Evaluation of a Physiologic Marker for Schizophrenia in First-Episode Psychosis

首发精神病中精神分裂症生理标志物的评估

• 批准号: 8619703
• 负责人: JEFFREY K YAO
• 金额: $ 21.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-24 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619703
• 关键词: Accounting; Antipsychotic Agents; Arachidonic Acids; Biochemical; Biological; Biological Assay; Blood; Blood flow; Blood specimen; Cell membrane; Chemicals; Classification; Control Groups; Cutaneous; DNA; DNA Repository; Data; Defect; Development; Diagnosis; Diagnostic Procedure; Disease; Early Diagnosis; Eicosanoids; Enrollment; Equilibrium; Evaluation; Exposure to; Flowmeters; Flushing; Freezing; Genetic Variation; Goals; Heterogeneity; Hospitals; Individual; Laser-Doppler Flowmetry; Lasers; Lead; Light; Link; Measures; Mediator of activation protein; Mental disorders; Methods; Modeling; N-amyl-N-methylnitrosamine; Nicotinic Acids; Onset of illness; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipids; Physiological; Plasma; Prevalence; Prostaglandins; Psychotic Disorders; Publishing; Reporting; Research; Research Design; Resources; Sampling; Schizoaffective Disorders; Schizophrenia; Signal Transduction; Site; Skin; Staging; Subgroup; Testing; Time; Whole Blood; Work; cost effective; disability; drug development; emerging adult; experience; first episode psychosis; follow-up; improved; meetings; neuropsychiatry; novel; patient population; public health relevance; response; trait

7. Project Summary/Abstract Schizophrenia (SZ) is a devastating neuropsychiatric illness with typical onset in early adulthood. Despite extensive research, its causes remain poorly understood. Our central hypothesis is that abnormalities in cell membrane phospholipids, particularly those involving arachidonic acid (AA) and related metabolites (collectively termed eicosanoids) are fundamental to at least one etiopathological pathway involved in SZ. The proposed work will test whether niacin subsensitivity can serve as a putative physiologic marker to identify a subset of individuals at onset of illness for SZ. Although niacin subsensitivity is a widely replicated physiological abnormality associated with SZ, issues of illness chronicity and exposure to antipsychotic medications confound most published data. The proposed research will effectively resolve this issue by studying a large sample of first-episode, drug-na¿ve (FEDN) patients. However, enrollment of such a unique group in the US can be challenging for a single study site. The proposed R21 project will thus be conducted exclusively at the Beijing Hui-Long-Guan Hospital. Because of its enriched resource for this unique patient population, it is not only feasible but also cost-effective to meet the recruitment goal of 300 FEDN patients. The following three specific aims are proposed: Aim 1: Estimate the prevalence of niacin subsensitivity in FEDN patients. We will use a Laser Doppler flowmeter to quantify the cutaneous blood flow response to increasing concentrations of topical ¿-methylnicotinate (AMN) in 300 FEDN psychosis patients, and 100 demographically-balanced healthy controls (HC) from Beijing site. We hypothesize that niacin sensitivity will be significantly reduced in 25% or more of FEDN-SZ subjects, but in fewer than 10% of HC and FEDN with other psychosis. Aim 2: Estimate the extent to which niacin subsensitivity is a stable marker that is predictive of SZ. We will build a classification model using initial niacin sensitivity from 300 FEDN patients (defined as the EC50 value for topical methylnicotinate to stimulate skin blood flow) to predict a diagnosis of SZ at 6-month reassessment. We hypothesize that niacin subsensitivity is a stable trait, and initial niacin sensitivity during early psychosis is predictive of a subsequent diagnosis of SZ. Aim 3: Evaluate the biochemical mechanisms underlying niacin subsensitivity. We will compare niacin sensitivity with likely chemical mediators (phospholipids, arachidonic acid and eicosanoids) from plasma and RBC samples between FEDN patients and HC groups (from Aim 1). We hypothesize that niacin subsensitivity will be associated with defects in the AA cascade. A model for prediction of EC50 values in the same enrolled FEDN and HC groups from Aim 1, will have at least one significant AA predictor after correction for multiple testing. While we do not believe that all patients have defects in AA signaling, the proposed study will establish the validity of an objective physiological marker that could help to identify a subset of SZ patients at a very early stage of illness. Elucidating its biochemical mechanism may lead to refined diagnostic methods and novel targets for drug development.

7.项目总结/摘要 精神分裂症（SZ）是一种典型的在成年早期发病的毁灭性神经精神疾病。 尽管进行了广泛的研究，但其原因仍然知之甚少。我们的核心假设是 在细胞膜磷脂中，特别是那些涉及花生四烯酸（AA）和相关代谢物的磷脂 类花生酸（统称为类花生酸）是SZ中涉及的至少一种病因病理学途径的基础。的 拟议的工作将测试烟酸亚敏感性是否可以作为一个假定的生理标志，以确定一个 SZ发病时的个体子集。尽管烟酸亚敏感性被广泛复制 与SZ相关的生理异常、疾病慢性化问题和抗精神病药物暴露 药物混淆了大多数已发表的数据。拟议的研究将有效解决这一问题， 研究了一个大样本的首次发病，药物初治（FEDN）患者。然而，这样一个独特的 对于单个研究中心而言，美国的研究组可能具有挑战性。因此，拟议的R21项目将在 在北京回龙观医院独家报道。因为它为这个独特的病人提供了丰富的资源 人口，这不仅是可行的，而且符合成本效益，以满足招募目标的300例FEDN患者。 提出了以下三个具体目标：目标1：估计烟酸不敏感的患病率， FEDN患者。我们将使用激光多普勒流量计来量化皮肤血流反应， 在300名FEDN精神病患者和100名FEDN精神病患者中增加局部<$-甲基烟酸酯（AMN）的浓度， 来自北京研究中心的人口统计学平衡的健康对照（HC）。我们假设烟酸敏感性将是 在25%或更多的FEDN-SZ受试者中显著降低，但在HC和FEDN中低于10%， 精神病目的2：评估烟酸不敏感性在多大程度上是预测SZ的稳定标志物。 我们将使用来自300名FEDN患者的初始烟酸敏感性（定义为EC 50）建立分类模型 局部甲基烟酸酯刺激皮肤血流的价值）预测6个月时SZ的诊断 重新评估我们假设烟酸不敏感性是一个稳定的性状， 早期精神病预示着随后的SZ诊断。目的3：评估生化机制 潜在的烟酸亚敏感性。我们将比较烟酸敏感性与可能的化学介质 （磷脂、花生四烯酸和类花生酸）从FEDN患者和 HC组（来自目标1）。我们假设烟酸的不敏感性与AA的缺陷有关 级联。用于预测目标1中相同入组FEDN和HC组的EC 50值的模型将 在多重检验校正后，至少有一个显著的AA预测因子。虽然我们并不认为所有 患者有缺陷的AA信号，拟议的研究将建立一个客观的生理有效性， 这可能有助于在疾病的早期阶段识别SZ患者的子集。阐明其 生物化学机制的研究可能会导致精细的诊断方法和药物开发的新靶点。