A Multidimensional Dissection of Antipsychotic Treatment Response in Early Schizophrenia

项目摘要 精神分裂症谱系障碍是所有精神疾病中最致残的， 这对经历这些疾病的个人以及他们的家庭成员和社会都是一种负担。高达35%的 患有这些疾病的个体对抗精神病药物治疗没有表现出足够的反应， 一线治疗难治，这会增加疾病的负担和发病率， 无法融入自己的社区。对潜在的神经生物学机制的有限理解 成功或不成功的抗精神病药物治疗继续阻碍新的治疗开发， 优化我们针对这些疾病的现有疗法。虽然最近的工作表明， 功能和光谱磁共振，以阐明抗精神病药物治疗的机制，一个更 缺乏对与治疗效果相关的分子和神经元变化的全面理解。 在这项研究中，我们利用高场，7-特斯拉的多维策略来解决这一知识差距 神经影像学，以解构抗精神病药反应的机制，在一个队列的个人与 早期精神分裂症该项目的重点是皮质-基底神经节系统与几个创新 方法，包括（1）通过神经黑色素敏感的MRI测定多巴胺系统;（2）磁 皮质γ-氨基丁酸和谷氨酸功能的共振光谱成像;和（3）两者 皮质基底神经节功能连接的假设和数据驱动的多变量方法。敏锐 精神病患者与早期精神分裂症谱系疾病将检查在这个自然的和前瞻性的 study.他们将在治疗开始期间接受扫描，每隔2周进行一次临床评估， 治疗8周后重新扫描。还将检查一组健康对照，以确定正常 我们的神经成像测量范围。这项工作的成果将为以下方面提供更全面的基础： 我们对抗精神病药物治疗相关神经生物学的理解，这将促进生物标志物的开发， 机械临床试验以及下一代治疗策略的开发。

PROJECT SUMMARY Schizophrenia spectrum disorders, among the most disabling of all psychiatric conditions, place a significant burden on the individuals who experience them, as well as their family members and society. Up to 35% of individuals with the disorders do not demonstrate an adequate response to antipsychotic treatment, and remain refractory to first-line therapies, which contributes to the burden and morbidity of the illness, often leaving patients unable to integrate with their communities. A limited understanding of the neurobiological mechanism underlying successful or unsuccessful antipsychotic treatment continues to hinder novel therapeutic development and optimization of our existing therapies for these disorders. While recent work has demonstrated the utility of functional and spectroscopic MR to elucidate the mechanisms underlying antipsychotic treatment, a more comprehensive understanding of molecular and neuronal changes associated with treatment efficacy is lacking. In this study, we address this knowledge gap by utilizing a multidimensional strategy with high-field, 7-Tesla neuroimaging to deconstruct the mechanism underlying antipsychotic response in a cohort of individuals with early schizophrenia. This project focuses on the cortical-basal ganglia system with several innovative approaches, including assays of (1) the dopamine system via neuromelanin-sensitive MRI; (2) magnetic resonance spectroscopic imaging of cortical γ-aminobutyric acid and glutamate functioning; and (3) both hypothesis and data-driven multivariate approaches to cortico-basal ganglia functional connectivity. Acutely psychotic patients with early schizophrenia spectrum illness will be examined in this naturalistic and prospective study. They will undergo scanning during treatment initiation, clinical assessments at 2-week intervals, and will be rescanned after 8 weeks of treatment. A group of healthy controls will also be examined to establish normal ranges of our neuroimaging measures. Results of this work will provide a more comprehensive foundation for our understanding of antipsychotic treatment-related neurobiology, which will facilitate biomarker development, mechanistic clinical trials, and the development of next-generation therapeutic strategies.