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

摘要 精神分裂症 (SZ) 是一种在成年早期发病的高度衰弱性神经精神疾病， 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 目前尚无生物标记物可有效减少精神病或改变病程 能够识别患有精神病的超高风险（UHR）对象，他们可能会转变为完全 临床综合征；或那些处于 SZ 早期阶段的人，他们可能对治疗有反应，并且可能会 可用的主动、对症或未来疾病缓解治疗的良好候选者；或那些 那些不会做出反应的人可以避免不必要的药物暴露。缺少这些至关重要 重要的生物标志物为当前的多学科、跨国研究提供了令人信服的理由 研究项目，旨在开发和验证极具前景的非侵入性和客观质子 基于磁共振波谱 (1H MRS) 的生物标志物用于评估 UHR 转化风险 受试者并监测首发精神病（FEP）患者的治疗反应。为了支持 这一总体目标的可行性取决于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 - 在未接受药物治疗和接受药物治疗的患者中异常升高 未接受药物治疗的 UHR、FEP 和慢性 SZ 队列； (b) 抗精神病药治疗的效果 药物可能会降低或使大脑中 Glu 和 GABA 的水平正常化； (c) Glu 升高 UHR 受试者的基线可能是转变为完全精神病的可靠预测指标。为了调查 这些体内脑 Glu 和 GABA 异常有可能作为转化风险的生物标志物 UHR 受试者和早期 SZ 的治疗反应，申请人建议使用 1H MRS 来 测量迄今为止最大的未接受药物治疗的 UHR 和 FEP 受试者群体中的 Glu 和 GABA 水平， UHR 受试者的基线和转换时或 2 年时；在基线和 4 周后 FEP 受试者的抗精神病治疗。要检验的假设是 (1) 基线升高 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 受试者的基线时 Glu 和 Glu 会升高，而第二代则降低或正常化 抗精神病治疗； (3) GABA 和 Glu 的水平与临床呈正相关 两组在基线时的测量结果和/或对 FEP 受试者的治疗反应呈阴性或无反应。 如果成功，拟议的研究有可能建立大脑 GABA 和 1H MRS 测量 Glu 作为转化风险的预测因子和治疗反应或无反应的生物标志物，支持 探索基于谷氨酸或 GABA 的新型治疗方法，这些治疗方法可能更有效且成本更低 风险，并为风险的出现和进展的大脑机制提供新的见解 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.