Predictors and Moderators of Long-Term Outcome of Persons at Clinical High Risk for Psychosis

说明/摘要 精神分裂症和相关的精神病是神经发育障碍，有病理证据表明， 发病前的神经运动和神经认知异常; 疾病前驱期的亚综合征精神病症状（也称为临床高风险）;以及 在青春期后期或成年早期的精神病综合征的完全表现。在过去的几年里， 在过去的2+十年中，提供了（i）对后来转化为完全精神病的风险因素的重要见解 疾病，（ii）开发“精神病风险计算器”，（iii）与精神病风险相关的生物标志物，以及（iv） 有证据表明，大脑的动态变化可能在疾病发作之前就存在，并继续演变 第一次发作的精神病（FEP），以及更多的慢性精神病。尽管有这些 在我们的进步的理解，长期的结果（5年以上），和轨迹， 在这一人群中，很少对诊断、症状和心理社会功能进行调查。Meta- 分析表明，20-30%的被鉴定的精神病患者在两年内发展为精神病。知之甚少 关于什么类型的精神病（情感与非情感）“宣布自己”后，最初的证据， 转化为精神病，后期精神病转化率（即2-3年随访期后）或风险 这些因素可能预示着精神病的后期发作。大多数符合条件的人并不 2年内出现明显的精神病，但结果从完全缓解到 持续的症状和功能障碍，至少在这个相对较短的时间内。长期 对患病个体的随访提供了一个独特而难得的机会来调查疾病的全部轨迹 从第一集->第一集->慢性疾病，以及有症状个体的长期结局 在确诊后2年内未发生精神病。已有大量证据表明， 多个生物标志物异常。具体来说，青少年在神经认知方面表现出缺陷， 区域皮质灰质、事件相关电位（ERP）振幅以及较高的多基因风险评分 (PRS)、炎症标志物和皮质醇。生物标志物还能预测 2年时转为精神病和功能结局。然而，尚不清楚这些生物标志物是否 预测更长期的转化和结果。具体目标是：1）长期（5-20年） 对多达2000名先前符合ESTA标准的个体进行诊断、症状和功能评估， 他们中的一些人在9个学术中心转化为精神病。2)确定5年以上精神病患者 使用基线人口统计学、临床、功能、神经认知和 生物标志物数据，以预测转换为糖尿病的个体的长期功能和诊断结果。 精神病和3）调查长期的诊断和功能的结果， 转换为精神病，并测试结果是否受到治疗和物质使用的影响。

Description/Abstract Schizophrenia and related psychotic illnesses are neurodevelopmental disorders with evidence of pathological changes beginning in utero; neuromotor and neurocognitive abnormalities in the premorbid period; subsyndromal psychotic symptoms in the prodromal period of illness (also called clinical high risk, CHR); and full manifestation of a psychotic syndrome during late adolescence or early adulthood. CHR research over the past 2+ decades, has provided (i) important insights into risk factors for later conversion to full psychotic illness, (ii) the development of a “Psychosis Risk Calculator”, (iii) biomarkers linked to psychosis riskand (iv) evidence of dynamic brain changes that are likely present before the onset of illness and continue to evolve into the first episode psychosis (FEP), as well as into more chronic forms of psychosis. Despite these advances in our understanding of the CHR state, the longer-term outcomes (5+ years), and the trajectory of diagnoses, symptoms and psychosocial function have been seldom investigated in this population. Meta- analyses show that 20-30% of identified CHR individuals develop psychosis within 2 years. Little is known about what type of psychosis (affective versus non-affective) "declares itself" after evidence of the initial conversion to psychosis, the rate of later psychotic conversion (i.e. post 2-3-year follow-up periods) or risk factors that might predict a later onset of psychosis. The majority of individuals who meet CHR criteria do not develop overt psychosis within 2 years but demonstrate outcomes ranging from complete remission to continued symptoms and functional impairment, at least within this relatively short time frame. Longer-term follow-up of CHR individuals provides a unique and rare opportunity to investigate the full trajectory of illness from CHR -> First Episode -> Chronic Illness, in addition to longer-term outcomes in symptomatic individuals who did not develop psychosis within 2 years after ascertainment. Substantial evidence already exists for multiple biomarker abnormalities in CHR subjects. Specifically, CHR youth show deficits in neurocognition, regional cortical gray matter, event related potential (ERP) amplitudes as well as higher polygenic risk scores (PRS), inflammatory markers and cortisol relative to comparison subjects. Biomarkers also predict who will convert to psychosis and functional outcomes at 2 years. However, it is not known whether these biomarkers predict longer term conversion and outcomes. The Specific Aims are to 1) Perform long-term (5-20 year) diagnostic, symptom and functional assessments of up to 2000 individuals who previously met CHR criteria, some of whom converted to psychosis, across 9 academic centers. 2) Determine the 5+ year psychotic conversion rate of CHR individuals and use baseline demographic, clinical, functional, neurocognitive and biomarker data to predict longer term functional and diagnostic outcomes of individuals who convert to psychosis and 3) Investigate the long-term diagnostic and functional outcomes of CHR individuals who do not convert to psychosis and test whether outcomes are influenced by treatment and substance use.