Antipsychotic Discontinuation in Alzheimer s Disease

描述（由申请人提供）：抗精神病药物已被证明对有精神病症状或行为控制障碍（在这里称为行为并发症）的阿尔茨海默病患者有效。然而，这些药物有各种短期和长期的副作用。尽管抗精神病药物对阿尔茨海默病患者的长期影响尚未确定，但美国联邦政府（OBRA）规定，养老院必须定期停用抗精神病药物。令人惊讶的是，在疗养院或门诊病人中，几乎没有经验证据支持或反驳这种方法。在NYSPl/Columbia站点nimh资助的一项研究（R01 MH55735）中，伴有行为并发症的AD门诊患者接受氟哌啶醇开放治疗20周。应答者随机，双盲，继续服用氟哌啶醇或安慰剂。使用安慰剂的患者复发率（80%）明显高于继续使用氟哌啶醇的患者（意向治疗分析中复发率为44.4%，使用限制复发定义的复发率为22.2%）。该研究的局限性在于受试者数量较少（随机选择19名应答者）和使用氟哌啶醇，氟哌啶醇是一种常规抗精神病药，通常会引起额外锥体体征（EPS），并且长期使用会导致迟发性运动障碍（TD）的高风险。拟议的多中心研究（四个学术中心；疗养院和门诊患者）将通过研究相对大量的使用非典型抗精神病药利培酮的AD患者来解决这些局限性，利培酮比氟哌啶醇对神经系统的副作用更小。研究非典型抗精神病药物延长治疗的其他原因包括药物毒性的风险和服用这些药物的费用。研究设计分为两个阶段。在第一阶段，200名伴有行为并发症的AD患者将接受为期16周的利培酮开放治疗。应答者将随机，双盲，在第二阶段的三个组中：(1)接下来32周继续使用利培酮，(2)接下来16周使用利培酮，随后16周使用安慰剂，或(3)接下来32周使用安慰剂。我们假设在第二阶段，在前16周，安慰剂组的复发时间明显短于利培酮组，并且安慰剂组的复发率明显大于利培酮组的复发率。该设计将提供有关利培酮长期治疗的疗效和副作用的有用数据，并提供有关从利培酮转为安慰剂的患者复发的可能性和时间以及复发预测因子的关键信息。这一信息对于指导临床医生在最具挑战性的患者之一——患有精神病或行为控制障碍的阿尔茨海默病患者中最佳地使用此类药物至关重要。结果将是相当有价值的执业临床医生，并有实质性的影响老年人护理的监管监督。

DESCRIPTION (provided by applicant): Antipsychotic medications have been shown to be efficacious in the treatment of patients with Alzheimer s disease who have psychotic symptoms or behavioral dyscontrol (called behavioral complications here). However, these medications have a variety of short and long-term side effects. Although their prolonged effects in AD patients are not established, Federal (OBRA) regulations have mandated periodic discontinuation of antipsychotic medications in nursing homes. Surprisingly, there is little empirical evidence to support or refute this approach in nursing homes or in outpatients. In an NIMH-funded study (R01 MH55735) at the NYSPl/Columbia site, AD outpatients with behavioral complications receive open treatment with haloperidol for 20 weeks. Responders are randomized, double-blind, to continuation haloperidol or placebo. Patients on placebo have shown a significantly higher relapse rate (80%) than patients who continue on haloperidol (44.4% relapse in intent-to-treat analyses, and 22.2% relapse using a restricted definition of relapse). The study's limitations are the small number of subjects (19 responders randomized) and the use of haloperidol, a conventional antipsychotic that commonly causes extra pyramidal signs (EPS), and is associated with a high risk of tardive dyskinesia (TD) with prolonged use. The proposed multicenter study (four academic sites; nursing homes and outpatients) will address these limitations by studying a relatively large number of AD patients using an atypical antipsychotic, risperidone, which has less neurological side effects than haloperidol. Other reasons for studying extended treatment with an atypical antipsychotic include the risk of medication toxicity and the expense of taking these medications. The study design has two phases. In Phase 1, 200 AD patients with behavioral complications will receive open treatment with risperidone for 16 weeks. Responders will be randomized, double-blind, to one of three arms in Phase 2:(1) continuation risperidone for the next 32 weeks, (2) risperidone for the next 16 weeks followed by placebo for 16 weeks, or (3) placebo for the next 32 weeks. We hypothesize that in Phase 2, during the first 16 weeks, the time to relapse will be significantly shorter on placebo than on risperidone, and that the relapse rate on placebo will be significantly greater than the relapse rate on risperidone. This design will provide useful data on the efficacy and side effects of longer-term treatment with risperidone, and provide critical information about the likelihood and time to relapse, as well as predictors of relapse, in patients switched from risperidone to placebo. This information is essential to guide the clinician toward optimal use of such medications in one of the most challenging types of patients: the AD patient with psychosis or behavioral dyscontrol. The results will be of considerable value to the practicing clinician and have substantial implications for the regulatory oversight of elder care.