Examining Tolerance to CNS Stimulants in ADD

描述(由申请人提供)：大量文献记载了兴奋剂治疗ADHD的短期益处。然而，通常需要定期增加剂量才能保持完全效果，即使持续服用药物超过十年，文献中也有一些支持长期有效的证据。我们认为这种莫名其妙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，接触一种药物会导致药物的效果随着时间的推移而减少，这可能是这种观察到的缺乏持续效果的原因之一。对兴奋剂治疗效果可能耐受的担忧可以追溯到25年前。耐受性是一种潜在的可治疗现象，也是疼痛医学中的许多研究领域。然而，还没有随机试验来评估ADHD人群对中枢神经系统兴奋剂的耐受性，也没有评估如何处理这种耐受性。为了解决文献中的这些空白，我们提出了一项两阶段的转化性研究：(1)使用最成熟的测量受控刺激效应的最成熟的协议-模拟教室-在夏季的受试者设计中对短期耐受性进行创新评估；(2)对相同参与者进行学年随访，以评估(A)在持续治疗期间耐受性的发展方面的个体差异，以及(B)周末药物假期是否缓解了剂量增加的需要。具体来说，250名患有ADHD的青少年将根据夏季模拟课堂环境中的表现，稳定在最佳剂量的OROS mph上。参与者将接受为期3周的交叉设计的OROS mph和安慰剂的测试。受试者内的药物-安慰剂在一项定时数学任务中的表现差异将在暴露的三周内进行比较。将计算每个受试者的个人容差估计数(目标1)。在第二阶段，所有受试者将根据他们的最佳夏季OROS每小时剂量开始新学年，并被随机分配到7次(连续剂量)或每周5天(周末假期)。学习内科医生将在整个学年期间开出兴奋剂药物。受试者将每月使用标准化的反应措施进行监测。当参与者表现出由MTA得出的预定阈值确定的次优症状控制(可能的耐受性)时，剂量将增加。将检查两组在剂量需求和症状严重程度方面的差异(目标2)。来自模拟教室的耐受性估计预测个别受试者随后的剂量模式的能力将被检验(目标3)，以确定实验室观察的耐受性是否可以预测真实世界的剂量。

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.