5/8-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约3%的人口与疾病，通常是慢性和致残。发病的高峰年龄在18-30岁之间，发生在生命中最富有成效的几年开始的时候。虽然遗传易感性和大脑发育异常是已知的促成因素，精神分裂症和相关综合征的病因学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，从脆弱到失调的转变是不可能的，因为大多数真正面临风险的人无法在发病前被识别出来。这妨碍了预防工作。然而，最近的进展，风险确定方法，使可靠的识别寻求帮助的人与精神病前期或“前驱”的临床综合征谁发展精神病在1-2年内在20%-50%之间的比率。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，由于精神分裂症的发病率低，临床高风险病例的结果的异质性，单点研究不能有效地利用风险标准，以确定精神病的预测因子和机制。NAPLS联盟就是为了解决这个问题而成立的。北美八个NIMH资助的研究前驱患者的网站使用一个共同的前驱评估工具汇总数据，以创建全球最大的样本，这样的人（N=291），其中35%转换为精神病后2年。基线数据的算法生成预测精神病，具有约80%的阳性预测能力和40%的灵敏度。在此修订提案中，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例适当对照，使用常见的标准化临床和神经生物学措施。其目的是收集一个足够的大小和权力的样本，严格测试的元素的责任和发展的精神病的生物标志物领域的大脑结构，电生理学，应激激素和基因组学，并在前驱表现和流行病学的临床领域。修订后的提案解决了审查者的关切，包括将研究计划和措施纳入一个统一框架。这些发现将提高我们识别精神病高危人群的能力，通过改进转换的预测因子，扩大我们对潜在神经机制的理解。这些知识对于未来早期发现、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以及社会经济损失的巨大负担。这个8个站点的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性干预策略至关重要。

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.