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

摘要 精神分裂症(SZ)是一种青壮年起病的高度衰弱的神经精神障碍。 全球导致残疾的主要原因。虽然在疾病的早期阶段提供的治疗可能是 在减少精神病或改变病程方面有效，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；或处于SZ早期阶段的患者，他们可能对治疗有反应，并将 积极主动、对症下药或未来改善疾病治疗的良好候选者；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东西 重要的生物标志物为当今的多学科、跨国的 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(1HMRS)的生物标志物评估UHR转归风险 研究对象和监测首发精神病(FEP)患者的治疗反应。为了支持 这一总体目标的可行性是申请者和其他人报告的大量数据表明 (A)谷氨酸(Glu)和氨基丁酸(-氨基丁酸)水平--分别为主要兴奋性和 抑制氨基酸神经递质系统-在药物治疗中异常升高-幼稚和 非药物UHR、FEP和慢性SZ队列；(B)抗精神病药物治疗的效果 药物可能是为了降低或正常化大脑中谷氨酸和氨基丁酸的水平；以及(C)谷氨酸升高 在UHR受试者中，基线水平可能是向完全精神病转化的可靠预测指标。为了调查 这些体内脑Glu和GABA异常作为转换风险的生物标志物的可能性 UHR受试者和早期深圳的治疗反应，申请人建议使用1H MRS 测量迄今为止最大的药物队列中的Glu和GABA水平-幼稚的UHR和FEP受试者， UHR受试者在基线和转换时或在2年；在基线和随后4周 FEP受试者的抗精神病药物治疗。需要检验的假设是：(1) 在UHR受试者中，Glu和GABA将预测转化为完全精神病的风险；(2)两者都 在FEP受试者中，谷氨酸在基线时会升高，第二代受试者会下降或正常化 抗精神病药物治疗；以及(3)GABA和Glu水平与临床呈正相关 两组在基线和或阴性或无治疗反应时对FEP受试者进行测量。 如果成功，拟议的研究有可能建立大脑GABA和 Glu作为转换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的新疗法，这些疗法可能更有效，目前更低 风险，并为脑部疾病的发生和发展机制提供了新的见解 深圳的神经化学异常。

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.