Nicotinic Receptors and 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。CATIE的研究表明，目前对精神分裂症的治疗并没有产生让临床医生或他们的患者完全满意的结果，因为两组人都反复更换药物，试图在副作用较少的情况下获得更好的治疗反应。认知康复的努力显示出类似的天花板效应。目前所有的药物都将D2-多巴胺受体阻断作为其主要药理作用。NIMH Matrics计划的建立是为了寻找精神分裂症的新治疗靶点，除了多巴胺-D2受体阻断之外，因为制药公司开发此类靶点的速度一直很慢。NIMH的重点是改善精神分裂症患者神经认知的候选机制。在NIIMH赞助的Matrics Consensus会议上，根据这一优点审查项目的结果，α7-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。还没有一家制药公司完成了对阿尔法7-尼古丁激动剂治疗精神分裂症的临床研究。 公共卫生相关性： 这个功绩审查项目在当前的资助期内的项目叙述工作已经确定了主要候选药物3-2，4二甲氧基亚苄基Anabaseine(DMXB-A)的证据，该药物是一种安全且表面上有效的α7-烟碱型乙酰胆碱受体激动剂。在拟议的更新中要检验的假设是，DMXB-A将在患有精神分裂症的退伍军人中产生显著的神经认知改善。

DESCRIPTION (provided by applicant): Project Summary Schizophrenia is a leading cause of disability for Veterans. The CATIE studies have demonstrated that the current treatment of schizophrenia does not produce results that are fully satisfactory to either clinicians or their patients, because both groups repeatedly switched medications to try to obtain better treatment response with fewer side effects. Cognitive rehabilitation efforts show similar ceiling effects. All currently available drugs have D2-dopamine receptor blockade as their primary pharmacological effect. The NIMH MATRICS program was established to find new therapeutic targets for schizophrenia, in addition to dopamine-D2 receptor blockade, because pharmaceutical companies have been slow to develop such targets. The NIMH emphasis was on candidate mechanisms that would improve neurocognition in schizophrenia. At the NIIMH-sponsored MATRICS consensus meeting, alpha7-nicotinic acetylcholine receptor agonism was selected as the leading candidate for new drug investigation, based on the findings of this Merit Review project. No pharmaceutical company has completed a clinical study of an alpha7-nicotinic agonist in schizophrenia. PUBLIC HEALTH RELEVANCE: Project Narrative Work by this Merit Review project in the current funding period has identified a proof of principle drug candidate, 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), that is a safe and apparently effective agonist for the alpha7-nicotinic acetylcholine receptor. The hypothesis to be tested in the proposed renewal is that DMXB-A will produce significant neurocognitive improvement in Veterans with schizophrenia.