Nicotinic Receptors and 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。CATIE研究表明，目前精神分裂症的治疗并不能产生令临床医生或患者完全满意的结果，因为两组患者都反复更换药物，试图获得更好的治疗反应，减少副作用。认知康复的努力显示出类似的天花板效应。所有目前可用的药物都具有D2-多巴胺受体阻滞剂作为其主要药理作用。NIMH MATRICS项目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受体阻滞剂，因为制药公司开发此类靶点的速度很慢。NIMH的重点是改善精神分裂症神经认知的候选机制。在NIIMH主办的MATRICS共识会议上，基于该Merit Review项目的发现，α 7-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。没有一家制药公司完成了精神分裂症中α 7-烟碱激动剂的临床研究。 公共卫生相关性： 在当前资助期内，该Merit Review项目的工作已经确定了一种候选药物3- 2，4-二甲氧基苯亚甲基anabaseine（DMXB-A）的原理证明，这是一种安全且明显有效的α 7-烟碱乙酰胆碱受体激动剂。在拟议的更新中要测试的假设是，DMXB-A将对患有精神分裂症的退伍军人产生显着的神经认知改善。

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.