Neurochemical and Clinical Effects of Glutamate Modulation in Schizophrenia

精神分裂症(SCZ)是一种常见疾病，与严重的残疾和负担有关。 抗精神病药物是唯一被批准的药物治疗。然而，大多数患者都是 对他们部分反应或完全没有反应，而那些有反应的人经常背负着 限制合规性的重大副作用。因此，迫切需要对SCZ进行新的治疗。 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。 感受器。相比之下，最近的替代神经化学理论关注的是大脑谷氨酸能障碍。 小路。虽然谷氨酸能功能正常化的最佳方法目前正在 发展和反映了在理解谷氨酸在脑血管疾病病理生理中的作用方面的重大进展 SCZ，治疗开发的速度一直很慢。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，研究人员可以通过它来确定实验的效果 谷氨酸能药物对SCZ患者大脑的影响。 我们建议使用磁共振波谱(MRS)来评估谷氨酸能 药物，N-乙酰半胱氨酸(NAC)，在大脑中。NAC是抗氧化剂谷胱甘肽(GSH)的前体 具有谷氨酸能作用，据报道可改善SCZ的症状。选择新来港定居人士的关键是 在临床前研究中，它表现出与其他药物一样的阻止五氯苯酚诱导的谷氨酸激增的能力 正在积极开发治疗方法。此外，内侧前额叶皮质(MPFC)的异常 谷氨酸(Glu)和谷胱甘肽(GSH)在无药物治疗的SCZ患者中已有报道。NAC的潜力 将这些神经化学物质恢复到正常水平的挑战为评估 NAC对孤束核谷氨酸能调制的影响。 为此，我们建议招募20名患有SCZ的抗精神病药物初学者和20名匹配的健康人。 正常受试者NAC前后mPFC中谷氨酸和谷胱甘肽的磁共振成像测量 挑战。我们假设，NAC挑战将导致这些患者基线异常的改善 SCZ中的神经化学物质，而健康对照组则没有变化。我们还将获得 对这些受试者的阳性、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求 谷氨酸系统的一种推定的谷氨酸能治疗剂，这是目前所缺乏的。这项研究可能 通过与临床疗效的比较，为评估新疗法的疗效奠定基础 在长期服药中。因此，本研究可能对成像领域产生实质性影响，并 潜在地提供了一个新的工具来研究谷氨酸能药物对大脑的影响，从而增加了 药物开发范例的有效性。

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.