Cummings Jeffrey L, Mackell Joan, Kaufer Daniel
UCLA Alzheimer Disease Center, UCLA, Los Angeles, CA, USA.
Alzheimers Dement. 2008 Jan;4(1):49-60. doi: 10.1016/j.jalz.2007.10.011.
Behavioral abnormalities and neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). Many clinical trials of cholinesterase inhibitors (ChE-Is) and memantine have included behavioral measures as primary or secondary outcomes, and most have observed behavioral benefits in conjunction with treatment. The purpose of this review was to determine the frequency of positive behavioral outcomes in AD clinical trials and clinical reports, to determine the symptoms most responsive to antidementia agents, and to explore factors that correlate with negative outcomes in clinical trials of antidementia agents with regard to behavioral measures.
We performed a computerized search of randomized clinical trials and open-label studies of ChE-Is and memantine for AD including a behavioral outcome measure. Studies involving 10 or more patients using therapeutic doses of the target agents and including a behavioral measure as a primary or secondary outcome were included in this review.
One hundred fifty-seven peer-reviewed articles and 68 publicly presented abstracts were identified in the literature search. Subsequent review established that 15 publications arising from 13 randomized, double-blind, placebo-controlled AD trials met the review inclusion criteria. Positive outcomes on behavioral measures were reported in 8 of 15 publications as a primary or secondary outcome. In most blinded AD clinical trials, behavioral measures were secondary outcomes. Mood symptoms and apathy have most commonly responded to ChE-Is, whereas memantine has been associated with a reduction in irritability and agitation. However, there is substantial variability among trials in terms of behavioral outcomes. Studies that assessed patients with more severe dementia, included patients with less severe behavioral disturbances at baseline, involved institutionalized patients, or were international in scope tended to have negative outcomes. In institutionalized patients there is commonly an improvement in the placebo group that confounds the observation of any drug-placebo difference.
Antidementia agents have been associated with beneficial behavioral outcomes in many randomized clinical trials and open-label studies. Most studies are not designed to test the psychotropic properties of antidementia drugs. Trials with negative behavioral outcomes are most likely to involve patients who are institutionalized and have few behavioral disturbances at baseline. Clinical trials designed to assess behavioral effects of antidementia agents should anticipate these factors.
行为异常和神经精神症状是阿尔茨海默病（AD）的常见表现。许多胆碱酯酶抑制剂（ChE-Is）和美金刚的临床试验都将行为指标作为主要或次要结局，并且大多数都观察到了治疗带来的行为改善。本综述的目的是确定AD临床试验和临床报告中积极行为结局的频率，确定对抗痴呆药物反应最明显的症状，并探讨在抗痴呆药物临床试验中与行为指标负面结局相关的因素。
我们对ChE-Is和美金刚治疗AD的随机临床试验和开放标签研究进行了计算机检索，这些研究包括行为结局指标。本综述纳入了涉及10名或更多患者、使用目标药物治疗剂量且将行为指标作为主要或次要结局的研究。
在文献检索中识别出157篇经同行评审的文章和68篇公开报告的摘要。随后的评审确定，来自13项随机、双盲、安慰剂对照AD试验的15篇出版物符合综述纳入标准。15篇出版物中有8篇将行为指标的积极结局报告为主要或次要结局。在大多数双盲AD临床试验中，行为指标是次要结局。情绪症状和淡漠最常对ChE-Is有反应，而美金刚与易怒和激越的减轻有关。然而，各试验在行为结局方面存在很大差异。评估痴呆程度较重患者的研究、纳入基线行为障碍较轻患者的研究、涉及住院患者的研究或范围为国际性的研究往往有负面结局。在住院患者中，安慰剂组通常会有改善，这混淆了对任何药物与安慰剂差异的观察。
在许多随机临床试验和开放标签研究中，抗痴呆药物与有益的行为结局相关。大多数研究并非旨在测试抗痴呆药物的精神otropic特性。行为结局为负面的试验最有可能涉及住院患者且基线时行为障碍较少的患者。旨在评估抗痴呆药物行为效应的临床试验应考虑到这些因素。
