Nicotinic Receptors and Schizophrenia

烟碱受体和精神分裂症

基本信息

批准号：
8819188
负责人：
Robert Freedman
金额：
--
依托单位：
VA EASTERN COLORADO HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-10-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8819188
关键词：
Acetylcholine Adverse effects Antipsychotic Agents Basic Science Body Weight decreased Cholinergic Receptors Clinical Clinical Research Clinical Trials Clinical effectiveness Clozapine Cognition Cognitive Consensus Data Development Dopamine Receptor Double-Blind Method Double-blind trial Effectiveness Generations Goals Metabolic Metabolic syndrome Morbidity - disease rate National Institute of Mental Health Neurocognition Neurocognitive Nicotinic Agonists Nicotinic Receptors Outcome Measure Patients Performance Pharmaceutical Preparations Phase Phase II Clinical Trials Placebos Presynaptic Terminals Property Psychometrics Randomized Resistance Risperidone Safety Schizophrenia Serotonin Receptors 5-HT-3 Symptoms Testing Therapeutic Therapeutic Effect Toxic effect Veterans acetylcholine receptor agonist anabaseine base cholinergic clinical effect cooperative study drug development experience functional outcomes improved mortality neurotransmission novel therapeutics olanzapine phase 2 study presynaptic primary outcome programs public health relevance receptor secondary outcome

项目摘要

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.

描述（由申请人提供）：尽管有许多抗精神病药物可供患有精神分裂症的退伍军人使用，但退伍军人管理局处方者更频繁地使用三种抗精神病药物：利培酮（因为其总体良好的副作用）、氯氮平（因为其卓越的疗效）和奥氮平（对于许多对药物没有完全反应的退伍军人）利培酮，但由于各种原因也不能服用氯氮平。然而，尽管奥氮平在临床上持续用于对更安全药物有耐药性的患者，但代谢综合征导致的发病率和死亡率显着增加。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，这是由突触前末梢释放的乙酰胆碱增加产生的。这种作用可能是由于氯氮平和奥氮平对血清素能受体（如胆碱能末端的 5-HT3 受体）的拮抗作用所致，这些受体通常会减少乙酰胆碱的释放。我们的初步数据表明，利培酮与研究中的烟碱激动剂 3-(2,4-二甲氧基)亚苯亚甲基阿那巴碱 (DMXB-A) 联合使用以实现多巴胺受体阻断，对精神分裂症的神经认知具有与奥氮平相似程度的影响。 DMXB-A 不会显着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，以测试目前被 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 组合治疗。主要结果指标将是 NIMH MATRICS 共识认知电池总量表评分，之所以选择该评分是因为它与功能结果的相关性及其有利的心理测量特性。我们假设利培酮/DMXBA 在神经认知和临床评分方面优于利培酮/安慰剂，并且在利培酮/DMXB-A 和奥氮平之间具有非劣效性，但利培酮/DMXB-A 组合的代谢参数有所改善。这项二期研究将使我们能够确定是否需要进行更长时间、更明确的试验（或许通过退伍军人管理局合作研究计划进行）。