Neurochemical and Clinical Effects of Glutamate Modulation in Schizophrenia

谷氨酸调节对精神分裂症的神经化学和临床效果

• 批准号: 8638307
• 负责人: Ragy Ramsis Girgis
• 金额: $ 21.48万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638307
• 关键词: Academia; Acetylcysteine; Address; Adverse effects; Amino Acids; Antioxidants; Antipsychotic Agents; Basic Science; Biological Markers; Brain; Brain imaging; Chronic; Clinical; Clinical Data; Clinical Trials; Cognitive; Cognitive deficits; Cysteine; Cystine; Data; Development; Dopamine Receptor; Dose; Effectiveness; Exhibits; Functional disorder; Future; Genetic; Glutamate Receptor; Glutamatergic Agents; Glutamates; Glutathione; Government; Image; Impairment; Individual; Lead; Magnetic Resonance Spectroscopy; Measurement; Measures; Medial; Metabolic; Metabolism; Methods; N-Methylaspartate; Neurobehavioral Manifestations; Outcome Measure; Oxidation-Reduction; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Prefrontal Cortex; Process; Public Health; Recruitment Activity; Reporting; Research Personnel; Role; Schizophrenia; Signal Transduction; Site; Symptoms; Synapses; System; Therapeutic Agents; Translating; Work; antiporter; base; clinical effect; clinical efficacy; design; disability burden; drug development; extracellular; imaging modality; improved; in vivo imaging; indexing; neurochemistry; novel; pre-clinical; preclinical study; public health relevance; theories; therapeutic development; therapy development; tool; treatment effect

Schizophrenia (SCZ) is a prevalent illness that is associated with significant disability and burden. Antipsychotic medications are the only approved pharmacological treatments. However, most patients are partially responsive or wholly unresponsive to them, and those that do respond are frequently burdened by significant side effects that limit compliance. Thus, newer treatments for SCZ are critically needed. All currently approved antipsychotic medications function primarily by blocking D2-type dopamine receptors. In contrast, recent alternative neurochemical theories focus on disturbances in brain glutamatergic pathways. While optimal approaches for normalization of glutamatergic function are currently under development and reflect significant progress in understanding the role of glutamate in the pathophysiology of SCZ, the rate of therapeutic development has been slow. One contributing factor to this lag is the lack of brain imaging-based biological markers by which researchers can determine the effects of experimental glutamatergic medications on the brain in SCZ. We propose to use Magnetic Resonance Spectroscopy (MRS) to assess the effects of a glutamatergic drug, N-acetylcysteine (NAC), on the brain. NAC is a precursor to glutathione (GSH), an antioxidant compound with glutamatergic effects that has been reported to improve symptoms in SCZ. Critical to the choice of NAC is that in preclinical studies it exhibits the same ability to block the PCP-induced glutamate surge as other agents under active development for therapy. Furthermore, abnormalities in medial prefrontal cortex (mPFC) glutamate (Glu) and GSH have been reported in medication-free individuals with SCZ. The potential for NAC challenge to restore these neurochemicals to normal levels presents a valuable opportunity to assess the effects of NAC on glutamatergic modulation in SCZ. To do so, we propose to recruit 20 antipsychotic naive individuals with SCZ and 20 matched healthy control subjects and perform MRS imaging measurements of Glu and GSH in the mPFC before and after NAC challenge. We hypothesize that NAC challenge will lead to amelioration of baseline abnormalities in these neurochemicals in SCZ, while no changes will be observed in healthy control subjects. We will also obtain clinical measures of positive, negative, and cognitive symptoms in these subjects. The proposed challenge design addresses the need for an imaging measure of engagement of the glutamate system by a putative glutamatergic therapeutic agent, which at present is lacking. This study could lay the groundwork for evaluating the efficacy of new treatments, by comparing this effect with clinical efficacy in chronic administration. Therefore, the present study could have a substantial impact on the imaging field and potentially provide a new tool to study the effects of glutamatergic agents on the brain, thereby increasing the effectiveness of drug development paradigms.

精神分裂症（SCZ）是一种与严重残疾和负担相关的流行疾病。 抗精神病药物是唯一批准的药物治疗。然而，大多数患者 部分响应或完全不响应，而那些响应的人往往负担着 严重的副作用限制了依从性。因此，迫切需要SCZ的新治疗方法。 目前批准的所有抗精神病药物主要通过阻断D2型多巴胺发挥作用 受体。 相比之下，最近的替代神经化学理论集中在脑神经元兴奋性障碍， 途径。虽然目前用于神经元功能正常化的最佳方法尚不成熟， 发展，并反映了在了解谷氨酸的作用，在病理生理学的重大进展， SCZ，治疗发展速度缓慢。造成这种滞后的一个因素是缺乏大脑 基于成像的生物标记物，研究人员可以通过这些标记物来确定实验 对SCZ的大脑有副作用。 我们建议使用磁共振波谱（MRS）来评估多巴胺能神经递质的作用。 药物，N-乙酰半胱氨酸（NAC），对大脑。NAC是谷胱甘肽（GSH）的前体，谷胱甘肽是一种抗氧化化合物 据报道，其具有能改善SCZ症状的镇痛作用。选择NAC的关键是 在临床前研究中，它表现出与其他药物相同的阻断PCP诱导的谷氨酸激增的能力 正在积极研发中此外，内侧前额叶皮层（mPFC） 谷氨酸（Glu）和谷胱甘肽已被报道在无药物治疗的SCZ个体。NAC的潜力 将这些神经化学物质恢复到正常水平的挑战提供了一个评估 NAC对SCZ神经递质调节的影响 为此，我们建议招募20名未接受过抗精神病药物治疗的SCZ患者和20名匹配的健康人， 对照受试者，并在NAC前后进行mPFC中Glu和GSH的MRS成像测量 挑战.我们假设NAC激发将导致这些患者基线异常的改善， SCZ中的神经化学物质，而在健康对照受试者中没有观察到变化。我们还将获得 这些受试者的阳性、阴性和认知症状的临床测量。 拟议的挑战设计解决了对参与的成像措施的需要， 谷氨酸系统通过推定的谷氨酸能治疗剂，目前缺乏。这项研究可能 通过将这种效果与临床疗效进行比较，为评估新治疗的疗效奠定基础 慢性给药。因此，本研究可能对成像领域产生重大影响， 潜在地提供了一种新的工具来研究多巴胺能药物对大脑的影响，从而增加了 药物开发模式的有效性。