Biomarker Strategies for Medication-Enhanced Cognitive Training in Schizophrenia

描述（由申请人提供）：本R34应用程序响应PAR-09-173，通过支持以下内容实现本FOA的第一个目标：“开发和/或试点测试新的或适应性干预措施。“本申请的两个首要目标是：1）测试急性给予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可预测地增强SZ认知训练的治疗益处的可行性。 SZ的药物治疗以抗多巴胺能药物为主，临床效果有限。某些形式的心理康复，如认知训练（CT），似乎可以有效地减轻症状，改善SZ的功能。本申请的前提是，增加特定认知能力的药物（包括WM）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。 我们报道了单剂量的广泛使用的阿尔茨海默病药物MEM（20 mg p.o.），在健康受试者中显著增加惊吓反射的前脉冲抑制（PPI）。MEM在健康受试者中的PPI增强作用与以下因素相关：1）WM增加;和2）与高活性Val 158 Met COMT多态性相关的表型。SZ患者的PPI持续受损;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改善，特别是在瓦尔/瓦尔患者中。然后，我们将检验MEM的急性PPI和WM增强作用预测MEM在接受CT的SZ患者中的治疗获益的假设。 本申请有两个目的：目的1将评估MEM（0 vs. 10或0 vs. 20 mg p.o.）在60名SZ患者中，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。目标2将评估在SZ患者中测试MEM作为CT辅助治疗的治疗获益的可行性，以及测试主要假设的可行性，即在目标1单次剂量MEM激发后，SZ患者的PPI和/或WM增加将预测此类获益。预计在完成目标1的受试者中招募受试者并完成在深圳门诊患者中进行的为期12周的对照CT试验的两个组将适合于测试MEM作为CT辅助治疗的总体有效性以及预测这种有效性的能力生物标志物识别的患者亚组。

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.