CLONIDINE IN ADHD

注意缺陷多动障碍（ADHD）是一种常见的精神健康障碍，发病率很高。在美国，每年约有10万名儿童使用可乐定（CLON）治疗，作为精神兴奋剂的替代疗法，或作为联合疗法。缺乏足够的ADHD疗效和安全性数据，CLON也未被FDA批准用于ADHD。与哌醋甲酯（MPH）联合使用的理由是，它可能具有协同作用，可能延长兴奋剂效果，和/或CLON可能解决仅用兴奋剂无法治疗的某些核心症状。没有数据支持这些理论，尽管联合治疗有严重不良事件的报道，但联合治疗越来越多地被开处方。CLON在原发性ADHD中的研究尚未全面展开，但由NINDS发起的一项评估CLON单独和联合MPH治疗伴有多动症（TACT）的抽动秽语综合征儿童的安全性和有效性的研究正在进行中。然而，TACT受试者可能主要是“注意力不集中”亚型，与复合型相反，复合型最常见于原发性多动症。TACT的数据也不能外推到原发性ADHD，因为在TACT中使用CLON治疗抽搐和ADHD是双重目标，因此给药间隔和潜在的安全性发现（如果不良事件与剂量相关）可能不容易应用于原发性ADHD。因此，TACT的疗效和安全性数据可能不足以用于原发性ADHD治疗，而大多数CLON都是用于原发性ADHD治疗。然而，TACT团队的临床试验机制和专业知识在研究CLON在原发性ADHD中的作用方面具有独特的优势。优势在于：1)利用TACT现有基础设施降低成本；2)有机会汇集所有研究的安全性数据，以便可以检测到低频率的不良事件；3)比较原发性ADHD与ADHD合并图雷特综合征的治疗结果，以确定CLON在“注意力不集中亚型”与“多动/冲动亚型”或合并亚型中是否有不同的效果；4)确定慢性MPH治疗是否有助于抽动障碍的发展。我们建议对原发性ADHD儿童进行多中心对照研究，研究CLON、MPH和CLON加MPH。该研究将A)确定CLON治疗儿童多动症的安全性和有效性；B)与标准MPH治疗相比，评估CLON+MPH联合治疗ADHD的安全性和有效性；C)在研究过程中为所有受试者提供随访tic发展的时间延长。

Attention Deficit, Hyperactivity disorder (ADHD) is a common mental health disorder of significant morbidity for which approximately 100,000 children yearly are treated with clonidine (CLON) in the US, either as an alternative to psychostimulants, or as combination therapy. Adequate ADHD efficacy and safety data are lacking and CLON is not FDA approved for ADHD. Rationales for combination with methylphenidate (MPH) are that it may be synergistic, may extend the stimulant effect, and/or that CLON may address certain core symptoms not treated by stimulants alone. No data support these rationales, yet the combination is increasingly being prescribed despite reports of serious adverse events linked to combination therapy. CLON has yet to be comprehensively studied in primary ADHD, but an NINDS sponsored evaluation of the safety and efficacy of CLON alone and in combination with MPH is currently being conducted in children with Tourette Syndrome with comorbid ADHD (TACT). TACT subjects however may be predominantly "inattentive" subtype, in contrast to combined type, most commonly seen in primary ADHD. TACT data also cannot be extrapolated to primary ADHD because treatment with CLON in TACT is dually targeted to the treatment of both tics and ADHD such that dosing interval and potentially safety findings (if adverse events are dose related) may not be readily applied to primary ADHD. Efficacy and safety data from TACT therefore may be inadequate for primary ADHD treatment, for which the majority of CLON is prescribed. The clinical trial machinery and expertise of the TACT team however is uniquely positioned to study CLON in primary ADHD. Advantages would be: 1) reduced cost by using TACT existing infrastructure; 2) an opportunity to pool safety data across studies such that low frequency adverse events may be detected; 3) to compare therapeutic outcomes in primary ADHD to ADHD with comorbid Tourette Syndrome to determine if CLON has differential effects in "inattentive subtype" versus "hyperactive/impulsive" or combined subtypes; and 4) to determine if chronic treatment with MPH can contribute to the development of tic disorder. We propose a multicenter, controlled study of CLON, MPH, and CLON plus MPH for children with primary ADHD. The study will A) determine the safety and efficacy of CLON for the treatment of ADHD in children; B) evaluate the safety and efficacy of combined CLON+MPH for treatment of ADHD compared to standard MPH therapy; C) provide a lyr extension for all subjects to follow-up tic development during course of the study.