Memantine augmentation of cognitive training in schizophrenia

响应RFA-MH-18-705，该应用程序开发并测试了一种新的治疗策略，以改善 药物强化认知疗法对精神分裂症患者认知功能的影响 (公约)，并直接满足了对这些致残障碍进行更有效治疗的迫切需要。 通过“自下而上”的基于感觉的有针对性的认知训练，可以获得SZ患者的认知益处 (TCT)疗法，但这种治疗是时间和资源密集型的，反应不完全和 变量。这个应用程序测试了一个理性的、有经验支持的平台，用于增强TCT的优势 FDA的一种名为美金刚(MEM)的抗精神病药物在SZ患者中的应用 批准用于治疗阿尔茨海默病认知功能障碍的药物。最近的荟萃分析 抗精神病药物治疗的SZ患者的MEM增强已证明其安全性、耐受性和 在简短的认知筛查测试中提高分数的有效性。我们假设MEM将扩大 TCT学习，从而从TCT中获得临床收益，这种PACT方法将是最有效的 在生物标记物定义的患者亚组中。对这些假设的初步支持来自我们的 与安慰剂相比，单剂量暴露于MEM的概念验证、随机对照研究。在这些 研究发现，MEM显著增强了听觉辨别的学习，这是听觉识别的关键组成部分 众所周知，TCT计划可以在30-50小时的TCT后推动SZ患者的认知进步。我们也 发现单剂量的MEM显著增强了几个早期感觉信息的生物标志物 抗精神病药物治疗SZ患者的处理。剂量-反应和时间进程研究证实 最佳MEM剂量(20毫克)，以获得最大的促进学习效果。此应用程序将对 SZ的这项协议战略：目标1)确认目标参与度：54名SZ患者将接受测试 确认MEM(20毫克)增强了TCT学习的措施；目标2)有效的初步测试：受试者来自 AIM 1将被随机分成2个治疗组(n=27/组)，进行双盲、安慰剂对照的30个疗程 MEM+TCT与安慰剂+TCT的临床试验，以确定每天服用MEM是否会增加 TCT收益的幅度、速度和/或持久性，以及这些收益是否与目标相关 参与，使用特定的进行/不进行的标准和症状、认知和现实生活的结果测量 目的3)PACT反应的预测性生物标记物识别，基于认知， 在TCT治疗前后评估电生理和基于表现的测量。这是一部高度小说， 高风险高回报应用程序，以开发基于PACT的治疗范例，以增强认知， 改善精神分裂症患者的康复和改善预后，并将决定未来， 对这种方法进行全面的“验证性疗效试验”是有必要的。

In response to RFA-MH-18-705, this application develops and tests a novel treatment strategy for improving cognition in patients with schizophrenia (SZ), via Pharmacologic Augmentation of Cognitive Therapies (PACTs), and directly addresses a critical need for more effective treatments for these disabling impairments. Cognitive benefits in SZ patients can be achieved via “bottom-up” sensory-based targeted cognitive training (TCT) therapies, but such treatments are time- and resource-intensive, and responses are incomplete and variable. This application tests a rational and empirically supported platform for augmenting the benefits of TCT in antipsychotic medicated SZ patients by adjunctive daily treatment of 20 mg memantine (MEM), an FDA approved medication for the treatment of cognitive dysfunction in Alzheimer's Disease. Recent meta-analyses of MEM augmentation in antipsychotic-medicated SZ patients have demonstrated its safety, tolerability, and effectiveness at improving scores on brief cognitive screening tests. We hypothesize that MEM will augment TCT learning and hence the clinical gains from TCT, and that this PACT approach will be most effective in biomarker-defined subgroups of patients. Preliminary support for these hypotheses comes from our proof-of-concept, randomized, controlled studies of single-dose exposure to MEM relative to placebo. In these studies, we found that MEM significantly enhanced learning in auditory discrimination, the key component of the TCT program which is known to drive the cognitive gains in SZ patients following 30-50h of TCT. We also found that a single dose of MEM significantly enhanced several biomarkers of early sensory information processing in antipsychotic medicated SZ patients. Dose-response and time course studies identified the optimal MEM dose (20 mg) for maximal pro-learning effects. This application conducts a careful assessment of this PACT strategy for SZ: Aim 1) Confirmation of target engagement: 54 SZ patients will be tested to confirm that MEM (20 mg) enhances measures of TCT learning; Aim 2) Efficient pilot testing: Subjects from Aim 1 will be randomized into 2 treatment arms (n=27/arm) for a double-blind placebo-controlled 30-session clinical trial of MEM+TCT vs. placebo+TCT, to determine whether daily dosing of MEM augments the magnitude, rate and/or durability of TCT gains, and whether these gains are associated with target engagement, using specific Go/No-Go criteria and outcome measures of symptoms, cognition and real-life function; Aim 3) Predictive biomarker identification of the PACT response, based on cognitive, electrophysiological, and performance-based measures assessed pre- and post-TCT. This is a highly novel, high-risk high-reward application to develop a PACT-based treatment paradigm that will enhance cognition, improve recovery and enhance outcomes for patients with schizophrenia, and will determine whether a future, fully-powered “Confirmatory Efficacy trial” of this approach is warranted.