Memantine effects on sensorimotor gating and neurocognition in schizophrenia

摘要 MH 94320寻求3年的新支持，以测试NMDA拮抗剂美金刚的作用 (MEM)精神分裂症（SZ）患者的听觉加工。FY 1-4的研究产生了令人惊讶的 前所未有的发现，一粒MEM（20毫克）显着增强（使“更正常”）3 SZ患者异常早期听觉信息处理（EAIP）的测量：前脉冲抑制（PPI）， 失匹配负波（MMN）和γ听觉稳态反应（ASSR）。基于结构方程 模型证据表明，EAIP是SZ功能障碍的根本原因， EAIP是一个令人信服的神经生物学信号，表明MEM正在进入大脑机制， 提供了一种治疗方法。然而，EAIP的急性增益不足以增强神经认知， SZ.该更新应用测试了MEM对听觉处理保真度功能测量的影响 (APF)和听觉学习的SZ患者和匹配的健康受试者（HS），以确定“中间 表型”，桥接即时MEM增强的EAIP与神经认知和功能的最终增益。 这些发现将暗示EAIP的神经生理学测量与EAIP之间的联系机制。 他们产生的神经认知和功能结果，并将确定候选生物标志物预测 在未来的临床试验中，对MEM的治疗反应，与靶向认知训练（TCT）配对。 虽然目前SZ的药物治疗并不能显著提高功能结局，但某些形式的药物治疗可能会降低功能结局。 基于药物的TCT有效地减轻了SZ的症状并改善了功能。本申请的一个前提是 TCT在SZ中的益处将通过增加特定认知能力的药物来增强，包括 听觉处理虽然MEM在SZ中的临床影响存在争议，但没有研究试图利用 MEM对EAIP的积极影响，以增加TCT的益处。我们建议测试一个机械原理， 一个未来的试验“药理学增强认知训练”（PACT）与MEM，其中MEM- 增强的EAIP通过获得APF和/或听觉学习改善SZ患者的神经认知和功能。 在3年内，MH 94320将检验MEM（20 mg p.o.）将极大地增强 41例SZ患者和41例HS患者通过双盲、安慰剂- 对照交叉设计（Aim 1）。将使区域来源的MEM增强EAIP本地化。的预测因素 将评估MEM敏感性，包括基线性能和谷氨酸受体中的特异性SNP 以前与MEM敏感性相关的基因。路径分析将确定MEM增强型EAIP是否会导致 改善APF/学习，从而建立治疗性增强认知的特定途径， （目标2-3）。研究结果将通过阐明MEM增强的机制来指导未来的工作。 EAIP产生神经认知和功能的增益，并通过识别MEM的“个性化”生物标志物， 灵敏度以及用于未来R61/R33应用的目标接合的候选生理信号。

Abstract MH94320 seeks 3 years of renewed support to test the effects of the NMDA antagonist, memantine (MEM), on auditory processing in patients with schizophrenia (SZ). Studies in FY 1-4 produced the surprising and unprecedented findings that a single pill of MEM (20 mg) significantly enhanced (made “more normal”) 3 measures of aberrant early auditory information processing (EAIP) in SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and gamma auditory steady-state response (ASSR). Based on structural equation modeling evidence that EAIP is a root cause of functional impairment in SZ, a drug-induced improvement in EAIP is a compelling neurobiological signal that MEM is accessing brain mechanisms that ultimately will provide a pathway to therapeutics. However, acute gains in EAIP are insufficient to enhance neurocognition in SZ. This renewal application tests the impact of MEM on functional measures of auditory processing fidelity (APF) and auditory learning in SZ patients and matched healthy subjects (HS), to identify “intermediate phenotypes”, bridging immediate MEM-enhanced EAIP with eventual gains in neurocognition and function. Such findings would implicate mechanisms connecting neurophysiological measures of EAIP to the neurocognitive and functional outcomes that they generate, and would identify candidate biomarkers predicting a therapeutic response to MEM, paired with Targeted Cognitive Training (TCT), in future clinical trials. While current medications for SZ do not significantly enhance functional outcome, some forms of auditory-based TCT effectively reduce symptoms and improve function in SZ. One premise of this application is that benefits of TCT in SZ will be enhanced by drugs that increase specific cognitive abilities, including auditory processing. While the clinical impact of MEM in SZ is controversial, no studies have tried to utilize MEM's positive effects on EAIP to augment the benefits of TCT. We propose to test a mechanistic rationale for a future trial of “Pharmacologic Augmentation of Cognitive Training” (PACT) with MEM, in which MEM- enhanced EAIP improves neurocognition and function in SZ patients via gains in APF and/or auditory learning. In 3 years, MH94320 will test the prediction that MEM (20 mg p.o.) will acutely enhance functional measures of APF and learning as well as EAIP in 41 SZ patients and 41 HS, via a double-blind, placebo- controlled cross-over design (Aim 1). Regional sources of MEM-enhanced EAIP will be localized. Predictors of MEM sensitivity will be assessed, including baseline performance, and specific SNPs in glutamate receptor genes previously associated with MEM sensitivity. Path Analyses will determine if MEM-enhanced EAIP leads to improved APF/learning, thus establishing a specific pathway to therapeutic enhancement of cognition and function (Aims 2-3). Findings will guide future efforts by explicating mechanisms by which MEM-enhanced EAIP produces gains in neurocognition and function, and by identifying “personalized” biomarkers of MEM sensitivity as well as candidate physiological signals of target engagement for a future R61/R33 application.