Memantine effects on sensorimotor gating and neurocognition in schizophrenia

摘要 MH94320寻求3年新的支持以测试NMDA拮抗剂美金刚的效果 (Mem)，关于精神分裂症(SZ)患者的听觉处理。第一财年至第四财年的研究得出了令人惊讶的结果 史无前例的发现是，单片MEM(20毫克)显著增强(使之更正常)3 SZ患者异常早期听觉信息处理(EAIP)的测量：脉冲前抑制(PPI)， 失配性负波(MMN)和伽马听觉稳态反应(ASSR)。基于结构方程 模拟证据表明，EAIP是SZ功能障碍的根本原因，是药物诱导的改善 EAIP是一个令人信服的神经生物学信号，表明MEM正在访问最终将 提供一条通往治疗学的途径。然而，EAIP的急剧增加不足以增强患者的神经认知 SZ.此续订应用程序测试MEM对听觉处理保真度的功能测量的影响 SZ患者和匹配的健康受试者(HS)的APF和听觉学习，以识别“中间” 表型“，将即时的MEM增强的EAIP与神经认知和功能的最终收益联系起来。 这些发现将暗示EAIP的神经生理学测量与 它们产生的神经认知和功能结果，并将确定预测的候选生物标记物 在未来的临床试验中，对MEM的治疗反应与靶向认知训练(TCT)相结合。 虽然目前治疗SZ的药物并不能显著提高功能结果，但某些形式的 以听觉为基础的TCT有效地减轻了SZ的症状，改善了功能。此应用程序的一个前提是 TCT在深圳的益处将被提高特定认知能力的药物所增强，包括 听觉处理。虽然MEM对SZ的临床影响存在争议，但还没有研究试图利用 MEM对EAIP的积极作用，以增加TCT的好处。我们建议测试一种机械论的基本原理 未来将与MEM一起进行“认知训练的药理学增强”(PACT)试验，其中MEM- 增强的EAIP通过改善APF和/或听觉学习，改善SZ患者的神经认知和功能。 在3年内，MH94320将检验MEM(20 mg P.O.)将极大地增强 采用双盲安慰剂对41例SZ患者和41例HS患者进行APF、学习和EAIP测定。 受控交叉设计(目标1)。MEM增强型EAIP的地区来源将本地化。预测因素 将评估MEM的敏感性，包括基线表现和谷氨酸受体中的特定SNPs 以前与MEM敏感性相关的基因。路径分析将确定MEM增强的EAIP是否领先 改善APF/学习，从而建立一条特定的途径来治疗增强认知和 功能(目标2-3)。这些发现将通过解释MEM增强的机制来指导未来的努力 EAIP在神经认知和功能方面取得进展，并通过识别MEM的“个性化”生物标记物 用于未来R61/R33应用的目标接合的灵敏度以及候选生理信号。

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.