluable as a drug to treat SAD, as well as jet lag, insomnia related to shift work, and sleep timing disorders. The proposed Specific Aims are (1) demonstrate luminescence reporter assay readout of activation of human melanopsin in 293T cells; (2) optimize the reporter system in several cell types; (3) identify by microarray analysis other, potentially better, reporters and evaluate their performance in the luminescence assay; and (4) adapt and validate the optimized assay from Aims 1-3 for a high-throughput screen for melanopsin agonists. There is, to our knowledge, no pharmaceutical precedent to this approach. PUBLIC HEALTH RELEVANCE: Millions of Americans suffer from a disease called Seasonal Affective Disorder (SAD). People with SAD exhibit classical symptoms of depression during the winter months, associated with the prolonged periods of darkness as are found in higher latitudes. Increasing evidence points to a disruption of the light-dark cycling that is inherent in humans as the primary cause of SAD. We are developing drugs that target the source of the light-dark cycling; cells in the eye that do not contribute to normal vision but detect whether it is night or day. Our therapy should be better than existing treatments, which are non-specific, as we are targeting the primary source of the disease.