Antipsychotic Discontinuation in Alzheimer s Disease

描述（由申请人提供）：抗精神病药物已被证明是有效的治疗阿尔茨海默病患者谁有精神病症状或行为失控（称为行为并发症在这里）。然而，这些药物有各种短期和长期的副作用。虽然其在AD患者中的长期作用尚未确定，但联邦（OBRA）法规已强制要求在疗养院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NYSP 1/哥伦比亚研究中心的NIMH资助的研究（R 01 MH 55735）中，具有行为并发症的AD门诊患者接受氟哌啶醇开放治疗20周。应答者随机、双盲接受持续氟哌啶醇或安慰剂治疗。接受安慰剂治疗的患者的复发率（80%）显著高于继续接受氟哌啶醇治疗的患者（意向治疗分析中复发率为44.4%，使用复发的限制性定义时复发率为22.2%）。该研究的局限性是受试者数量少（随机分配19名应答者）和氟哌啶醇的使用，氟哌啶醇是一种常规抗精神病药物，通常会导致锥体外系体征（EPS），并且与长期使用迟发性运动障碍（TD）的高风险相关。拟议的多中心研究（四个学术研究中心;疗养院和门诊患者）将通过研究相对大量的AD患者使用非典型抗精神病药利培酮来解决这些局限性，利培酮的神经系统副作用比氟哌啶醇少。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例有行为并发症的AD患者将接受利培酮开放治疗16周。应答者将被随机、双盲地分配至2期的三个组之一：（1）在接下来的32周内继续使用利培酮，（2）在接下来的16周内使用利培酮，随后使用安慰剂16周，或（3）在接下来的32周内使用安慰剂。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，安慰剂组的复发率明显高于利培酮组。该设计将提供利培酮长期治疗的疗效和副作用的有用数据，并提供从利培酮转换为安慰剂的患者复发的可能性和时间以及复发预测因素的关键信息。这些信息对于指导临床医生在最具挑战性的患者类型之一（患有精神病或行为控制障碍的AD患者）中最佳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和老年护理的监管监督有实质性的影响。

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.