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ADHD的短期益处。然而，通常需要定期增加剂量以保持完全效果，即使在十年内持续服用药物，文献中也很少支持长期获益。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，其中暴露于药物导致药物作用随时间推移而降低，这是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的现象，并且一直是疼痛医学的许多研究领域。然而，还没有随机试验来评估ADHD人群对CNS兴奋剂的耐受性或如何管理它的评估。为了解决文献中的这些空白，我们提出了一个两阶段的翻译研究：（1）使用最完善的测量受控刺激效果的协议-模拟教室-对短期耐受性进行创新性评估，在夏季进行受试者内设计;（2）对相同受试者进行学年随访，以评价（a）持续治疗耐受性发展的个体差异，以及（B）周末休药是否减轻了剂量增加的需要。具体来说，250名患有ADHD的青少年将根据夏季模拟教室环境中的表现，稳定在最佳剂量的OROS MPH上。将在交叉设计中对参与者进行为期3周的OROS MPH和安慰剂暴露测试。将在暴露的三周内比较受试者内药物-安慰剂在定时数学任务上的表现差异。将计算每例受试者的个体耐受性估计值（AIM 1）。在第2阶段，所有受试者将开始学年，接受最佳夏季OROS MPH剂量，并随机分配至每周7天（连续给药）或每周5天（周末假期）给药。研究医生将在整个学年期间开具兴奋剂药物。将使用标准化反应指标每月对受试者进行监测。当受试者表现出由MTA得出的预定阈值确定的次优症状控制（可能的耐受性）时，将增加剂量。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值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可预测真实的世界给药。

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.