Examining Tolerance to CNS Stimulants in ADD

描述（由申请人提供）：大量文献记录了兴奋剂药物治疗多动症的短期疗效。然而，通常需要定期增加剂量才能保持完全的效果，并且即使在药物持续服用超过十年的情况下，文献中也很少支持长期受益。我们认为这种无法解释的有效性丧失是儿童精神药理学中最重要的问题之一。耐受性被定义为一种适应状态，在这种状态下，接触某种药物会导致药物的作用随着时间的推移而减弱，这是对观察到的缺乏持续作用的一种可能解释。对兴奋剂治疗效果可能产生耐受性的担忧可以追溯到25年前。耐受性是一种潜在的可治疗现象，一直是疼痛医学的许多研究领域。然而，目前还没有随机试验来评估多动症人群对中枢神经系统兴奋剂的耐受性，也没有评估如何控制这种耐受性。为了解决这些文献上的空白，我们提出了一项两阶段的转化研究：(1)在夏季的受试者内部设计中，使用最完善的测量受控兴奋剂效应的方案-模拟教室-对短期耐受性进行创新评估；(2)对同一参与者进行一学年的随访，以评估(a)持续治疗中耐受性发展的个体差异，以及(b)周末用药假期是否减轻了剂量增加的需要。具体来说，250名患有多动症的青少年将根据他们在夏季模拟教室环境中的表现，稳定使用最佳剂量的OROS MPH。参与者将在交叉设计中接受为期3周的OROS MPH和安慰剂暴露测试。受试者服用药物安慰剂后，在一项定时数学任务上的表现差异将在三周内进行比较。将计算每个受试者的个体容忍度估计（AIM 1）。在第二阶段，所有受试者将以最佳夏季OROS MPH剂量开始学年，并随机分为7次（连续给药）或每周5天给药（周末假期）。学习医生将在整个学年期间开一些兴奋剂药物。受试者将使用标准化的反应测量方法进行月度监测。当参与者表现出由MTA确定的预定阈值确定的次优症状控制（可能耐受）时，剂量将增加。将检查剂量需求和症状严重程度的组间差异（AIM 2）。将检查模拟教室的耐受性估计预测个体受试者后续给药模式的能力（AIM 3），以确定实验室观察到的耐受性是否能预测现实世界的给药模式。

DESCRIPTION (provided by applicant): A large literature documents the short-term benefits of stimulant medication for the treatment of ADHD. However, a regular increase in dose is typically needed to maintain full effect, and there is a little support in the literature for long-erm benefit even when medication is consistently taken over a decade. We consider this unexplained loss of effectiveness to be one of the most important issues in child psychopharmacology. Tolerance, as defined as a state of adaptation in which exposure to a drug results in a decrease of the drug's effects over time, is one possible explanation for this observed lack of sustained effect. Concerns about possible tolerance to therapeutic effects of stimulants date back 25 years. Tolerance is a potentially treatable phenomenon and has been the area of much research in pain medicine. However, there have been no randomized trials to evaluate the presence of tolerance to CNS stimulants in ADHD populations or evaluations of how to manage it. To address these gaps in the literature, we propose a two phase translational study: (1) an innovative evaluation of short-term tolerance using the most well established protocol for measuring controlled stimulant effects - the analog classroom - in a within subjects design during the summer; and (2) a school-year follow-up of the same participants to evaluate (a) individual differences in the development of tolerance over sustained treatment, and (b) if weekend drug holidays mitigate the need for dose increases. Specifically, 250 youth with ADHD will be stabilized on an optimal dose of OROS MPH based on performance in the summer analog classroom setting. Participants will be tested over 3-weeks of exposure to both OROS MPH and placebo in a crossover design. Within-subject drug-placebo differences in performance on a timed math task will be compared over the three weeks of exposure. Individual tolerance estimates will be computed for each subject (AIM 1). In phase 2, all subjects will begin the school year on their optimal summer OROS MPH dose and be randomized to 7 (continuous dosing) or 5 day a week dosing (weekend holidays). Study physicians will prescribe stimulant medication for the duration of the school year. Subjects will be monitored monthly using standardized measures of response. When a participant exhibits suboptimal symptom control (possible tolerance) determined by predetermined thresholds derived from the MTA, dose will be increased. Group differences in dosage needs and symptom severity will be examined (AIM 2). The ability of the tolerance estimates from the analog classroom to predict subsequent dosing patterns for individual subjects will be examined (AIM 3) to ascertain if laboratory observed tolerance predicts real world dosing.