Neurochemical and Clinical Effects of Glutamate Modulation in Schizophrenia

描述（由申请人提供）：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，大多数患者对这些药物有部分反应或完全无反应，而那些有反应的患者经常受到限制依从性的显著副作用的困扰。因此，迫切需要SCZ的新治疗方法。所有目前批准的抗精神病药物主要通过阻断D2型多巴胺受体发挥作用。相比之下，最近的替代神经化学理论的重点是在大脑的神经递质通路的干扰。虽然目前正在开发使谷氨酸能功能正常化的最佳方法，并反映了在理解谷氨酸在SCZ病理生理学中的作用方面取得的重大进展，但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基于脑成像的生物标记物，研究人员可以通过这些生物标记物来确定实验性多巴胺能药物对SCZ大脑的影响。我们建议使用磁共振波谱（MRS）来评估一种神经递质药物N-乙酰半胱氨酸（NAC）对大脑的影响。NAC是谷胱甘肽（GSH）的前体，谷胱甘肽是一种具有抗氧化作用的抗氧化化合物，据报道可改善SCZ的症状。选择NAC的关键是，在临床前研究中，它表现出与其他正在积极开发的治疗药物相同的阻断PCP诱导的谷氨酸盐激增的能力。此外，在内侧前额叶皮层（mPFC）谷氨酸（Glu）和谷胱甘肽异常已报告在无药物治疗的SCZ个体。NAC挑战将这些神经化学物质恢复到正常水平的潜力为评估NAC对SCZ中神经递质调节的影响提供了宝贵的机会。为此，我们建议招募20名未经抗精神病药治疗的SCZ患者和20名匹配的健康对照受试者，并在NAC激发前后对mPFC中的Glu和GSH进行MRS成像测量。我们假设，NAC的挑战将导致改善的基线异常，这些神经化学物质在SCZ，而没有变化将在健康对照组中观察到。我们还将获得这些受试者的阳性、阴性和认知症状的临床指标。所提出的挑战设计解决了通过推定的谷氨酸能治疗剂对谷氨酸系统的参与进行成像测量的需要，这是目前缺乏的。这项研究可以通过将这种效果与慢性给药的临床疗效进行比较，为评估新治疗的疗效奠定基础。因此，本研究可能对成像领域产生重大影响，并可能提供一种新的工具来研究多巴胺能药物对大脑的影响，从而提高药物开发范式的有效性。

DESCRIPTION (provided by applicant): 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.