Translational Research to Enhance Cognitive Control

虽然目前的药物治疗改善ADHD的行为症状， 反应或耐受性是常见的。最令人困惑的是，考虑到ADHD相关的认知缺陷， 尽管有几百项研究证明了对兴奋剂的急性行为反应， 几十年的研究证明了长期的，刺激相关的学习增强。这 目前治疗的明显不足突出了开发治疗的潜在重要性， 特别是修复执行功能缺陷作为改善结果重要途径。 神经化学对ADHD认知功能的影响是复杂的。这个过度假设 最佳的行为和认知反应是可能的治疗， 多巴胺（DA）和去甲肾上腺素（NE）。我们的目标是测试一种联合疗法的短期疗效 药物治疗，来自转化研究和临床观察，针对标准兴奋剂 单药治疗对症状和认知终点的影响。此外，这项研究的一个新方面是， 前瞻性测试行为和认知的双重益处是否预示临床显著性 在长期治疗中学习的改善。最后，根据我们的初步数据和 假设的治疗反应机制，拟议的研究将检查的潜力， 脑电图（EEC）预测最佳长期获益。该临床试验将招募180名 儿童和青少年ADHD-混合型的一项活性对照随机平行组研究 测试胍法辛（GUAN）、哌甲酯（MPH）和联合用药的比较疗效 GUAN/MPH对ADHD症状和临床应答率的影响。急性期认知功能的改善 治疗阶段将预示着在12个月的维持期内取得更大的学术成就。 该项目将代表转化治疗研究新阶段的初步科学投资 关于发展性精神病理学中的认知在拟议试验中测试的设计和方法 将作为测试其他干预措施的平台。

Although current medication therapies ameliorate ADHD behavioral symptoms, problems with inadequate response or tolerability are common. Most perplexing, in consideration of ADHD-related cognitive deficits and in spite of several hundred studies demonstrating acute behavioral response to stimulants, is the failure of many decades of research to demonstrate long-term, stimulated-related enhancements in learning. This manifest inadequacy of current therapies highlights the potential importance of developing treatments that specifically remediate executive function deficits as an important path to improve outcome. Neurochemical influences on cognitive functions in ADHD are complex. The over-arching premise of this project is that optimal behavioral and cognitive responses are possible with treatments that robustly enhance both dopamine (DA) and norepinephrine (NE). Our goal is to test the short-term efficacy of a combination pharmacotherapy, derived from translational research and clinical observations, against standard stimulant monotherapy on both symptom and cognitive endpoints. In addition, a novel aspect of the study will be to test prospectively whether a dual benefit on both behavior and cognition predicts clinically significant improvements in learning over longer-term treatment. Lastly, based upon our preliminary data and hypothesized mechanisms of treatment response, the proposed study will examine the potential of electroencephalography (EEC) in predicting optimal long-term benefit. The clinical trial will enroll 180 children and adolescents with ADHD-Combined Type in an active-controlled randomized parallel group study testing the comparative efficacy of guanfacine (GUAN), methylphenidate (MPH), and combination GUAN/MPH on ADHD symptoms and clinical response rates. Improvements in cognition during the acute treatment phase will predict greater academic achievement over the 12 month maintenance period. The project will represent an initial scientific investment in a new phase of translational treatment research on cognition in developmental psychopathologies. The designs and methodology tested in the proposed trial will serve as a platform for testing other interventions.