Memantine augmentation of cognitive training in schizophrenia

美金刚增强精神分裂症认知训练

• 批准号: 10596484
• 负责人: GREGORY A LIGHT
• 金额: $ 74.13万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596484
• 关键词: Address; Affect; Alzheimer' s Disease; Antipsychotic Agents; 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; Learning; Life; 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; Placebo Control; Placebos; Process; Psychotic Disorders; Randomized; Recovery; Resources; Safety; Schizophrenia; Sensory; Symptoms; Testing; Therapeutic; Time; Training Programs; Verbal Learning; arm; auditory discrimination; 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; pharmacologic; pill; pilot test; pilot trial; predictive marker; 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.

为了响应RFA-MH-18-705，该应用程序开发并测试了改进的新型治疗策略 精神分裂症患者（SZ）的认知，通过药理学的增强认知疗法 （PACT），并直接解决了针对这些残疾障碍的更有效治疗的关键需求。 可以通过“自下而上”的目标认知训练来实现SZ患者的认知益处 （TCT）疗法，但是这种治疗是时间和资源密集的，反应是不完整的，并且 多变的。该申请测试了一个合理且经验支持的平台，以增强TCT的好处 在抗精神病药物中，通过辅助性每日治疗20 mg美容（MEM），FDA 批准治疗阿尔茨海默氏病认知功能障碍的药物。最近的荟萃分析 抗精神病药物质的SZ患者的MEM增强已证明其安全性，耐受性和 在短暂认知筛查测试中提高分数的有效性。我们假设MEM将增加 TCT学习，因此从TCT中获得临床收益，这种协议方法将是最有效的 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 概念验证，随机，对照研究的单剂量暴露于MEM相对于安慰剂。在这些 研究，我们发现MEM显着增强了听觉歧视的学习，这是 TCT计划在TCT 30-50H之后驱动SZ患者的认知增长。我们也是 发现一剂MEM显着增强了早期感觉信息的几种生物标志物 在抗精神病药中的SZ患者进行处理。剂量反应和时间课程研究确定了 最佳内存剂量（20 mg），以最大程度地学习效果。该应用程序仔细评估 SZ的此协议策略：目标1）确认目标参与：将测试54名SZ患者 确认MEM（20 mg）增强了TCT学习的测量；目标2）有效的试点测试：来自 AIM 1将随机分为2个治疗臂（n = 27/ARM），以进行双盲安慰剂对照30分。 MEM+TCT与安慰剂+TCT的临床试验，以确定MEM AUGMENTS的每日剂量是否 TCT收益的大小，速率和/或耐用性，以及这些收益是否与目标相关 参与，使用特定的GO/NO-GO标准以及症状，认知和现实生活的结果指标 功能;目的3）基于认知的PACT反应的预测性生物标志物鉴定 电生理和基于绩效的措施评估了TCT前后。这是一个非常新颖的 高风险的高回报应用以开发基于公正的治疗范例，以增强认知， 改善精神分裂症患者的恢复并提高预后，并将确定未来是否是否 有必要对此方法进行完全驱动的“验证性试验”。