Memantine effects on sensorimotor gating and neurocognition in schizophrenia

描述（由申请人提供）：本R01将通过鉴定预测SZ患者中促认知药物作用的生物标志物，为精神分裂症（SZ）的新型治疗策略建立生物学基础。这些促认知作用将被用于专门增强SZ认知疗法（CT）的临床影响;类似的策略正在有效地推进焦虑症的治疗。本申请将测试低亲和力NMDA拮抗剂美金刚（MEM）的"激发剂量"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志物对这些MEM效应的调节影响相关的特定假设。MEM积极作用的预测因子将用于确定富集的"MEM敏感" SZ患者队列，用于使用MEM增强CT治疗效果的试验。 SZ的药物治疗以临床影响有限的药物为主。某些形式的CT，包括更广泛的认知康复和认知训练形式，有效地减轻了SZ的症状并改善了功能。本申请的前提是，增加特定认知能力（包括工作记忆（WM））的药物可能会增强CT在SZ中的获益，即使这些促认知药物在不使用CT的情况下给药时缺乏临床影响。本申请的主要目标是开发一种创新的干预策略，通过向生物标志物识别的敏感患者给予促认知药物，增强SZ中CT的临床获益。 我们最近报道，单剂量的安全，神经保护，广泛使用的阿尔茨海默病药物，MEM（20毫克口服），在健康受试者中显著增加惊吓的前脉冲抑制（PPI）。MEM的这些PPI增强作用与以下因素相关：1）WM增加;和2）与高活性Val158Met COMT多态性相关的表型。SZ患者的PPI受损;患者的PPI水平最低与：1）功能结局差;和2）瓦尔/瓦尔COMT基因型相关。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增加，特别是在瓦尔/瓦尔患者中。然后，我们将定位于检验MEM的急性PPI和WM增强效应预测MEM在接受CT的SZ患者中的治疗益处的假设。本申请将评估MEM（0 vs. 10或0 vs. 20 mg p.o.）在80名SZ患者和80名健康受试者中，测试MEM将增加SZ患者的PPI和增强WM的预测，特别是在那些以低基础PPI水平和/或瓦尔/瓦尔COMT基因型为特征的患者中。错配阴性和伽马带同步也将被评估为潜在的信息性MEM敏感和功能相关生物标志物。这项研究的结果将指导未来的临床试验， 通过识别生物标志物定义的最有可能从这种治疗方案中获益的患者，确定MEM作为CT辅助治疗的有效性; PI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具有中等效果。本申请旨在开发一种通过使用促认知药物来增加精神分裂症中认知疗法的有效性的策略。将研究特定的生物标志物，以确定对这些促认知药物最敏感的患者，基于健康对照的提示性发现，未来的目标是在精神分裂症药物增强认知干预的大型临床试验中使用这些生物标志物。

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.