A Multidimensional Dissection of Antipsychotic Treatment Response in Early Schizophrenia

项目总结 精神分裂症谱系障碍，在所有精神疾病中最致残的疾病之一，在 给经历过这种情况的个人以及他们的家庭成员和社会带来负担。高达35%的 患有精神障碍的个体对抗精神病药物治疗没有表现出足够的反应，并且仍然 对一线治疗无效，这增加了疾病的负担和发病率，通常会使患者 无法融入他们的社区。对潜在的神经生物学机制的了解有限 成功或失败的抗精神病药物治疗继续阻碍新的治疗开发和 优化我们针对这些疾病的现有治疗方法。虽然最近的研究已经证明了 功能和光谱磁共振，以阐明抗精神病药物治疗的潜在机制，更 对与治疗疗效相关的分子和神经元变化缺乏全面的了解。 在这项研究中，我们通过利用高场7特斯拉的多维策略来解决这一知识差距 神经成像解构抗精神病药物反应的潜在机制 早期精神分裂症。本项目的重点是皮质-基底节系统，具有几个创新的 方法，包括(1)通过神经黑色素敏感的磁共振成像检测多巴胺系统；(2)磁性 皮质γ-氨基丁酸和谷氨酸功能的共振光谱成像；以及(3)两者 皮质-基底节功能连接的假说和数据驱动的多变量方法。尖锐地 有早期精神分裂症谱系疾病的精神病患者将在这份自然和前瞻性的报告中被检查。 学习。他们将在治疗开始期间接受扫描，每两周进行一次临床评估，并将 在治疗8周后重新扫描。还将对一组健康对照进行检查，以确定正常 我们神经成像测量的范围。这项工作的成果将为 我们对抗精神病药物治疗相关神经生物学的理解，这将促进生物标记物的发展， 机械性临床试验，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.