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。项目摘要/摘要 精神分裂症（SZ）是一种毁灭性的神经精神疾病，成年初期典型发作。 尽管进行了广泛的研究，但其原因仍然知之甚少。我们的中心假设是异常 在细胞膜磷脂中，特别是涉及花生四烯酸（AA）和相关代谢物的磷脂 （统称为eicosanoids）至少是SZ中涉及的一种病理学途径的基础。这 拟议的工作将测试烟酸的降低性是否可以用作假定的生理标志物来识别 SZ发病时个体的子集。虽然烟酸降低性是广泛复制的 与SZ相关的生理异常，疾病慢性问题和暴露于抗精神病药物 药物混淆了大多数已发表的数据。拟议的研究将通过 研究了大量的第一集，药物（FedN）患者。但是，这样一个独特的注册 在一个研究地点可能会挑战美国的小组。因此，将进行拟议的R21项目 独家在北京北古岛医院。因为它为这个独特的患者提供了丰富的资源 人口不仅可行，而且还可以实现300名联邦快递患者的招聘目标。 提出了以下三个特定目的：目标1：估计烟酸降低率在 联邦医生。我们将使用激光多普勒流量计来量化皮肤血流反应 300名FEDN精神病患者中的局部局部局部 - 甲基二酸（AMN），100例 来自北京站点的人口统计健康控制（HC）。我们假设烟酸敏感性将是 在25％或更多的FedN-SZ受试者中，显着降低了，但不到10％的HC和Fedn与其他 精神病。目的2：估计烟酸降低性是一种可预测SZ的稳定标记的程度。 我们将使用300名FedN患者的初始烟酸敏感性建立分类模型（定义为EC50 局部甲基肽酸刺激皮肤血流的值）预测SZ在6个月时的诊断 重新评估。我们假设烟酸降低性是一种稳定的性状，并且在 早期精神病可以预测随后的SZ诊断。目标3：评估生化机制 潜在的烟酸下敏。我们将将烟酸敏感性与可能的化学介质进行比较 （磷脂，花生四烯酸和类花生酸）来自联邦杂志患者和RBC样品的血浆和RBC样品 HC组（来自AIM 1）。我们假设烟酸降低性将与AA中的缺陷有关 级联。从AIM 1中同一注册的FedN和HC组预测EC50值的模型，将 校正多次测试后，至少具有一个重要的AA预测因子。虽然我们不相信这一切 患者在AA信号中存在缺陷，拟议的研究将确定客观生理的有效性 可以帮助鉴定出在疾病早期阶段的SZ患者子集的标记。阐明它的 生化机制可能导致精致的诊断方法和药物开发的新靶标。