2/8-Predictors and Mechanisms of Conversion to Psychosis

描述（由申请人提供）：精神分裂症和其他形式的精神病影响了大约3%的人口，这些疾病通常是慢性和致残的。发病的高峰年龄在18-30岁之间，正好是人生最富有成效的时期。虽然遗传倾向和大脑发育异常是已知的致病因素，但精神分裂症及其相关综合征的病因和病理生理学在很大程度上是未知的。迄今为止，对发病的前瞻性观察，即从易感性到障碍的转变是不可能的，因为大多数处于真正危险的人不能在发病前被识别出来。这妨碍了预防工作。然而，最近在风险确定方法方面取得的进展，已经能够可靠地识别那些在1-2年内以20%-50%的比率发展为精神病前或“前驱”临床综合征的求助者。因此，临床高危人群现在可用于前瞻性跟踪精神病的发展和出现。然而，由于精神分裂症的低发病率和临床高危病例结果的异质性，单点研究不能有效地利用风险标准来识别精神病的预测因素和机制。NAPLS联盟的成立就是为了解决这个问题。北美的8个nimh资助的站点使用一种常见的前驱评估工具对前驱患者进行研究，汇集了数据，创建了全球最大的此类患者样本（N=291），其中35%的患者在2年后转化为精神病。生成一种基线数据预测精神病的算法，其阳性预测能力约为80%，灵敏度为40%。在这个修订后的提案中，我们描述了一项合作前瞻性研究，我们将在5年内招募800例病例和400例适当的对照，使用常见的，标准化的临床和神经生物学测量。目的是收集足够的样本，以严格测试在脑结构、电生理学、应激激素和基因组学的生物标志物领域以及在前驱症状和流行病学的临床领域对精神病的责任和发展至关重要的因素。修订后的提案解决了审稿人的担忧，包括将研究计划和措施整合到一个统一的框架中。这一发现将提高我们识别即将发生精神病的高危人群的能力，通过完善转化的预测因素，并扩大我们对潜在神经机制的理解。这些知识对未来早期发现、干预和预防精神障碍的努力至关重要。公共卫生相关性：预防精神分裂症和其他精神病可以减轻个人和家庭痛苦的巨大负担以及对社会的经济损失。这个8点项目旨在提高我们在发病前识别高风险个体的能力，并查明精神障碍出现背后的神经生物学变化。这些努力对于制定有效的精神障碍预防干预策略至关重要。

DESCRIPTION (provided by applicant): Schizophrenia and other forms of psychosis affect approximately 3% of the population with a disorder that is usually chronic and disabling. The peak age of onset is between ages 18-30, occurring just as life's most productive years are beginning. Although genetic liability and abnormal brain development are known contributing factors, the etiology and pathophysiology of schizophrenia and related syndromes is largely unknown. To date, prospective observation of onset, i.e., the transition from vulnerability to disorder has not been possible because most persons at true risk cannot be identified premorbidly. This has hampered efforts at prevention. However, recent progress in risk ascertainment methodology has enabled reliable identification of help-seeking persons with pre-psychotic or "prodromal" clinical syndromes who develop psychosis within 1-2 years at rates between 20%-50%. Thus, clinical high-risk populations are now available for tracking prospectively the development and emergence of psychosis. However, because of the low incidence of schizophrenia and the heterogeneity of outcomes in clinical high-risk cases, single site studies cannot efficiently exploit the risk criteria in identifying predictors and mechanisms of psychosis. The NAPLS consortium was created to solve this problem. Eight NIMH-funded sites in North America studying prodromal patients using a common prodromal assessment instrument pooled data to create the largest sample of such persons worldwide (N=291), 35% of whom converted to psychosis after 2 years. An algorithm of baseline data was generated predicting psychosis with about 80% positive predictive power and 40% sensitivity. In this revised proposal, we describe a collaborative prospective study for which we will recruit 800 cases and 400 appropriate controls over 5 years using common, standardized clinical and neurobiological measures. The aim is to collect a sample with sufficient size and power to rigorously test elements critical to the liability for and development of psychosis in the biomarker domains of brain structure, electrophysiology, stress hormones, and genomics, and in the clinical domains of prodromal presentation and epidemiology. The revised proposal addresses reviewers' concerns, including the integration of the research plan and measures into a unifying framework. The findings will enhance our ability to identify persons at high risk for imminent psychosis, by refining predictors of conversion, and expanding our understanding of the underlying neural mechanisms. Such knowledge is critical for future efforts at early detection, intervention and prevention of psychotic disorders. PUBLIC HEALTH RELEVANCE: Preventing schizophrenia and other psychoses could relieve an enormous burden of personal and family suffering and economic losses to society. This 8-site project aims to increase our ability to identify high-risk individuals prior to onset and to pinpoint neurobiological changes that underlie the emergence of a psychotic disorder. These efforts are critical to the development of effective preventative intervention strategies for psychotic disorders.