fMRI of Cholinergic Mechanisms in Schizophrenia

描述(由申请人提供)： 项目摘要精神分裂症是导致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)研究了目前使用的抗精神病药物的效果，强调了一个发人深省的事实，即只有不到50%的患者成功地使用了任何常用的抗精神病药物。多巴胺D2受体阻断药物的这种缺乏有效性导致了最近对开发超越多巴胺能机制的精神分裂症治疗方法的极大兴趣。NIMH Matrics计划的建立是为了寻找精神分裂症的新治疗靶点。在NIMH赞助的Matrics Consensus会议上，根据我们丹佛退伍军人精神分裂症中心的研究结果，17-烟碱型乙酰胆碱受体激动剂被选为新药研究的主要候选药物。在2009年美国神经精神药理学会(ACNP)年会上，公布了评估几种新疗法候选药物的临床试验的初步结果。这些试验包括作用于GABA能、谷氨酸和胆碱能系统的药物，并将认知功能作为结果衡量标准。令人失望的是，报告的调查结果并不多，甚至在大多数情况下都是完全否定的。尽管17尼古丁胆碱能激动剂DMXB-A是少数几个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衡量标准可能不能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。在当前的功绩评审获奖期间，我们在开发神经对DMXB-A反应的功能磁共振成像(FMRI)测量方面取得了实质性进展。功能磁共振成像无创性地检测反映神经元活动的大脑血液动力学反应的变化。因此，使用功能磁共振成像来测量与疾病病理和潜在治疗化合物的神经生物学效应相关的大脑反应可能会改善药物开发的途径。这份续订申请建议使用眼球运动期间海马体反应的fMRI测量和更一般的静息状态反应或“默认网络”的测量，以探索潜在的尼古丁激动剂治疗精神分裂症的关键治疗变量。该提案的目标是确定是否在吸烟者中观察到药物效应，17尼古丁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尼古丁受体基因的变异来优化DMXB-A的效果。

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.