A peripheral diagnostic biomarker for Major Depressive Disorder

描述（由申请人提供）：世界卫生组织估计，到2020年，重度抑郁症（MDD）将成为全世界最常见的致残原因。在美国，抑郁症的医疗和非医疗费用每年超过800亿美元。虽然大约六分之一的美国人在他们的一生中会遭受重度抑郁症的折磨，但大约一半的重度抑郁症患者在初级保健机构没有得到诊断，另外五分之一的人被错误地诊断为重度抑郁症，而实际上他们患有另一种精神疾病。考虑到重度抑郁症未确诊或未治疗时所产生的巨大医疗、经济和社会成本，迫切需要一种简单的基于办公室的生物标志物测试来帮助临床医生准确识别重度抑郁症。对于具有临床价值的精神病学诊断测试，它不仅必须可靠地区分重度抑郁症和健康个体，而且还必须区分重度抑郁症和其他可能被误认为重度抑郁症的显著I轴障碍（如双相情感障碍或焦虑症）。目前还没有能够准确诊断重度抑郁症并将其与其他精神疾病区分开来的测试。对重度抑郁症进行准确诊断测试的潜在市场非常大。医疗服务的付款人将支付这种诊断测试的费用，因为准确识别和治疗重度抑郁症将减少因向未经治疗的抑郁症患者提供医疗服务而产生的高额医疗费用，并改善患有糖尿病或心脏病等合并症的患者的治疗结果。MDD诊断测试的另一个市场是制药公司。这些公司一致退出了情绪障碍的发现工作，部分原因是临床试验失败率很高，部分原因被认为是由于招募了不合适的患者。MDD的客观测试可以通过确定所招募患者的适当性来解决这一问题，从而增强试验结果准确反映所研究化合物的真实疗效（或无效）的信心。Pax神经科学诊断生物标志物Gsa隔离试验（Gsa）测量Gsa的定位，Gsa是一种关键的G蛋白，可以激活腺苷酸环化酶产生环磷酸腺苷（cAMP）并启动下游事件。葡萄糖在脂筏（相对不活跃）和非脂筏（更容易激活腺苷酸环化酶）的隔离状态之间穿梭。Pax Neuroscience的GSA生物标志物测量了这些状态之间的GSA比率。我们的初步数据表明，与非抑郁对照组相比，MDD患者在脂膜中捕获的Gs¿的比例明显更高，这与其他研究一致，表明MDD患者的Gs¿、腺苷酸环化酶和cAMP功能紊乱。这些发现表明Pax Neuroscience的GSA生物标志物可以准确地识别患有重度抑郁症的患者。拟议的研究将验证这样的假设，即脂筏的进出比例是MDD诊断目的的准确和特定的生物标志物。

DESCRIPTION (provided by applicant): The World Health Organization estimates that by 2020 major depressive disorder (MDD) will be the most common cause of disability worldwide. The medical and non-medical costs of MDD in the US exceed $80 billion annually. Although approximately 1 in 6Americans will suffer from MDD during their lifetime, roughly half of all patients with MDD go undiagnosed in primary care settings, and another fifth are incorrectly diagnosed as having MDD when they in fact have another psychiatric illness. Given the substantial medical, economic and social costs incurred when MDD is undiagnosed or untreated, there is tremendous need for a simple office- based biomarker test to aid clinicians in accurately identifying MDD. For a psychiatric diagnostic test to have clinical value, it must reliably distinguish not only between MDD and healthy individuals, but also between MDD and other significant Axis I disorders (e.g. bipolar disorder or anxiety disorders) that may present with symptoms that could be mistaken for MDD. No test currently exists that can accurately diagnose MDD and distinguish it from other psychiatric conditions. The potential market for an accurate diagnostic test for MDD is very large. Payers of medical services would cover the cost of such a diagnostic test because accurately identifying and treating MDD would reduce the high medical costs arising from medical service delivery to patients with untreated depression, as well as improving outcomes for patients with comorbid medical conditions such as diabetes or heart disease. Another market for an MDD diagnostic test are pharmaceutical companies. These companies have uniformly retreated from discovery efforts in mood disorders, in part due to the high rate of failed clinical trials, thought to arise in part from enrollment of inappropriae patients. An objective test of MDD could address this concern by providing certainty about the appropriateness of recruited patients, thereby enhancing confidence that trial results accurately reflect the true efficacy (or inefficacy) of investigated compounds. The Pax Neuroscience diagnostic biomarker Gsa Sequestration Assay (GSA), measures the localization of Gs¿, a crucial G protein that activates adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP) and initiate downstream events. Gs¿ shuttles between a state of sequestration in lipid rafts (relatively inactive), and a non-lipid raft location where it is freer to activate adenylyl cyclase. The Pax Neuroscience GSA biomarker measures the ratio of Gs¿ between those states. Our preliminary data indicate that MDD patients have a significantly greater proportion of Gs¿ captured in lipid rafts compared to non-depressed controls, which is consistent with other research indicating disrupted function of Gs¿, adenylyl cyclase and cAMP in MDD patients. These findings suggest the Pax Neuroscience GSA biomarker can accurately identify patients suffering from MDD. The proposed study will test the hypothesis that the ratio of Gs¿ in and out of lipid rafts is an accurate and specific biomarker for MDD diagnostic purposes.