Escitalopram for Agitation in Alzheimer Disease

艾司西酞普兰治疗阿尔茨海默病的躁动

• 批准号: 9739349
• 负责人: CONSTANTINE G LYKETSOS
• 金额: $ 352.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9739349
• 关键词: Adverse effects; Affective; Affective Symptoms; Agitation; Algorithms; Alzheimer' s Disease; Alzheimer' s disease patient; Antipsychotic Agents; Attention; Blood; Brain; Cardiac; Caregivers; Citalopram; Clinical; Cognition; Cognitive; Data; Development; Disease; Dose; Double-Blind Method; Electrocardiogram; Enrollment; Escitalopram; Evaluation; Frequencies; Future; Generic Drugs; Genetic; Impaired cognition; Individual; Intervention; Lexapro; Link; Methods; Modeling; Nerve Degeneration; Nonpharmacologic Therapy; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Placebo Effect; Placebos; Randomized; Relapse; Risk; Safety; Selective Serotonin Reuptake Inhibitor; Sequential Treatment; Serotonergic System; Severities; Specific qualifier value; Subgroup; Symptoms; System; Time; age group; clinically significant; effective therapy; efficacy evaluation; enantiomer; evidence base; experience; follow-up; improved; indexing; monoamine; neurotransmission; new therapeutic target; novel; novel therapeutics; older patient; patient subsets; pharmacokinetic model; placebo group; polygenic risk score; predicting response; psychosocial; public health priorities; public health relevance; rapid growth; relapse prediction; response; standard of care; targeted treatment; therapy development; trait; treatment response

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.

描述(由申请人提供)：激动症在阿尔茨海默病(AD)中很常见，这是患者和照顾者的主要负担。找到有效的治疗方法是当务之急。护理标准建议最初使用非药物性药物，然后再使用药物干预。这种方法在现实世界中面临着几个挑战，包括疗效未知，非药物疗法的稀疏使用，以及带有重大风险的抗精神病药物的广泛使用(通常是不适当的)。有必要将非药理学方法与新的药理学方法相结合，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群进行靶向治疗，从而有效地治疗躁动。阿尔茨海默病焦虑症的一个假设原因是神经变性破坏了大脑上升的5-羟色胺能通路，然后破坏了它。为了开发一种针对5-羟色胺系统的新疗法，我们在AD患者中进行了西妥普兰(Citad)，这是一项双盲对照试验，对所有人实施现实世界中可用的心理社会干预，并另外随机接受SSRI西酞普兰30 mg/天或安慰剂治疗。在CITAD，消旋西酞普兰对激动症有效，40%的接受西酞普兰治疗的参与者经历了显著的临床改善，而安慰剂只有26%。然而，西酞普兰与认知恶化和心电图-QTC间期延长有关。在血药浓度模型中，认知和心脏改变与R-对映体有关，而临床改善主要与S对映体(艾司匹兰)有关。我们建议S-Citad在这些发现的基础上再接再厉。我们将开发一种循证、循序渐进的方法来治疗AD患者的焦虑症，并在现实中适用于患者。我们将招募589名患有阿尔茨海默病和激越的患者，并实施Citad使用的心理社会干预。3周后躁动症状没有明显临床改善的患者将被随机分为药物组或安慰剂组。鉴于Citad的研究结果，由于Citad中使用的西酞普兰的剂量可能在老年患者中是禁忌的，我们将使用S-西酞普兰(最初的市场名称为Lexapro(R)，现在是仿制药)，而不是Citad中使用的外消旋西酞普兰。在心理社会干预无效的患者中，我们将在12周内评估其有效性和安全性(目标1)。我们还将评估Citad建议的预先指定的反应预测因子(AIM 2)。最后，我们将跟踪在心理社会干预方面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、时间进程和后续复发的预测因素(目标3)。影响：S-Citad将为临床医生和支付者提供关于真实世界中可用的、立即可用的治疗AD焦虑症的方法的实用信息。S-CITAD的研究结果也将为以后的治疗开发奠定基础，提供这种序贯方法不同阶段无应答者的信息，并成为如何评估NPS治疗研究中应答预测因素的模型。