Apathy in Alzheimer's Disease Methylphenidate Trial

描述（由申请人提供）：阿尔茨海默氏痴呆症（AD）的冷漠是一个重大的公共卫生问题，对患者和护理人员有严重的不良后果。大约70%的阿尔茨海默病患者患有冷漠，使其成为最常见的神经精神症状之一（m.s. Mega, Cummings, Fiorello, & Gornbein, 1996; Steinberg et al., 2006; Steinberg et al., 2007）。尽管阿尔茨海默病中冷漠的患病率很高，但目前尚无有效的治疗方法。虽然非药物治疗研究不足，但临床经验表明可靠但疗效有限。最近的研究已经开始探索药理学选择，如胆碱酯酶抑制剂（ChEIs）。但ChEIs似乎对冷漠没有特异性，有关其功效的发现尚未得到广泛复制。抗抑郁药物也被认为是一种选择，但一些证据表明，它们在治疗阿尔茨海默病的冷漠方面可能是有害的，而不是有益的。因此，迫切需要更好的药物选择来治疗阿尔茨海默病的冷漠。多巴胺能药物有望治疗阿尔茨海默病患者的冷漠。使用它们的基本原理是基于脑损伤人群中多巴胺能中边缘大脑奖励系统的活动与动机行为的表达之间的紧密联系。使用多巴胺能药物的证据也来自病例报告和在非痴呆人群中进行的小型开放标签研究。一项双盲、安慰剂对照的单点交叉先导研究的初步数据表明，多巴胺激动剂哌醋甲酯治疗阿尔茨海默病冷漠的效果优于安慰剂（lanctt, in press）。拟开展的失智症患者冷漠试验（ADMET）的目标是在这一令人鼓舞的初步工作基础上，通过评估失智症患者的治疗效果来扩大研究范围。本研究采用多地点、平行、随机、双盲、安慰剂对照设计。它将汇集已经成功合作执行正在进行的阿尔茨海默病抑郁症研究（DIADS-2）和已完成的临床抗精神病药物干预有效性试验（CATIE-AD）的研究人员。ADMET将检验哌甲酯治疗阿尔茨海默病患者临床显著性冷漠的有效性和安全性。这将是一项双盲、6周、随机、安慰剂对照试验，涉及100名AD患者。ADMET将从门诊、养老院和辅助生活环境中招募AD患者。该项目非常重要，因为它将探索一种有前途的多巴胺激动剂治疗阿尔茨海默病冷漠的有效性和安全性，目前尚无证实的治疗方案。如果发现哌甲酯有效，它可能会成为阿尔茨海默病冷漠的一线治疗方法。此外，通过检查反应的预测因子，ADMET将为未来的研究奠定基础，以了解哌甲酯和其他多巴胺激动剂对冷漠的影响机制。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，这导致了这种疾病的巨大情感和经济成本。冷漠是阿尔茨海默病最常见的行为症状之一，尽管它被认为是阿尔茨海默病依赖性的少数潜在可治疗原因之一，但目前尚无有效的治疗方法。这项研究的目的是开发一种新的治疗阿尔茨海默病冷漠的方法，可以减少其衰弱的后果，减少患者对照顾者的依赖，为患者和他们的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.