Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia

摘要 精神分裂症（SZ）是一种高度衰弱的神经精神障碍，发病于青年期， 全球残疾的主要原因。虽然在疾病的早期阶段提供的治疗可能是有效的， 有效地减少精神病或改变疾病的进程，目前还没有生物标志物 能够识别可能完全转化为精神病的超高风险（UHR）受试者 临床综合征;或那些在SZ的早期阶段，可能对治疗有反应， 良好的候选人，可用于积极的，对症的或未来的疾病改善治疗;或 他们不会有反应，可以避免不必要的药物暴露。缺乏这些至关重要的 重要的生物标志物为目前的多学科、跨国、 研究项目，旨在开发和验证非常有前途的非侵入性和客观的质子 基于磁共振波谱（1H MRS）的生物标志物用于评估UHR的转换风险 受试者和监测首次发作精神病（FEP）患者的治疗反应。为支持 这一总体目标的可行性是申请人和其他人报告的大量数据，这些数据表明 (a)谷氨酸（Glu）和γ-氨基丁酸（GABA）的水平分别是主要的兴奋性和 抑制性氨基酸神经递质系统-在未经药物治疗的患者中异常升高， 未用药的UHR、FEP和慢性SZ队列;（B）抗精神病药物治疗的效果 药物可能是降低或正常化大脑水平的Glu和GABA;和（c）Glu升高 在基线时UHR受试者可能是一个可靠的预测转换为完全精神病。探讨 这些体内脑Glu和GABA异常作为转化风险的生物标志物的潜力， UHR受试者和早期SZ的治疗反应，申请人建议使用1H MRS， 测量迄今为止最大的药物初治UHR和FEP受试者队列中的Glu和GABA水平， UHR受试者在基线和转换时或2年时;以及在基线和4周后 FEP受试者的抗精神病药物治疗。要检验的假设是：（1） UHR受试者中的Glu和GABA将预测转化为完全精神病的风险;（2）GABA FEP受试者的基线和Glu将升高，第二代受试者将降低或恢复正常。 抗精神病药物治疗;（3）GABA和Glu水平与临床表现呈正相关。 两组基线和/或FEP受试者治疗反应为阴性或无。 如果成功，拟议的研究有可能建立脑GABA的1H MRS测量， Glu作为转换风险的预测因子和治疗应答或无应答的生物标志物，支持 探索新的谷氨酸或GABA为基础的治疗，可能更有效，目前较低 风险，并为大脑机制的出现和发展提供新的见解。 SZ的神经化学异常。

ABSTRACT Schizophrenia (SZ) is a highly debilitating neuropsychiatric disorder of young adulthood onset and a leading cause of disability worldwide. While treatments delivered at early stages of the disorder may be effective at reducing psychosis or altering the course of the disease, there are currently no biomarkers capable of identifying subjects at ultra-high risk (UHR) for psychosis who are likely to convert to the full clinical syndrome; or those in early stages of SZ who are likely to respond to treatment and would be good candidates for available proactive, symptomatic or future disease-modifying treatments; or those who would not respond and can be spared unnecessary medication exposure. The lack of these vitally important biomarkers provides a compelling rationale for the present multidisciplinary, transnational research project, which aims to develop and validate highly promising noninvasive and objective proton magnetic resonance spectroscopy (1H MRS)-based biomarkers for assessing conversion risk in UHR subjects and monitoring treatment response in first-episode psychosis (FEP) patients. In support of the viability of this overall objective is a large body of data, reported by the applicants and others, that show (a) that levels of glutamate (Glu) and -aminobutyric acid (GABA) – respectively, the major excitatory and inhibitory amino acid neurotransmitter systems - are abnormally elevated in medication-naïve and unmedicated UHR, FEP and chronic SZ cohorts; (b) that the effect of treatment with antipsychotic medications may be to lower or normalize brain levels of both Glu and GABA; and (c) that Glu elevations at baseline in UHR subjects may be a reliable predictor of conversion to full psychosis. To investigate the potential of these in vivo brain Glu and GABA abnormalities to serve as biomarkers of conversion risk in UHR subjects and of treatment response in early-stage SZ, the applicants propose to use 1H MRS to measure Glu and GABA levels in the largest cohorts of medication-naïve UHR and FEP subjects to date, at baseline and at conversion or at 2 years in UHR subjects; and at baseline and following 4 weeks of antipsychotic treatment in FEP subjects. The hypotheses to be tested are that (1) baseline elevations of Glu and GABA in UHR subjects will predict the risk of conversion to full psychosis; that (2) both GABA and Glu will be elevated at baseline in FEP subjects and decrease or normalize with second-generation antipsychotic treatment; and that (3) levels of both GABA and Glu will correlate positively with clinical measures in both groups at baseline and or negatively or not with treatment response in FEP subjects. If successful, the proposed studies have the potential to establish 1H MRS measures of brain GABA and Glu as predictors of conversion risk and biomarkers of treatment response or non-response, support the exploration of novel glutamate- or GABA-based treatments that may be more effective and present lower risks, and contribute new insights into the brain mechanisms of the emergence and progression of neurochemical abnormalities in SZ.