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，影响温带气候地区1-3%的人口，主要是女性。目前，没有针对SAD的特定药物治疗。患者被规定一般抗抑郁药或明亮的光疗法。SAD的症状包括情绪低落、失去兴趣、难以集中注意力、精力丧失和疲劳。此外，SAD患者往往在下午或晚上食欲增加，体重增加和碳水化合物渴望，特别是甜食。尽管睡眠时间增加，但白天经常会有强烈的困倦感。SAD是一种未满足的医疗需求。SAD的患病率和缺乏特异性，有效和安全的药物治疗保证了一个项目的启动，以发现一种基于疾病生物学的治疗方法。所提出的工作的最终目标是通过靶向哺乳动物视网膜中发现的表达黑视素的固有光敏视网膜神经节细胞（ipRGC）来开发SAD的药物治疗。该途径在生物学上得到了验证，因为刺激ipRGC的亮光疗法在SAD患者中是有效的，并且已经发现具有特定黑视蛋白突变的患者患SAD的可能性高约6倍。该途径在其顶点处具有黑视素，一种仅在靶细胞中表达的G蛋白偶联受体（GPCR）。一种激活黑视素的药物应该能够在视交叉上核中携带和转移昼夜节律起搏器，因此作为治疗SAD以及时差反应、与轮班工作相关的失眠和睡眠时间紊乱的药物将是非常宝贵的。提出的具体目的是（1）证明293 T细胞中人黑视素激活的发光报告基因测定读出;（2）优化几种细胞类型中的报告基因系统;（3）通过微阵列分析鉴定其他可能更好的报告基因并评价它们在发光测定中的性能;和（4）调整和验证来自目的1-3的优化的测定用于黑视素激动剂的高通量筛选。据我们所知，这种方法没有制药先例。 公共卫生相关性：数百万美国人患有一种称为季节性情感障碍（SAD）的疾病。SAD患者在冬季表现出典型的抑郁症状，与高纬度地区长时间的黑暗有关。越来越多的证据表明，人类固有的明暗循环的破坏是SAD的主要原因。我们正在开发针对光暗循环来源的药物;眼睛中的细胞对正常视力没有贡献，但可以检测是白天还是黑夜。我们的疗法应该比现有的非特异性治疗更好，因为我们针对的是疾病的主要来源。

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.