Memantine effects on sensorimotor gating and neurocognition in schizophrenia

描述（由申请人提供）：该R01将通过识别预测SZ患者认知药物作用的生物标志物，为精神分裂症（SZ）的新治疗策略建立生物学基础。这些促认知效应将被用来特异性地增强认知疗法（CTs）对SZ的临床影响；类似的策略正在有效地用于治疗焦虑症。该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；具体的假设将测试有关生理和遗传生物标志物对这些MEM效应的调节作用。MEM积极作用的预测因子将用于鉴定富集的“MEM敏感”SZ患者队列，用于使用MEM增强ct治疗效果的试验。SZ的药物治疗一直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，可以有效地减轻SZ的症状和改善功能。这项应用的前提是，即使这些促进认知的药物在不使用CT的情况下缺乏临床效果，但增强特定认知能力（包括工作记忆）的药物可能会增强CT在SZ中的益处。本应用程序的主要目标是开发一种创新的干预策略，通过对生物标志物识别的敏感患者使用促认知药物来增强CT在SZ中的临床益处。我们最近报道，单剂量安全、神经保护、广泛使用的阿尔茨海默病药物MEM （20mg / o）可显著增加健康受试者的脉冲前抑制（PPI）。MEM对ppi的增强作用与以下因素有关：1)WM增加；2)与高活性Val158Met COMT多态性相关的表型。SZ患者PPI受损；患者PPI水平低与以下因素相关：1)功能预后差；2) Val/Val COMT基因型。如果我们在健康受试者中的MEM发现在SZ患者中重现，我们将发现MEM相关的PPI和WM增加，特别是在Val/Val患者中。然后，我们将验证MEM的急性PPI和wm增强作用预测MEM在接受CT治疗的SZ患者中的治疗效果的假设。本应用将在80名SZ患者和80名健康受试者中评估MEM的急性效应（0 vs. 10或0 vs. 20 mg p.o），以验证MEM会增加SZ患者的PPI和WM的预测，特别是那些基础PPI水平低和/或Val/Val COMT基因型的患者。失配负性和伽马带同步也将被评估为潜在的信息memm敏感和功能相关的生物标志物。本研究结果将指导未来的临床试验

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.