Biomarker Strategies for Medication-Enhanced Cognitive Training in Schizophrenia

描述(由申请人提供)：此R34应用程序响应PAR-09-173，通过支持：“开发和/或试点测试新的或适应的干预措施”来实现本FOA的第一个目标。这项应用的两个主要目标是：1)测试急性应用NMDA拮抗剂美金刚(MEM)对精神分裂症(SZ)患者感觉运动门控和工作记忆(WM)的影响，以及2)评估使用MEM可预测地提高SZ认知训练的治疗效果的可行性。SZ的药物治疗一直以抗多巴胺能药物为主，临床疗效有限。一些形式的心理社会康复，如认知训练(CT)，似乎能有效地减轻SZ的症状和改善其功能。这一应用的前提是，CT在SZ的好处可能会通过包括西药在内的提高特定认知能力的药物来增强，即使这些促进认知的药物在没有CT的情况下使用时缺乏临床效果。这项应用的主要目标是开发一种创新的干预策略，通过向生物标记物识别的敏感患者给予促进认知剂来增强CT在SZ的临床益处。我们报道了广泛使用的阿尔茨海默病药物MEM(20 mg P.O.)的单剂量显著增加了健康受试者惊跳反射的脉冲前抑制(PPI)。在健康受试者中，MEM增强PPI的作用与：1)增加WM；以及2)与高活性Val158Met COMT多态相关的表型。PPI在SZ患者中持续受损；患者的PPI水平低与：1)功能结局差；2)Val/Val COMT基因。如果我们在健康受试者中的MEM结果在SZ患者中重现，我们将检测到与MEM相关的PPI和WM的改善，特别是在Val/Val患者中。然后，我们将检验这一假设，即MEM的急性PPI和WM增强效应可以预测MEM在接受CT治疗的SZ患者中的疗效。此应用程序有两个目标：目标1将评估MEM的急性影响(0比10或0比20 mg P.O.)在60例SZ患者中，验证MEM将增加SZ患者的PPI和增强WM的预测，特别是那些具有低基础PPI水平和/或Val/Val COMT基因型的患者。失配负性和伽马波段同步也将被评估为潜在的信息、MEM敏感和功能相关的生物标记物。目的2将评估在SZ患者中测试MEM作为CT辅助治疗益处的可行性，以及检验在AIM 1单剂量MEM挑战后SZ患者PPI和/或WM增加将预测这种益处的基本假设的可行性。据预测，在完成目标1的受试者中，在深圳门诊患者中进行为期12周的受控CT试验的受试者招募和完成，将适合于测试MEM作为CT辅助手段的整体有效性以及在生物标记物识别的患者亚组中预测这种有效性的能力。 公共卫生相关性：认知训练在减轻精神分裂症患者的症状和改善生活功能方面是适度有效的。本申请开发了一种策略，通过使用促进认知的药物来提高认知训练的有效性。将研究确定对这些促进认知药物最敏感的患者的特定生物标记物，以测试在精神分裂症药物增强认知训练的大型临床试验中使用这些生物标记物的可行性。

DESCRIPTION (provided by applicant): This R34 application responds to PAR-09-173, to achieve the first goal of this FOA by supporting: "the development and/or pilot testing of new or adapted interventions." The two overarching goals of this application are: 1) to test the effects of the acute administration of the NMDA antagonist, memantine (MEM), on sensorimotor gating and working memory (WM) in schizophrenia (SZ) patients, and 2) to assess the feasibility of using MEM to predictably enhance the therapeutic benefits of cognitive training in SZ. The pharmacotherapy of SZ has been dominated by antidopaminergic drugs with limited clinical impact. Some forms of psychosocial rehabilitation, such as cognitive training (CT), appear to effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CT in SZ might be enhanced by drugs that increase specific cognitive abilities, including WM, even if these pro-cognitive drugs lack clinical impact when administered without CT. The main goal of this application is to develop an innovative intervention strategy that enhances the clinical benefits of CT in SZ through administration of a pro-cognitive agent to biomarker-identified sensitive patients. We reported that a single dose of the widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of the startle reflex in healthy subjects. PPI-enhancing effects of MEM in healthy subjects are associated with: 1) increased WM; and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is consistently impaired in SZ patients; lowest levels of PPI in patients are associated with: 1) poor functional outcome; and 2) the Val/Val COMT genotype. If our MEM findings in healthy subjects are reproduced in SZ patients, we will detect MEM-associated improvements in PPI and WM, particularly among Val/Val patients. We will then be positioned to test the hypothesis that acute PPI and WM- enhancing effects of MEM predict therapeutic benefit of MEM in SZ patients undergoing CT. This application has two aims: Aim 1 will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 60 SZ patients, to test the prediction that MEM will increase PPI and enhance WM in SZ patients, particularly in those characterized by low basal PPI levels and/or the Val/Val COMT genotype. Mismatch negativity and gamma band synchronization will also be assessed as potentially informative MEM-sensitive and functionally relevant biomarkers. Aim 2 will assess the feasibility of testing the therapeutic benefit of MEM as an adjunct to CT in SZ patients, and the feasibility of testing the primary hypothesis that such benefit will be predicted by increased PPI and/or WM in SZ patients after the Aim 1 single dose MEM challenge. It is predicted that subject recruitment and completion in both arms of a controlled 12-week CT trial in SZ out- patients among subjects completing Aim 1 will be appropriate for testing both the overall effectiveness of MEM as an adjunct to CT and the ability to predict this effectiveness among biomarker-identified patient subgroups. PUBLIC HEALTH RELEVANCE: Cognitive training is moderately effective at reducing symptoms and improving life function in schizophrenia patients. The present application develops a strategy for increasing the effectiveness of cognitive training through the use of pro-cognitive medications. Specific biomarkers will be studied that identify patients most sensitive to these pro-cognitive medications, to test the feasibility of using these biomarkers in a large clinical trial of medication-enhanced cognitive training in schizophrenia.