Examining Tolerance to CNS Stimulants in ADD

检查 ADD 患者对中枢神经系统兴奋剂的耐受性

• 批准号: 8506817
• 负责人: WILLIAM E PELHAM
• 金额: $ 71.75万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-17 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506817
• 关键词: Absence of pain sensation; Accounting; Address; Analgesics; Anticonvulsants; Area; Attention deficit hyperactivity disorder; Back; Behavior Therapy; Central Nervous System Agents; Central Nervous System Stimulants; Child; Clinical; Combined Modality Therapy; Crossover Design; Development; Dose; Effectiveness; Evaluation; Exhibits; Exposure to; Frequencies; Genetic Crossing Over; Holidays; Impairment; Individual; Individual Differences; Laboratories; Literature; Measures; Medicine; Monitor; Outcome; Pain; Pain Disorder; Participant; Pattern; Performance; Pharmaceutical Preparations; Phase; Physicians; Placebos; Population; Protocols documentation; Psychopharmacology; Randomized; Research; Sampling; Schools; Seizures; Severities; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Protocols; Youth; analog; arm; base; clinical application; clinical practice; clinically significant; combat; control trial; design; discount; dosage; experience; follow-up; improved; indexing; innovation; meetings; prevent; primary outcome; public health relevance; randomized trial; response; standardize measure; translational study

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.

描述（由申请人提供）：大量文献记录了刺激药物治疗多动症的短期益处。但是，通常需要定期增加剂量以保持全部效果，即使在十年中持续服用药物，文献中也有很少的支持。我们认为这种无法解释的有效性丧失是儿童心理药理学中最重要的问题之一。耐受性被定义为适应状态，在这种适应状态下，暴露于药物会随着时间的推移而导致药物的作用降低，这是这种观察到的缺乏持续作用的一种可能解释。人们对兴奋剂治疗作用的可能耐受性的担忧可以追溯到25年。耐受性是一种潜在的可治疗现象，并且是止痛医学研究的领域。但是，尚无随机试验来评估ADHD种群中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差距，我们提出了一项两阶段的翻译研究：（1）使用最确立的协议来对短期耐受性进行创新评估，以测量夏季的主题设计中的受控刺激效果 - 模拟教室 - 模拟教室； （2）对相同参与者的学年随访，以评估（a）在持续治疗方面的耐受性发展方面的个体差异，以及（b）如果周末药物假期减轻了剂量增加的需求。具体而言，根据夏季模拟教室环境的表现，将在最佳剂量的OROS MPH上稳定250名ADHD青年。在跨界设计中，将对参与者进行3周暴露于OROS MPH和安慰剂。在暴露的三周内，将比较在定时数学任务上表现的受试者内部的药物差异差异。将为每个受试者计算单个公差估计（AIM 1）。在第2阶段，所有受试者都将从最佳的夏季OROS MPH剂量开始学年，并随机分为7（连续给药）或每周5天（周末节日）。学习医生将在学年期间开处方刺激药物。将使用标准化的响应度量来监控受试者。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（可能的公差）时，剂量将增加。将检查剂量需求和症状严重程度的群体差异（AIM 2）。将检查来自模拟教室的公差估计能够预测单个受试者的后续给药模式的能力（AIM 3）确定实验室观察到的耐受性是否可以预测现实世界的剂量。