Apathy in Alzheimer's Disease Methylphenidate Trial

描述(由申请人提供)：阿尔茨海默氏症(AD)的冷漠是一个严重的公共卫生问题，对患者和照顾者造成严重的不良后果。冷漠影响了大约70%的AD患者，使其成为最常见的神经精神症状之一(M.S.Mega，Cummings，Fiorello，&Gornbein，1996；Steinberg等人，2006；Steinberg等人，2007)。尽管阿尔茨海默病的冷漠很普遍，但还没有得到证实的治疗方法。虽然非药物治疗研究不足，但临床经验表明疗效可靠但有限。最近的研究已经开始探索药理选择，如胆碱酯酶抑制剂(ChEIs)。但CHEI似乎不是针对冷漠的，关于其有效性的发现也没有被广泛复制。抗抑郁药物也被认为是一种选择，但一些证据表明，它们在治疗AD患者的冷漠方面可能是有害的，而不是帮助。因此，迫切需要更好的药物选择来治疗AD的冷漠。多巴胺能药物有望成为治疗阿尔茨海默病患者冷漠的药物。使用它们的理由是基于多巴胺能中脑边缘奖励系统的活动与脑损伤人群中动机行为的表达之间的密切联系。在非痴呆人群中使用多巴胺能药物的证据也来自病例报告和小型开放标签研究。一项双盲、安慰剂对照的单部位交叉试点研究的初步数据表明，多巴胺激动剂哌醋甲酯在治疗AD患者的冷漠方面优于安慰剂(Lancttt，正在出版中)。拟议的痴呆冷漠甲酯试验(ADMET)的目标是通过评估哌醋甲酯对AD患者冷漠的治疗，在这一令人鼓舞的前期工作的基础上扩展。这项研究将采用多点、平行、随机、双盲、安慰剂对照设计。它将把成功合作执行正在进行的阿尔茨海默病抑郁症研究(DIADS-2)和已完成的干预有效性临床抗精神病试验(CATIE-AD)的研究人员聚集在一起。ADMET将检查哌醋甲酯治疗AD患者临床上有意义的冷漠的有效性和安全性。这将是一项为期6周的双盲、随机、安慰剂对照试验，涉及100名AD患者。ADMET将从门诊、疗养院和辅助生活环境中招募AD患者。这个项目非常重要，因为它将探索一种有前途的多巴胺激动剂治疗AD冷漠的有效性和安全性，AD的治疗方案尚未得到证实。如果哌醋甲酯被发现有效，它很可能成为治疗AD冷漠的一线疗法。此外，通过检测反应的预测因素，ADMET将为未来的研究奠定基础，以了解哌醋甲酯和其他多巴胺激动剂对冷漠的影响所涉及的机制。公共卫生相关性：500万患有阿尔茨海默病(AD)的美国人缺乏独立性，这导致了这种疾病带来的巨大情感和经济代价。冷漠是阿尔茨海默病最常见的行为症状之一，尽管它被认为是少数几个潜在的阿尔茨海默病依赖的潜在治疗原因之一，但目前还没有有效的治疗方法。这项研究旨在开发一种治疗AD冷漠的新方法，以减少其衰弱后果，减少患者对照顾者的依赖，为患者及其亲人提供当之无愧的缓解。

DESCRIPTION (provided by applicant): Apathy in Alzheimer's dementia (AD) is a significant public health problem with serious adverse consequences for patients and caregivers. Apathy affects approximately 70% of AD patients, making it one of the most common neuropsychiatric symptoms (M. S. Mega, Cummings, Fiorello, & Gornbein, 1996; Steinberg et al., 2006; Steinberg et al., 2007). Despite the high prevalence of apathy in AD, there are no proven treatments for this condition. While non-pharmacologic treatments have been understudied, clinical experience suggests reliable but limited efficacy. Recent studies have begun to explore pharmacologic options, such as cholinesterase inhibitors (ChEIs). But ChEIs appear to be non-specific to apathy and findings regarding their efficacy have not been widely replicated. Antidepressant medications have also been considered as an option, but some evidence suggests that they could be detrimental rather than helpful in the treatment of apathy in AD. Therefore, better pharmacologic options are urgently needed for the treatment of apathy in AD. Dopaminergic agents show promise as treatments for apathy in AD. The rationale for their use is based on the strong tie between activity of the dopaminergic mesolimbic brain reward system and the expression of motivated behaviors in brain damaged populations. Evidence for the use of dopaminergic agents also comes from case reports and small open-label studies in nondemented populations. Preliminary data from a double blind, placebo controlled single-site crossover pilot study suggest that the dopamine agonist methylphenidate was superior to placebo for the treatment of apathy in AD (Lancttt, in press). The goal of the proposed Apathy in Dementia Methylphenidate Trial (ADMET) is to expand upon this encouraging preliminary work by evaluating methylphenidate for the treatment of AD patients with apathy. This study will employ a multi-site, parallel, randomized, double-blind, placebo-controlled design. It will bring together investigators who have collaborated successfully in the execution of the ongoing Depression in Alzheimer's Disease study (DIADS-2) and the completed Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE-AD). ADMET will examine the efficacy and safety of methylphenidate for the treatment of clinically significant apathy in AD patients. It will be a double-blind, 6 week, randomized, placebo-controlled trial involving 100 patients with AD. ADMET will enroll AD patients from outpatient, nursing home, and assisted living settings. This project is of great importance because it will explore the efficacy and safety of a promising dopamine agonist for treating apathy in AD, where there are no proven treatment options. Should methylphenidate be found effective, it will likely become a first line therapy for apathy in AD. In addition, by examining predictors of response, ADMET will lay the foundation for future studies to understand the mechanisms involved in the effects of methylphenidate and other dopamine agonists on apathy. PUBLIC HEALTH RELEVANCE: The 5 million Americans who suffer from Alzheimer's disease (AD) experience a lack of independence that contributes to the large emotional and economic costs of this disease. Apathy is one of the most common behavioral symptoms of AD and although it is thought to be one of the few potentially treatable causes of dependency in AD, currently there are no effective treatments for apathy. This study aims to develop a new treatment for apathy in AD that could decrease its debilitating consequences and reduce patients' dependency on caregivers, providing well-deserved relief to patients and their loved ones.