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：
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
项目类别：
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&apos 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

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.