Clinical Trials with Glutamatergic Agents

这是西尔维奥·O·孔特神经科学中心临床试验部分为 精神分裂症中谷氨酸调节失调的研究通过与Dr。 丹尼尔·贾维特。我们将扩展头五年的调查结果，并将审查 对D-环丝氨酸和“Constant”六个月试验阴性结果的可能解释 试验，对甘氨酸和D-环丝氨酸进行了4个月的比较--对阴性症状或 认知力。因为D-环丝氨酸和甘氨酸都不能满足贾维特博士的IND，我们将进行一项 甘氨酸部位部分激动剂D-丝氨酸的安慰剂对照试验未见显著改善 在阴性或认知症状之后，将采用一种新的方法，其中D-环丝氨酸是 每周给药一次。这种设计旨在避免对D-环丝氨酸重复给药的耐受性； 动物研究和最近对恐惧症患者的研究表明，单次注射可显著改善 认知功能，但这种耐受性在大约两周的每日剂量后形成。我们 将进行D-丝氨酸联合治疗的试验。这项研究源于蔡崇信和他之前的一项研究 同事们认为，更有效、更全面的激动剂D-丝氨酸可能对积极、消极和认知有效 症状无耐受证据，反复服药。最近完成的毒理学研究 将使我们能够在明年内获得D-丝氨酸研究的IND。与尤格伦博士合作- 托德，我们将在D-丝氨酸试验的基线和第8周进行功能磁共振成像，以延长我们之前的 D-环丝氨酸增强颞叶激活与改善 阴性症状。我们将扩大我们的DNA样本收集和广泛的数据库 从200到500名患者收集表型信息，以便检查与谷氨酸能相关的等位基因 调节与临床特征和对谷氨酸能药物的反应有关。的研究 G72和D-氨基酸氧化酶的多态作为D-丝氨酸反应的预测因子就是一个例子。我们 我们还将通过在更大的样本中检测另外两个多态来进一步研究GCPII。 与尤格伦-托德博士合作，我们还将检查NAA/NAAG浓度在 前皮质作为GCPII活性的潜在生物标志物。

This revised submission of the Clinical Trials Section of the Silvio O. Conte Neuroscience Center for the study of Glutamate Dysregulation in Schizophrenia has been enhanced by a new collaboration with Dr. Daniel Javitt. We will extend findings produced during the first five years and will examine possible explanations for the negative findings of our six month trial with D-cycloserine and the "CONSIST" trial, a 4 month comparison of glycine and D-cycloserine-- neither found effects on negative symptoms or cognition. Because neither D-cycloserine nor glycine may adequing Dr. Javitt's IND, we will conduct a placebo-controlled trial of D-serine a glycine site partial agonist, did not produce siginificant improvement in negative or cognitive symptoms will be followed-up by a new approach in which D-cycloserine is administered once-weekly. This design is intended to avoid tolerance to repeated dosing with D-cycloserine; animal studies and recent studies in patients with phobia indicate that single doses substantially improve cognitive function, but that tolerance develops after approximately two weeks of daily dosing. We will conduct a trial of D-serine co-treatment. This study follows from a previous finding by Tsai and colleagues that the more potent, full agonist D-serine may be effective for positive, negative and cognitive symptoms without evidence for tolerance with repeated dosing. The recent completion of toxicology studies will allow us to obtain an IND for study of D-serine within the next year. In collaboration with Dr. Yurgelun- Todd, we will perform fMRI at baseline and week 8 of the D-serine trial to extend our previous finding of enhanced temporal lobe activation with D-cycloserine which correlated with improvement of negative symptoms. We will expand our collection of DNA samples and our extensive database of phenotypic information from 200 to 500 patients to allow examination of alleles relevant to glutamatergic regulation in relation to clinical characteristics and response to glutamatergic agents. Study of polymorphisms of G72 and D-amino acid oxidase as predictors of D-serine response is one example. We will also further pursue our studies of GCPII by examining two additional polymorphisms in a larger sample. In collaboration with Dr. Yurgelun-Todd, we will also examine NAA/NAAG concentrations in prefrental cortex as a potential biological marker of GCPII activity.