Memantine augmentation of cognitive training in schizophrenia

美金刚增强精神分裂症认知训练

基本信息

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
项目类别：
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&apos 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

项目摘要

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一种新的治疗策略，以改善通过认知疗法的药物增强来提高精神分裂症 (SZ) 患者的认知能力 (PACT)，并直接解决对这些致残障碍进行更有效治疗的迫切需求。 SZ 患者的认知益处可以通过“自下而上”的基于感觉的有针对性的认知训练来实现 (TCT) 疗法，但此类治疗需要大量时间和资源，且反应不完全且该应用程序测试了一个合理且有经验支持的平台，以增强 TCT 的优势。在接受抗精神病药物治疗的 SZ 患者中每日辅助治疗 20 毫克美金刚 (MEM)，FDA 批准最近的荟萃分析批准了治疗阿尔茨海默病认知功能障碍的药物。 MEM 增强疗法在抗精神病药物 SZ 患者中的应用已证明其安全性、耐受性和我们发现 MEM 将提高简短认知筛选测试分数的有效性。 TCT 学习以及 TCT 的临床收益，并且这种 PACT 方法将是最有效的这些假设的初步支持来自我们的生物标志物定义的患者亚组。这些是相对于安慰剂单剂量暴露于 MEM 的概念验证、随机、对照研究。研究中，我们发现 MEM 显着增强了听觉辨别能力的学习，而听觉辨别能力的关键组成部分 TCT 计划在 30-50 小时的 TCT 后可促进 SZ 患者认知能力的提高。发现单剂量的 MEM 显着增强了早期感觉信息的多种生物标志物抗精神病药物治疗的 SZ 患者的剂量反应和时间过程研究确定了最佳 MEM 剂量（20 毫克）可实现最大的促进学习效果该应用程序对以下内容进行了仔细评估。 SZ 的 PACT 策略：目标 1) 确认目标参与：将对 54 名 SZ 患者进行测试确认 MEM（20 毫克）增强 TCT 学习措施；目标 2) 高效试点测试：受试者来自目标 1 将被随机分为 2 个治疗组（n=27/组），进行 30 个疗程的双盲安慰剂对照治疗 MEM+TCT 与安慰剂+TCT 的临床试验，以确定每天服用 MEM 是否会增强 TCT 增益的幅度、速率和/或持久性，以及这些增益是否与目标相关参与，使用具体的通过/不通过标准以及症状、认知和现实生活的结果测量功能；目标 3) 基于认知、PACT 反应的预测生物标志物识别， TCT 前后评估的电生理学和基于表现的测量方法是一种非常新颖的方法。高风险高回报的应用程序开发基于 PACT 的治疗范式，以增强认知，改善精神分裂症患者的康复并提高治疗结果，并将决定未来是否这种方法的全面“有效性验证试验”是有必要的。