fMRI of Cholinergic Mechanisms in Schizophrenia

描述（由申请人提供）： 精神分裂症是退伍军人残疾的主要原因。临床抗精神病药物干预有效性试验（CATIE）研究目前使用的抗精神病药物的效果突出了一个令人清醒的事实，即不到50%的患者成功地使用任何常用的抗精神病药物治疗。多巴胺D2受体阻断药物的这种缺乏疗效导致最近对开发超越多巴胺能机制的精神分裂症治疗方法的兴趣。NIMH MATRICS项目的建立是为了寻找精神分裂症的新治疗靶点。在NIMH主办的MATRICS共识会议上，17-烟碱乙酰胆碱受体激动剂被选为新药研究的主要候选药物，基于我们丹佛VA精神分裂症中心的发现。在2009年美国神经精神药理学学会（ACNP）年会上，介绍了评估几种新型候选治疗药物的临床试验的初步结果。这些试验包括作用于GABA能、谷氨酸能和胆碱能系统的药物，并使用认知功能作为结局指标。令人不安的是，报告的结果不多，在大多数情况下完全是阴性的。虽然17烟碱胆碱能激动剂DMXB-A是少数具有阳性结果的候选治疗药物之一，但使用认知变量作为结果指标可能无法为早期治疗开发提供足够的敏感性。需要的是更接近新化合物的理论神经生物学效应的措施。在目前的优异奖评审期间，我们在开发功能性磁共振成像（fMRI）测量DMXB-A神经元反应方面取得了实质性进展。功能磁共振成像非侵入性地检测反映神经元活动的脑血流动力学反应的变化。因此，使用功能磁共振成像来测量与疾病病理学和潜在治疗化合物的神经生物学效应相关的脑反应可能会改善药物开发途径。该更新申请提出使用眼球运动期间海马反应的fMRI测量和更一般的静息状态反应或“默认网络”的测量，以探索使用烟碱激动剂治疗精神分裂症的潜在治疗中的关键治疗变量。该提案的目标是确定是否在吸烟患者中观察到药物作用，17烟碱受体基因的变异是否影响药物反应，并确定是否可以通过考虑17烟碱受体基因的变异来优化DMXB-A的作用。 公共卫生相关性： 精神分裂症是退伍军人中最常见的使人衰弱的精神疾病，占整个医疗服务卫生保健支出的10%以上。虽然目前的治疗方法是有效的，但大多数患有精神分裂症的退伍军人仍然病得太重，无法恢复全面的生产生活。因此，需要开发新的治疗方法。该项目使用大脑成像来更好地了解DMXB-A的作用，DMXB-A是一种潜在的精神分裂症新药。该项目的主要目标是了解吸烟的影响以及遗传变异对DMXB-A效应的影响。

DESCRIPTION (provided by applicant): Project Summary Schizophrenia is a leading cause of disability for Veterans. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study of the effects of currently used neuroleptics drugs highlights the sobering fact that fewer than 50% of patients are successfully treated with any of the commonly used neuroleptics. This lack of efficacy of dopamine D2 receptor-blocking drugs has led to much recent interest in developing therapeutics for schizophrenia that extend beyond dopaminergic mechanisms. The NIMH MATRICS program was established to find new therapeutic targets for schizophrenia. At the NIMH-sponsored MATRICS consensus meeting, 17-nicotinic acetylcholine receptor agonism was selected as the leading candidate for new drug investigation, based on the findings of our Denver VA Schizophrenia Center. At the 2009 American College of Neuropsychopharmacology (ACNP) annual meeting, preliminary results of clinical trials evaluating several novel therapeutic candidates were presented. These trials included agents that acted on GABAergic, glutamatergic and cholinergic systems, and used cognitive function as outcome measures. Disappointingly, modest or in most cases completely negative findings were reported. Although the 17 nicotinic cholinergic agonist DMXB-A is one of the few therapeutic candidates with positive findings, it is possible that the use of cognitive variables as outcome measures does not provide adequate sensitivity for early therapeutic development. What is needed are measures more proximal to the theoretical neurobiological effects of novel compounds. During the current Merit Review award period, we have made substantial progress developing functional magnetic resonance imaging (fMRI) measures of neuronal response to DMXB-A. fMRI non-invasively detects changes in the brain hemodynamic response that reflect neuronal activity. As such, using fMRI to measure brain responses relevant to both disease pathology and neurobiological effects of potential therapeutic compounds may improve the drug development pathway. This Renewal Application proposes the use of an fMRI measure of hippocampal response during eye movements and a measure of the more general resting state response, or "default network," to explore key therapeutic variables in the potential treatment of schizophrenia with a nicotinic agonist. Goals of the proposal are to determine if drug effects are observed in smoking patients, if variations in the 17 nicotinic receptor gene affect drug response, and to determine if DMXB-A effects can be optimized by accounting for variations in the 17 nicotinic receptor gene. PUBLIC HEALTH RELEVANCE: Schizophrenia is the most common debilitating mental illness in Veterans, accounting for over 10% of the overall Medical Service health care expenditures. While current treatments are effective, most Veterans with schizophrenia remain too ill to return to a fully productive life. New treatment development is therefore needed. This project uses brain imaging to better understand the effects of DMXB-A, a potential new drug for schizophrenia. The primary goals of the project are to understand the effects of smoking and the impact of genetic variations on DMXB-A's effects.