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.

作为对RFA-MH-18-705的响应，本申请开发了一种新的慢性 精神障碍，通过认知疗法的药物增强（PACTs），从而直接 解决了对这些破坏性大脑疾病更有效治疗的迫切需求。尽管60年来 作为慢性精神病包括精神分裂症的主要治疗手段，抗精神病药物可能不 显著改变这些疾病的病程或实际功能影响。在这些方面的适度临床获益 患者可以通过特定的认知疗法（CT）来实现，包括“自下而上”的基于感觉的靶向治疗。 认知训练（TCT），但这种治疗是时间和资源密集型的，而且反应不完全 和变量。本申请寻求一种实用的方法来增加TCT在精神分裂症患者中的益处。 我们假设，特定的促认知剂将增加TCT的临床获益， 精神分裂症患者，这种PACT方法将特别有效，在生物标志物定义的 患者的亚组。这一假设的初步支持来自PI的研究（MH 59803）： 抗精神病药物治疗的精神分裂症患者，前注意力药物，d-苯丙胺，显着增强 听觉辨别任务中的学习（Posit Science“Sound Sweeps”）。“声扫”是一个关键 TCT项目的一个组成部分，已知在精神分裂症患者中产生临床收益。安非他明- 精神分裂症患者听觉处理速度（APS）学习的增强与 特定神经生理学生物标志物的基线（给药前）水平。剂量反应和时间过程研究 确定了最佳安非他明剂量（5 mg po）和时间（TCT前1小时），以获得最大的促学习效果。 与大量文献一致，安非他明在该患者人群中安全且耐受性良好。 本申请在3个目标中对精神分裂症的PACT策略进行了仔细评估： 目的1）确认目标接合：将对54名特征良好的精神分裂症患者进行 测试以确认安非他明（5 mg po）增强APS学习; 目标2）有效的初步试验：将目标1的受试者随机分为2个治疗组（n=27/组） 一项比较安非他明+TCT与PBO+TCT的双盲PBO对照30次临床试验，以确定 安非他明是否增加TCT诱导的增益的幅度、速率和/或持久性，以及是否 这些收益与目标交战有关，使用特定的行动/不行动标准和结果测量 症状，神经认知和现实生活功能; 目的3）基于神经认知，识别PACT反应的生物标志物预测因子， TCT前后评估的电生理、心理生理和基于性能的测量。 这是一种高度新颖、高风险、高回报的应用，用于开发一种新的治疗模式， 从而减轻慢性精神病患者的痛苦。