Pharmacologic augmentation of targeted cognitive training in schizophrenia

精神分裂症针对性认知训练的药物增强

• 批准号: 10039026
• 负责人: NEAL R SWERDLOW
• 金额: $ 74.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039026
• 关键词: Acute; Address; Amphetamines; Antipsychotic Agents; Anxiety Disorders; Attention; Attentional deficit; Auditory; Biological Assay; Biological Markers; Brain; Brain Diseases; Chronic; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive Therapy; Cognitive deficits; Data; Dextroamphetamine; Disease; Dose; Double-Blind Method; Electrophysiology (science); Exercise; Exhibits; Experimental Designs; Extinction (Psychology); Future; Hour; Impairment; Intervention; Laboratories; Learning; Life; Literature; Logistics; Measures; Medicine; Neurocognition; Neurocognitive; Outcome Measure; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Placebos; Process; Psychiatric therapeutic procedure; Psychophysiology; Psychotic Disorders; Randomized; Reaction Time; Resources; Safety; Schizophrenia; Science; Sensory; Symptoms; Testing; Therapeutic; Time; Training; Training Programs; arm; auditory discrimination; auditory processing; base; cognitive benefits; cognitive training; cohort; computerized; confirmatory trial; cost; effective therapy; functional gain; high reward; high risk; improved functioning; information processing; neurophysiology; novel; patient population; patient subsets; performance based measurement; pilot trial; predictive marker; processing speed; psychostimulant; reduce symptoms; response; sound; tool; treatment arm; treatment strategy; vigilance

In response to RFA-MH-18-705, this application develops a novel treatment strategy for chronic psychotic disorders, via Pharmacologic Augmentation of Cognitive Therapies (PACTs), and thereby directly addresses a critical need for more effective treatments for these devastating brain disorders. Despite 60 years as the major therapeutic tool for chronic psychotic disorders, including schizophrenia, antipsychotics may not significantly alter the course or real-life functional impact of these disorders. Modest clinical benefits in these patients can be achieved via specific cognitive therapies (CTs), including “bottom-up” sensory-based targeted cognitive training (TCT), but such treatments are time- and resource-intensive, and responses are incomplete and variable. This application seeks a practical way to augment the benefits of TCT in schizophrenia patients. We hypothesize that specific pro-cognitive agents will augment the clinical gains from TCT in schizophrenia patients, and that this PACT approach will be particularly effective in biomarker-defined subgroups of patients. Preliminary support for this hypothesis comes from the PI's studies (MH59803): in antipsychotic-medicated schizophrenia patients, the pro-attention drug, d-amphetamine, significantly enhanced learning in an auditory discrimination task (Posit Science “Sound Sweeps”). “Sound Sweeps” is a key component of a TCT program known to produce clinical gains in schizophrenia patients. Amphetamine- enhanced gains in auditory processing speed (APS) learning in schizophrenia patients were associated with baseline (pre-drug) levels of specific neurophysiological biomarkers. Dose-response and time course studies identified optimal amphetamine dose (5 mg po) and time (1 h pre-TCT) for maximal pro-learning effects. Consistent with a large literature, amphetamine was safe and well tolerated in this patient population. This application conducts a careful assessment of this PACT strategy for schizophrenia in 3 Aims: Aim 1) Confirmation of target engagement: 54 well-characterized schizophrenia patients will be tested to confirm that amphetamine (5 mg po) enhances APS learning; Aim 2) Efficient pilot testing: Subjects from Aim 1 are randomized into 2 treatment arms (n=27/arm) for a double-blind PBO-controlled 30-session clinical trial of amphetamine+TCT vs. PBO+TCT, to determine whether amphetamine augments the magnitude, rate and/or durability of TCT-induced gains, and whether these gains are associated with target engagement, using specific Go/No-Go criteria and outcome measures of symptoms, neurocognition and real-life function; Aim 3) Identify biomarker predictors of the PACT response, based on neurocognitive, electrophysiological, psychophysiological and performance-based measures assessed pre- and post-TCT. This is a highly novel, high-risk high-reward application to develop a novel treatment paradigm and thereby relieve suffering in patients with chronic psychotic disorders.

为了响应RFA-MH-18-705，该应用程序开发了一种新型的慢性治疗策略 精神病性疾病，通过认知疗法的药理学增强（PACT），从而直接 解决了这些毁灭性脑疾病的更有效治疗的关键需求。尽管有60年 作为包括精神分裂症在内的慢性精神疾病的主要治疗工具，抗精神病药可能不会 这些中等的临床益处 可以通过特定的认知疗法（CTS）来实现患者，包括基于“自下而上”的目标目标 认知培训（TCT），但是这种治疗时间是时间和资源密集的，反应是不完整的 和变量。该应用程序寻求一种实用方法来增强TCT在精神分裂症患者中的好处。 我们假设特定的亲认知剂将增加TCT的临床收益 精神分裂症患者，这种条约方法将在生物标志物定义中特别有效 患者亚组。对此假设的初步支持来自PI的研究（MH59803）： 抗精神病药物精神分裂症患者，促进性药物，D-原苯丙胺，显着增强 在听觉歧视任务中学习（理由科学“声音扫”）。 “扫荡”是关键 TCT计划的成分已知，该计划可在精神分裂症患者中产生临床增长。苯丙胺 - 精神分裂症患者的听觉处理速度（AP）学习的增长与 基线（药物前）特定神经生理生物标志物的水平。剂量反应和时间课程 确定了最佳的苯丙胺剂量（5 mg PO）和时间（TCT 1 h），以实现最大的促学习效果。 与大型文献一致，苯丙胺在该患者人群中是安全且耐受性的。 该申请在3个目标中仔细评估了精神分裂症的该协定策略： 目的1）确认目标参与：54名特征良好的精神分裂症患者将是 测试以确认苯丙胺（5 mg PO）增强了APS学习； AIM 2）有效的试点测试：AIM 1的受试者被随机分为2个治疗臂（n = 27/ARM） 对于苯丙胺+TCT与PBO+TCT的双盲PBO控制的30条临床试验，以确定 苯丙胺是否会增强TCT诱导的增益的幅度，速率和/或耐用性，以及是否增加 这些收益与目标参与，使用特定的GO/NO-GO标准和结果指标有关 症状，神经认知和现实生活功能； 目标3）确定基于神经认知的PACT反应的生物标志物预测指标 电池生理，心理生理和基于绩效的措施评估了TCT前后。 这是一种高度新颖，高风险的高级应用，用于开发一种新型的治疗范式和 从而营救患有慢性精神病患者的痛苦。