Memantine augmentation of cognitive training in schizophrenia

美金刚增强精神分裂症认知训练

• 批准号: 10353409
• 负责人: GREGORY A LIGHT
• 金额: $ 75.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353409
• 关键词: Address; Affect; Alzheimer' s Disease; Antipsychotic Agents; Attention; Auditory; Biological Assay; Biological Markers; Chronic; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive Therapy; Dose; Double-Blind Method; Educational Intervention; Effectiveness; Electroencephalography; Electrophysiology (science); Exercise; Exhibits; Exposure to; FDA approved; Family; Future; Health system; Hour; Impaired cognition; Impairment; Intervention; Laboratories; Lead; Learning; Life; Logistics; Measures; Medicine; Memantine; Memory; Meta-Analysis; N-Methyl-D-Aspartate Receptors; Neurocognitive; Neuronal Plasticity; Outcome; Outcome Measure; Participant; Patient-Focused Outcomes; Patients; Perceptual learning; Performance; Pharmaceutical Preparations; Pharmacology; Placebo Control; Placebos; Process; Psychotic Disorders; Randomized; Reaction Time; Recovery; Resources; Safety; Schizophrenia; Sensory; Symptoms; Testing; Therapeutic; Time; Training Programs; Verbal Learning; arm; auditory discrimination; base; biomarker identification; cognitive benefits; cognitive function; cognitive training; computerized; confirmatory trial; cost; design; disability; early detection biomarkers; effective therapy; functional gain; high reward; high risk; improved; information processing; neurophysiology; neuropsychiatry; novel; novel strategies; patient subsets; performance based measurement; pill; pilot test; pilot trial; predictive marker; predictive test; psychosocial; psychotic symptoms; randomized controlled study; response; screening; sound; therapy design; treatment arm; treatment response; treatment strategy

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.

作为对RFA-MH-18-705的回应，本申请开发并测试了一种新的治疗策略， 精神分裂症（SZ）患者的认知，通过认知疗法的药物增强 （PACTs），并直接解决了对这些致残性损伤的更有效治疗的迫切需求。 可以通过“自下而上”的基于感觉的有针对性的认知训练来实现SZ患者的认知益处 (TCT)治疗，但这种治疗是时间和资源密集型的，反应是不完整的， 变量这个应用程序测试了一个合理的和经验支持的平台，以增加TCT的好处 在抗精神病药物治疗的SZ患者中，通过每日连续治疗20 mg美金刚胺（MEM），FDA 批准用于治疗阿尔茨海默病认知功能障碍的药物。近期荟萃分析 在接受抗精神病药物治疗的SZ患者中，MEM强化治疗的安全性、耐受性和 在提高简短的认知筛查测试分数方面的有效性。我们假设MEM会增加 TCT学习，因此从TCT中获得临床收益，这种PACT方法将是最有效的 在生物标志物定义的患者亚组中。对这些假设的初步支持来自我们的 MEM相对于安慰剂单次给药暴露的概念验证、随机化、对照研究。在这些 研究中，我们发现MEM显著增强了听觉辨别力的学习，听觉辨别力的关键组成部分， TCT程序，已知该程序可在30- 50小时TCT后驱动SZ患者的认知增益。我们也 发现单剂量MEM显著增强了早期感觉信息的几种生物标志物 抗精神病药物治疗SZ患者的处理。剂量反应和时间过程研究确定了 最佳MEM剂量（20 mg），以获得最大的促学习效果。本申请对以下方面进行了仔细评估： SZ的PACT策略：目标1）确认目标接合：将对54名SZ患者进行测试， 证实MEM（20 mg）增强TCT学习的测量;目标2）有效的试点测试：来自 目标1将随机分配至2个治疗组（n=27/组），进行30次双盲安慰剂对照治疗 MEM+TCT与安慰剂+TCT的临床试验，以确定每日给予MEM是否增加了 TCT增益的幅度、速率和/或持久性，以及这些增益是否与目标 参与，使用特定的Go/No-Go标准和症状，认知和现实生活的结局指标 3）基于认知， TCT前后评估的电生理和基于性能的测量。这是一个非常新颖的， 高风险高回报的应用，以开发一种基于PACT的治疗模式， 改善精神分裂症患者的康复和改善预后，并将决定未来， 这种方法的完全有效的“抗炎疗效试验”是必要的。