Escitalopram for Agitation in Alzheimer Disease

描述（由申请人提供）：躁动在阿尔茨海默病（AD）中很常见，是患者和护理人员的主要负担。找到有效的治疗方法是当务之急。标准治疗建议首先使用非药物，然后进行药物干预。这种方法在真实的世界中有几个挑战，包括未知的疗效，非药物治疗的稀疏使用，以及广泛的，往往不适当的，使用抗精神病药物，带来重大风险。需要有效的治疗激越，结合非药物与新的药理学方法，减少抗精神病药物的使用，并针对这种异质性疾病的适当亚组进行治疗。AD患者躁动的一个假设原因是神经退行性变，它会破坏大脑上行的多巴胺能通路。试图开发一种针对5-羟色胺系统的新疗法，我们进行了西酞普兰治疗AD（CitAD），这是一项双盲对照试验，对所有参与者进行真实的世界可用的心理社会干预，并将参与者随机分配到30 mg/天的SSRI西酞普兰或安慰剂组。在CitAD中，外消旋西酞普兰对激越有效，40%的西酞普兰治疗参与者经历了实质性的临床改善，而安慰剂组仅为26%。然而，西酞普兰与认知恶化和ECG-QTc间期延长相关。在血药浓度模型中，认知和心脏变化与R-对映体相关，而临床改善主要与S-对映体（艾司西酞普兰）相关。我们建议S-CitAD建立并扩展这些发现。我们将开发一种循证的、序贯的方法来治疗AD患者的激越，并在真实的世界中适用于患者。我们将招募589例AD和激越患者，并实施CitAD中使用的心理社会干预。3周后未显示激越临床显著改善的患者将被随机分配至药物组或安慰剂组。鉴于西酞普兰的研究结果，由于西酞普兰在老年患者中使用的剂量可能是禁忌的，我们将使用S-西酞普兰（最初以Lexapro（r）销售，现在是仿制药）代替西酞普兰。在心理社会干预无应答者中，我们将在12周内评估疗效和安全性（AIM 1）。我们还将评估CitAD（AIM 2）建议的预先指定的反应预测因子。最后，我们将随访在心理社会干预后表现出显著改善的患者，以研究反应的预测因素，以及改善的持续时间和频率，时间过程和随后复发的预测因素（AIM 3）。影响：S-CitAD将为临床医生和付款人提供关于真实的世界可用的、立即可用的AD激越治疗方法的实用信息。S-CitAD研究结果也将成为后期治疗开发的基础，提供这种序贯方法不同阶段的无应答者信息，并成为如何评价抗抑郁治疗研究中应答预测因子的模型。

DESCRIPTION (provided by applicant): Agitation is common in Alzheimer's disease (AD), a major burden to patients and caregivers. Finding effective treatments is a priority. The standard of care recommends initial use of non-pharmacologic followed by pharmacologic interventions. This approach has several challenges in the real world including unknown efficacy, sparse use of non-pharmacologic therapies, and widespread, often inappropriate, use of antipsychotics that carry significant risks. There is need for effective therapies for agitation combining non-pharmacologic with novel pharmacologic approaches, reducing antipsychotic use, and targeting therapies to appropriate subgroups of this heterogeneous condition. A hypothesized cause of agitation in AD is neurodegeneration that disrupts, then destroys, brain ascending serotonergic pathways. Attempting to develop a novel therapy targeting the serotonin system, we conducted Citalopram in AD (CitAD), a double blind, controlled trial that administered a real world-usable psychosocial intervention to all and additionally randomized participants to the SSRI citalopram at 30mg/day or placebo. In CitAD, racemic citalopram was effective for agitation with 40% of citalopram-treated participants experiencing substantial clinical improvement vs. only 26% on placebo. However, citalopram was associated with cognitive worsening and prolongation of the ECG-QTc interval. In blood concentration models, cognitive and cardiac changes were associated with the R-enantiomer, while clinical improvements were primarily associated with the S-enantiomer (escitalopram). We propose S-CitAD to build on and extend these findings. We will develop an evidence-based, sequential approach to treating agitation in AD with real world applicability for patients. We will enroll 589 patients with AD and agitation and administer the psychosocial intervention used in CitAD. Patients not showing clinically significant improvement in agitation after 3 weeks will be randomized to drug or placebo. Given the findings of CitAD, since the dose of citalopram used in CitAD may be contraindicated in older patients, we will use S-citalopram (originally marketed as Lexapro(r), now generic) instead of the racemic citalopram used in CitAD. In psychosocial intervention non-responders, we will evaluate for efficacy and safety over 12-weeks (AIM 1). We will also evaluate pre-specified predictors of response suggested by CitAD (AIM 2). Finally, we will follow patients showing significant improvement on the psychosocial intervention to study predictors of response, as well as duration of improvement and frequency, time course, and predictors of subsequent relapse (AIM 3). IMPACT: S-CitAD will provide clinicians and payers practical information about a real world-usable, immediately available approach to treating agitation in AD. S-CitAD findings will also form the basis for later treatment development providing information on non-responders in different phases of this sequential approach, and becoming a model of how to evaluate predictors of response in NPS treatment studies.