Nicotinic enhancement of cognitive remediation training in schizophrenia

描述（由申请人提供）：精神分裂症的认知缺陷是长期心理社会和职业结局的重要预测因素，目前可用的药物不能显著改善。认知补救训练可以缓解与精神分裂症相关的认知缺陷，但这种治疗的影响和实用性 这种方法在很大程度上受到效果大小和/或实现临床显著改善所需时间的限制。拟议的项目是测试一种新的策略，旨在增强认知补救训练的药理学。因此，该项目不是寻求能够改善认知功能本身的代理，而是寻求将努力转向能够增强训练挑战的有益效果的代理。原型烟碱激动剂烟碱促进感觉处理、警觉性、注意力以及学习和记忆，因此显示出促进训练益处的理想效果概况。因此，认知训练期间的间歇性尼古丁暴露预计会加速和增强训练效果，从而为指导寻找其他更具选择性的化合物提供原理证明。将50名精神分裂症患者纳入为期10周、每周5天的计算机化听觉和视觉认知训练方案，并随机分为两个治疗组之一。每周一和周四，尼古丁组的受试者将在培训前接受尼古丁polacrilex含片（2或4 mg，取决于吸烟状态），安慰剂组的受试者将接受安慰剂含片。结果测量是由MATRICS共识认知成套测验评估的神经认知功能、日常生活功能水平、生活质量和精神症状。在第0周（基线）、第4周、第7周、第10周和第16周（干预结束后4周）的非锭剂日（星期三）进行这些测量。预计尼古丁可增强这些措施中训练诱导的增强作用，并缩短诱导临床显著改善所需的训练持续时间。这些结果将为干预提供概念证据，可以显着改善精神分裂症的一些最衰弱的症状。这些结果也将成为研究尼古丁调节的关键训练成分和神经元变化的基础;不同患者亚组的成功率，不同的药物背景，吸烟状况和其他变量;以及更有选择性的尼古丁激动剂，专门针对增强认知训练结果。

DESCRIPTION (provided by applicant): Cognitive deficits in schizophrenia are critically important predictors of long-term psychosocial and occupational outcome and are not significantly ameliorated by currently available medications. Cognitive remediation training can alleviate cognitive deficits associated with schizophrenia, but the impact and practicality of this approach has been limited, largely, by effect sizes and/or the time requirements needed to achieve clinically significant improvement. The proposed project is testing a novel strategy aiming at pharmacological enhancement of cognitive remediation training. Thus, rather than seeking agents capable of improving cognitive functions per se, this project is seeking to redirect efforts toward agents capable of enhancing the beneficial effects of training challenges. The prototypical nicotinic agonist nicotine facilitates sensory processing, alertness, attention, and learning and memory and thus displays an ideal effects profile for promoting training benefits. Thus, intermittent nicotine exposure during cognitive training sessions is expected to accelerate and enhance the training effects, thereby providing the proof of principle to guide the search for other, more selective compounds. Fifty people with schizophrenia will be enrolled into a 10-week, 5 days/week, computerized auditory and visual cognitive training regimen and randomized into one of two treatment groups. Every Monday and Thursday, participants in the nicotine group will receive a nicotine polacrilex lozenge (2 or 4 mg, depending on smoking status) prior to the training and participants in the placebo group a placebo lozenge. Outcome measures are neurocognitive functions assessed by the MATRICS consensus cognitive battery, level of everyday-life functioning, quality of life, and psychiatric symptoms. These measures are taken on a no-lozenge day (Wednesday) in week 0 (baseline), 4, 7, 10 and 16 (4 weeks after the intervention ends). Nicotine is expected to potentiate training-induced enhancements in these measures and to shorten the training duration necessary to induce clinically significant improvement. These results would provide proof of concept for an intervention that can markedly improve some of the most debilitating symptoms of schizophrenia. The results would also form the basis for studies of the critical training components and neuronal changes modulated by nicotine; of success rates in different patient subgroups, with different medication backgrounds, smoking status and other variables; and of more selective nicotinic agonists specifically targeted at potentiating cognitive training outcome.