Nicotinic Receptors and Schizophrenia

描述（由申请人提供）： 尽管有许多抗精神病药物可用于退伍军人精神分裂症患者，但VA处方者更频繁地使用三种药物-利培酮，因为其总体副作用良好，氯氮平，因为其上级疗效，奥氮平用于许多对利培酮不完全应答的退伍军人，但由于各种原因也不能服用氯氮平。然而，尽管奥氮平持续用于对安全药物耐药的患者的临床治疗，但其代谢综合征的发病率和死亡率仍很高。基础科学和临床研究表明，氯氮平和奥氮平增强疗效的机制之一是增加胆碱能神经传递，由突触前末梢释放的乙酰胆碱增加产生。这种作用可能是由于氯氮平和奥氮平对胆碱能受体如胆碱能末梢上的5-HT 3受体的拮抗作用，其通常减少乙酰胆碱的释放。我们有初步数据显示，利培酮，以实现多巴胺受体阻滞剂，和研究烟碱激动剂3-（2，4-二甲氧基）苯亚甲基anabaseine（DMXB-A）的组合对精神分裂症的神经认知的影响与奥氮平相似。DMXB-A不会显著增强奥氮平的神经认知作用，这与奥氮平已经激活胆碱能受体的假设一致。因此，我们建议在60名退伍军人中进行一项随机双盲2期临床试验，以测试目前由VA临床医生判断需要奥氮平的患者是否可以安全有效地接受利培酮DMXB-A联合治疗。主要结局指标将是NIMH MATRICS共识认知成套测验总量表评分，选择该评分是因为其与功能结局的相关性及其有利的心理测量学特性。我们假设利培酮/DMXBA优于利培酮/安慰剂，利培酮/DMXB-A与奥氮平在神经认知和临床评分方面具有非劣效性，但利培酮/DMXB-A联合治疗可改善代谢参数。这项2期研究将使我们能够确定是否有必要进行一项更长、更明确的试验，也许是通过VA合作研究计划。

DESCRIPTION (provided by applicant): Although a number of antipsychotic drugs are available for Veterans with schizophrenia, three are used more frequently by VA prescribers-risperidone because of its overall favorable side effect profile, clozapine because of its superior efficacy, and olanzapine for many Veterans who do not respond completely to risperidone, but who also cannot take clozapine for various reasons. However, olanzapine, despite its persistent clinical use for patients resistant to safer drugs, produces significant morbidity and mortality from metabolic syndrome. Basic science and clinical studies suggest that one mechanism of the enhanced efficacy of clozapine and olanzapine is increased cholinergic neurotransmission, produced by the increased release of acetylcholine from presynaptic terminals. This effect possibly results from clozapine's and olanzapine's antagonism of serotonergic receptors like the 5-HT3 receptors on cholinergic terminals, which normally decrease acetylcholine release. We have preliminary data showing that the combination of risperidone, to achieve dopamine receptor blockade, and the investigational nicotinic agonist 3-(2,4-dimethoxy)benzylidene anabaseine (DMXB-A) has effects on neurocognition in schizophrenia of similar magnitude to olanzapine. DMXB-A does not significantly enhance the neurocognitive effect of olanzapine, consistent with the hypothesis that olanzapine is already activating cholinergic receptors. We therefore propose a randomized double-blind Phase 2 clinical trial in 60 veterans to test whether patients who currently are judged by their VA clinicians to require olanzapine can be safely and effectively treated with a risperidone DMXB-A combination. The primary outcome measure will be the NIMH MATRICS Consensus Cognitive Battery Total Scale Score, chosen because of its correlation with functional outcomes and its favorable psychometric properties. We hypothesize superiority of risperidone/DMXBA to risperidone/placebo and non-inferiority between risperidone/DMXB-A and olanzapine for neurocognition and clinical ratings, but improvement in metabolic parameters on the risperidone/DMXB-A combination. This phase 2 study will enable us to determine if a longer, more definitive trial, perhaps through the VA Cooperative Studies Program, is warranted.