A Multidimensional Dissection of Antipsychotic Treatment Response in Early Schizophrenia

早期精神分裂症抗精神病药物治疗反应的多维剖析

• 批准号: 10427451
• 负责人: Deepak K Sarpal
• 金额: $ 65.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427451
• 关键词: Acute; Address; Aftercare; Antipsychotic Agents; Basal Ganglia; Biological Assay; Cells; Characteristics; Classification; Clinical Trials; Clinical assessments; Communities; Computing Methodologies; Corpus striatum structure; Data; Development; Disease; Dissection; Dopamine; Dopamine D2 Receptor; Economic Burden; Exhibits; Family member; Foundations; Functional disorder; Glutamates; Healthcare Systems; Heterogeneity; Hippocampus (Brain); Image; Individual; Knowledge; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Methodology; Methods; Midbrain structure; Molecular; Morbidity - disease rate; National Institute of Mental Health; Neurobiology; Neurons; Neurotransmitters; Normal Range; Patients; Persons; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Prefrontal Cortex; Prospective Studies; Proxy; Psychoses; Public Health; Publishing; Radiation exposure; Refractory; Research; Resolution; Scanning; Schizophrenia; Secondary to; Societies; System; Testing; Thalamic structure; Treatment Efficacy; Treatment Failure; Work; base; biomarker development; cohort; computational neuroscience; dopamine system; experience; gamma-Aminobutyric Acid; glutamatergic signaling; imaging study; in vivo; innovation; magnetic resonance spectroscopic imaging; multimodality; neurobiological mechanism; neuroimaging; neuromechanism; neuromelanin; neurotransmission; next generation; novel; novel therapeutics; personalized therapeutic; presynaptic; prospective; psychotic symptoms; responders and non-responders; response; schizophrenia-spectrum disorder; spectroscopic imaging; success; therapeutic development; transmission process; treatment effect; treatment responders; treatment response

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.

项目摘要 精神分裂症谱系障碍是所有精神病患者中最残疾的疾病，它具有重要的 体验他们以及他们的家人和社会的个人负担。最多35％ 患有疾病的人没有表现出对抗精神病药物的足够反应，并保持 对一线疗法的难治性，这有助于疾病的灼伤和发病率 无法与他们的社区融合。对基础神经生物学机制的有限理解 成功或失败的抗精神病药物继续阻碍新的治疗性发育 对这些疾病的现有疗法的优化。虽然最近的工作证明了 功能和光谱MR阐明了抗精神病药物的基础机制，更多 缺乏对与治疗效率相关的分子和神经元变化的全面了解。 在这项研究中，我们通过使用高场，7-Tesla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 早期精神分裂症。该项目着重于具有几种创新性的皮质基层神经节系统 方法，包括（1）通过神经素敏感的MRI的多巴胺系统的测定； （2）磁性 皮质γ-氨基丁酸和谷氨酸功能的共振光谱成像； （3）两个 假设和数据驱动的多元方法的皮质神经节功能连通性。敏锐 在这种自然主义和前瞻性中，将检查患有早期精神分裂症患者的精神病患者 学习。他们将在治疗计划中进行扫描，以2周的间隔进行临床评估，并将 经过8周的治疗后，被扫描。还将检查一组健康对照以建立正常 我们的神经影像措施的范围。这项工作的结果将为更全面的基础 我们对抗精神病药物相关的神经生物学的理解，这将促进生物标志物的发展， 机械临床试验以及下一代治疗策略的发展。

项目成果

A longitudinal investigation of GABA, glutamate, and glutamine across the insula during antipsychotic treatment of first-episode schizophrenia.

对首发精神分裂症抗精神病药物治疗期间岛叶中 GABA、谷氨酸和谷氨酰胺的纵向研究。

• DOI: 10.1016/j.schres.2022.08.008
• 发表时间: 2022
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Sonnenschein,SusanF;Mayeli,Ahmad;Yushmanov,VictorE;Blazer,Annie;Calabro,FinneganJ;Perica,Maria;Foran,William;Luna,Beatriz;Hetherington,HobyP;Ferrarelli,Fabio;Sarpal,DeepakK
• 通讯作者: Sarpal,DeepakK