Impulsivity and Stimulant Response in Early- and Late-Onset CD with Comorbid ADHD

描述（由申请人提供）：本研究的目的是确定哌甲酯治疗对实验室测量的两组青少年冲动行为的剂量反应效应，这些青少年患有儿童期或青少年期的行为障碍并注意缺陷/多动障碍（CD/ADHD）。与单独的乳糜泻或ADHD相比，乳糜泻/ADHD在表现、预后和结果上有明显的不同。虽然兴奋剂被推荐为患有CD/ADHD合并症的个体的一线药物治疗，但对这些药物影响的潜在行为机制，或者CD发病年龄与这些机制的关系知之甚少。研究人员假设兴奋剂是通过影响与冲动相关的行为过程来起作用的，但这还没有得到直接的测试。因为冲动性是一个复杂的结构，所以需要一个多维的方法来充分表征兴奋剂对这种行为的影响。在这项研究中，我们将招募三组青少年：儿童期发病的CD/ADHD（早发性）和青春期发病的CD/ADHD（晚发性），以及一组健康青少年（对照组）。将比较三个实验室测量的冲动性成分的基线（未服药）表现，包括反应启动、反应抑制和后果敏感性的组成过程。基线表现评估后，将在开始三周随机哌甲酯治疗前确认哌甲酯治疗的耐受性，该治疗采用双盲交叉设计，使用三种剂量的哌甲酯（即0,20和40mg）。在这三周的时间里，青少年、家长和老师将在家里和学校对他们的行为进行评估，以测试“真实世界”的治疗反应。在每个随机治疗周结束时，将使用冲动性的实验室行为测量来评估青少年，以确定哌甲酯的剂量依赖性作用。主要目的和假设与我们的初步数据一致：(1)确定在实验室测量的冲动性的每个主要组成部分的表现如何随乳糜泻发病年龄的不同而不同；(2)确定哌醋甲酯对冲动性各主要成分表现的剂量依赖性；(3)确定乳糜泻发病年龄与哌甲酯对实验室测量的冲动性和自我/观察者行为评分的改善之间的差异关系。本研究的创新和临床意义在于，它将确定兴奋剂治疗对儿童期或青春期发病的乳糜泻合并ADHD的青少年群体的影响差异；传统的自我/观察者评级和新的基于实验室的策略来测量脉冲行为的离散成分将被使用。相对于单独患有乳糜泻或ADHD的个体，合并乳糜泻/ADHD组的发育预后异常差；因此，从这项调查中获得的知识将为这一难以治疗的人群的未来治疗策略提供信息。公共卫生相关性：本研究将通过确定一种常见药物治疗在儿童期和青春期开始的普遍和难以治疗的合并症中的潜在作用机制，得出回答基础和应用研究问题的数据，并将得出关于临床观察到的个体治疗差异的实用信息。

DESCRIPTION (provided by applicant): The purpose of this study is to determine the dose-response effects of methylphenidate treatment on laboratory-measured impulsive behavior of two groups of adolescents, those with either childhood- or adolescent-onset Conduct Disorder comorbid with Attention Deficit/Hyperactivity Disorder (CD/ADHD). CD/ADHD has been shown to be distinctly different in presentation, prognosis, and outcome than either CD or ADHD alone. While stimulants are recommended as the first line of medication treatment for individuals with comorbid CD/ADHD, little is known about the underlying behavioral mechanisms affected by these medications, or how age of CD onset relates to these mechanisms. Researchers have hypothesized that stimulants work by affecting behavioral processes related to impulsivity, but this has not been directly tested. Because impulsivity is a complex construct, a multidimensional approach is necessary to adequately characterize the effects of stimulants on this behavior. For this study, we will recruit three groups of adolescents: childhood-onset CD/ADHD (Early-Onset) and adolescent-onset CD/ADHD (Late-Onset), as well as a group of healthy adolescents (Controls). Baseline (unmedicated) performance on three laboratory- measured components of impulsivity will be compared, including component processes of response initiation, response inhibition, and consequence sensitivity. After baseline performance is evaluated, tolerability for methylphenidate treatment will be confirmed prior to beginning the 3 weeks of randomized methylphenidate treatments using a double-blind, crossover design using three doses of methylphenidate (i.e., 0, 20, and 40 mg). During this 3-week period, behavior will be assessed at home and at school by adolescents, parents, and teachers to test "real-world" treatment response. At the end of each randomized treatment week, adolescents will be assessed using laboratory behavioral measures of impulsivity to determine the dose-dependent effects of methylphenidate. The primary aims and hypotheses are consistent with our preliminary data are: (1) to determine how performance on each of the major components of laboratory-measured impulsivity differs by age of CD onset; (2) to determine the dose-dependent effects of methylphenidate on performance on each of the major components of impulsivity; and (3) to determine how age of CD onset is differentially related to improvements produced by methylphenidate in both laboratory-measured impulsivity and self/observer ratings of behavior. The innovation and clinical significance of this study is that it will determine how stimulant treatment differentially affects groups of adolescents with either childhood- or adolescent-onset CD comorbid with ADHD; both traditional self/observer ratings and newer laboratory-based strategies for measuring discrete components of impulsive behavior will be used. Relative to individuals having either CD or ADHD alone, the comorbid CD/ADHD group has an exceptionally poor developmental prognosis; therefore, the knowledge gained from this investigation will inform future treatment strategies for this difficult-to-treat population. PUBLIC HEALTH RELEVANCE: This study will yield data that answers both basic and applied research questions by identifying the underlying mechanism of action of a common medication treatment in a prevalent and difficult-to-treat comorbid condition that starts in childhood and adolescence, and will yield practical information regarding individual treatment differences observed in the clinic.