Pharmacologic augmentation of targeted cognitive training in schizophrenia

为了响应RFA-MH-18-705，该应用程序开发了一种新的慢性 精神障碍，通过认知疗法(PACTS)的药物强化，从而直接 解决了对这些毁灭性的大脑疾病进行更有效治疗的迫切需要。尽管已经60年了 作为包括精神分裂症在内的慢性精神障碍的主要治疗工具，抗精神病药物可能不会 显著改变这些疾病的病程或现实生活中的功能影响。对这些患者的临床益处不大 患者可以通过特定的认知疗法(CT)来实现，包括“自下而上”的基于感官的靶向疗法 认知训练(TCT)，但这样的治疗是时间和资源密集型的，而且反应不完全 而且是可变的。这项应用寻求一种实用的方法来增加TCT对精神分裂症患者的好处。 我们假设，特定的认知促进剂将增加TCT的临床收益 精神分裂症患者，这种PACT方法将在生物标志物定义的情况下特别有效 患者的亚组。对这一假设的初步支持来自PI的研究(MH59803)： 服用抗精神病药物的精神分裂症患者，注意力促进药物d-苯丙胺显著增强。 在听觉辨别任务中的学习(假设科学“声音清扫”)。“声音清扫”是关键 TCT计划的组成部分，已知可为精神分裂症患者带来临床收益。安非他命- 精神分裂症患者在听觉处理速度(APS)学习方面的增强与 特定神经生理学生物标志物的基线(用药前)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)和最佳时间(TCT前1小时)以达到最大的促进学习效果。 与大量文献一致的是，苯丙胺在这些患者群体中是安全和耐受性良好的。 这个应用程序在3个目标中对精神分裂症的这一PACT策略进行了仔细的评估： 目标1)确认目标参与：54名特征良好的精神分裂症患者将 试验证实，苯丙胺(5 Mg Po)可增强APS学习； 目标2)有效的先导试验：目标1的受试者被随机分成2个治疗组(n=27/组) 对于苯丙胺+TCT与PBO+TCT的双盲对照30疗程临床试验，以确定 苯丙胺是否增加了TCT引起的收益的幅度、速度和/或持久性，以及是否 这些收益与目标参与度相关，使用特定的进行/不进行标准和结果衡量标准 症状、神经认知和现实生活功能； 目的3)基于神经认知，确定PACT反应的生物标志物预测因子， 在TCT前后评估电生理、心理生理学和基于表现的测量。 这是一种高度新颖、高风险、高回报的应用程序，旨在开发一种新的治疗范式和 从而减轻慢性精神病患者的痛苦。

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.