Memantine effects on sensorimotor gating and neurocognition in schizophrenia

描述(由申请人提供)：本R01将通过识别预测SZ患者前认知药物效果的生物标记物，为精神分裂症(SZ)的新治疗策略建立生物学基础。这些促进认知的效应将被用来特别增强认知疗法(CT)对SZ的临床影响；类似的策略正在有效地推进用于焦虑症的治疗。这项应用将测试低亲和力NMDA拮抗剂美金刚(MEM)的“挑战剂量”对SZ患者感觉运动门控和神经认知的影响；将测试与生理和遗传生物标记物对这些MEM影响的缓和影响有关的特定假设。MEM积极效应的预测指标将被用来确定丰富的“MEM敏感”的SZ患者队列，用于使用MEM进行试验，以增强CTs的治疗效果。SZ的药物治疗一直以临床疗效有限的药物为主。一些形式的CT，包括更广泛的认知康复和认知训练形式，有效地减轻了症状，改善了SZ的功能。这一应用的前提是，CT在SZ的好处可能会通过增加特定认知能力的药物来增强，包括工作记忆(WM)，即使这些促进认知的药物在没有CT的情况下使用时没有临床效果。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药物来增强CT在SZ的临床益处。我们最近报道，安全、神经保护、广泛使用的阿尔茨海默病药物MEM(20 mg P.O.)单剂量显著增加健康受试者对惊厥的脉冲前抑制(PPI)。MEM的这些PPI增强作用与：1)增加WM；以及2)与高活性Val158Met COMT多态相关的表型。PPI在SZ患者中受损；患者PPI水平低与：1)功能预后不良；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MEM相关的PPI和WM的增加，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。此应用程序将评估MEM的急性影响(0比10或0比20 mg P.O.)在80名SZ患者和80名健康受试者中，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SZ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。这项研究的发现将指导未来的临床试验，测试总体 通过确定生物标记物定义的患者最有可能从这种治疗方案中受益，MEM作为CT的辅助手段的有效性；此类试验的可行性目前正在由 少年派的R34 MH093453。 公共卫生相关性：认知疗法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。本申请旨在开发一种策略，通过使用促进认知的药物来提高精神分裂症认知治疗的有效性。根据健康对照的提示性发现，将研究特定的生物标记物，以识别对这些促进认知药物最敏感的患者，未来的目标是将这些生物标记物用于精神分裂症药物强化认知干预的大型临床试验。

DESCRIPTION (provided by applicant): This R01 will establish the biological basis for a novel treatment strategy for schizophrenia (SZ), by identifying biomarkers that predict pro-cognitive drug effects in SZ patients. These pro-cognitive effects would be utilized to specifically enhance the clinical impact of cognitive therapies (CTs) for SZ; similar strategies are being effectively advanced for the treatment of anxiety disorders. This application will test the effects of a "challenge dose" of the low-affinity NMDA antagonist, memantine (MEM), on sensorimotor gating and neuro- cognition in SZ patients; specific hypotheses will be tested in relation to the moderating impact of physiological and genetic biomarkers on these MEM effects. Predictors of positive effects of MEM will be used to identify enriched "MEM-sensitive" SZ patient cohorts for trials using MEM to augment the therapeutic effects of CTs. The pharmacotherapy of SZ has been dominated by drugs with limited clinical impact. Some forms of CTs, including the broader formats of cognitive rehabilitation and cognitive training, effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CTs in SZ might be enhanced by drugs that increase specific cognitive abilities, including working memory (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 pro-cognitive agents to biomarker-identified sensitive patients. We recently reported that a single dose of the safe, neuroprotective, widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of startle in healthy subjects. These PPI-enhancing effects of MEM are associated with: 1) increased WM; and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is 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 increases 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 will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 80 SZ patients and 80 healthy subjects, 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. Findings from this study will guide future clinical trials testing the overall effectiveness of MEM as an adjunct to CT by identifying biomarker-defined patients most likely to benefit from this therapeutic regimen; the feasibility of such trials is now being tested by the PI's R34 MH093453. PUBLIC HEALTH RELEVANCE: Cognitive therapies are moderately effective at reducing symptoms and improving life function in schizophrenia patients. The present application aims to develop a strategy for increasing the effectiveness of cognitive therapies in schizophrenia through the use of pro-cognitive medications. Specific biomarkers will be studied that identify patients most sensitive to these pro-cognitive medications, based on suggestive findings in healthy controls, with the future aim of using these biomarkers in a large clinical trial of medication-enhanced cognitive interventions in schizophrenia.