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

描述(申请人提供)：这项研究的目的是确定哌醋甲酯治疗对两组青少年实验室测量的冲动行为的剂量-反应效应，这些青少年患有儿童期或青春期起病的行为障碍并伴有注意缺陷/多动障碍(CD/ADHD)。CD/ADHD在临床表现、预后和预后方面与单纯CD或ADHD明显不同。虽然兴奋剂被推荐作为CD/ADHD共病患者的一线药物治疗，但人们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，兴奋剂通过影响与冲动相关的行为过程发挥作用，但这一假设尚未得到直接测试。因为冲动是一个复杂的结构，所以需要一个多维的方法来充分描述刺激剂对这一行为的影响。在这项研究中，我们将招募三组青少年：儿童期起病的CD/ADHD(早发组)和青春期起病的CD/ADHD(晚发组)，以及一组健康青少年(对照组)。将比较实验室测量的冲动的三个组成部分的基线(未用药)表现，包括反应启动、反应抑制和后果敏感性的组成过程。在基线表现评估后，在开始为期3周的随机治疗之前，将采用双盲交叉设计，使用三种剂量(即0、20和40 mg)的哌酸甲酯，确认对哌甲酸甲酯治疗的耐受性。在这3周的时间里，青少年、家长和老师将在家里和学校评估他们的行为，以测试“真实世界”的治疗反应。在每个随机治疗周结束时，将使用实验室冲动行为测量来评估青少年，以确定哌醋甲酯的剂量依赖效应。主要目的和假设与我们的初步数据是一致的：(1)确定实验室测量的冲动的每个主要组成部分的表现如何随CD发病年龄的不同而不同；(2)确定哌醋甲酯对冲动的每个主要成分的表现的剂量依赖性影响；以及(3)确定CD的发病年龄如何与实验室测定的冲动和自我/观察者行为评级的改善存在差异关系。这项研究的创新和临床意义在于，它将确定刺激治疗如何对患有儿童期或青春期CD合并ADHD的青少年群体产生不同影响；将使用传统的自我/观察者评级和基于实验室的新策略来衡量冲动行为的离散成分。相对于单独患有CD或ADHD的个体，CD/ADHD共病组的发育预后非常差；因此，从这项调查中获得的知识将为这一难以治疗的人群未来的治疗策略提供参考。公共卫生相关性：这项研究将提供数据，通过确定常见药物治疗在儿童和青少年时期开始的普遍和难以治疗的并存疾病中的潜在作用机制，回答基本和应用研究问题，并将提供关于在临床上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.