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: 9082863
• 负责人: CONSTANTINE G LYKETSOS
• 金额: $ 318.3万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082863
• 关键词: Adverse effects; Affective; Affective Symptoms; Agitation; Algorithms; Alzheimer' s Disease; 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; Health; Impaired cognition; Individual; Intervention; Lexapro; Link; Marketing; Methods; Modeling; Nerve Degeneration; Outcome; Participant; Patients; Pharmaceutical Preparations; 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; base; clinically significant; control trial; effective therapy; enantiomer; evidence base; experience; follow-up; improved; indexing; monoamine; neurotransmission; new therapeutic target; novel; novel therapeutics; older patient; pharmacokinetic model; predicting response; psychosocial; public health priorities; rapid growth; 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）：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。寻找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治疗，然后进行药物治疗。这种方法在现实世界中面临着一些挑战，包括未知的疗效，非药物治疗的稀疏使用，以及广泛且经常不适当地使用具有重大风险的抗精神病药物。需要将非药物治疗与新型药物治疗相结合，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。阿尔茨海默病中躁动的一个假设原因是神经退行性变，它扰乱并破坏了大脑上升的血清素能通路。为了开发一种针对血清素系统的新疗法，我们对阿尔茨海默病进行了西酞普兰治疗（CitAD），这是一项双盲对照试验，对所有参与者进行了现实世界可用的社会心理干预，另外随机分配给SSRI西酞普兰30mg/天或安慰剂。在CitAD中，外消旋西酞普兰对躁动有效，40%的西酞普兰治疗参与者有明显的临床改善，而安慰剂组只有26%。然而，西酞普兰与认知恶化和ECG-QTc间期延长有关。在血药浓度模型中，认知和心脏变化与r -对映体有关，而临床改善主要与s -对映体（艾司西酞普兰）有关。我们建议S-CitAD在这些发现的基础上进行扩展。我们将开发一种循证的、顺序的方法来治疗阿尔茨海默病患者的躁动，并具有现实世界的适用性。我们将招募589例伴有AD和躁动的患者，并实施CitAD中使用的社会心理干预。3周后躁动症状未出现显著改善的患者将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是老年患者的禁忌症，我们将使用s -西酞普兰（最初作为Lexapro(r)销售，现在是通用的）代替CitAD中使用的外消旋西酞普兰。在心理社会干预无反应者中，我们将在12周内评估其有效性和安全性（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，我们将对在心理社会干预方面有显著改善的患者进行随访，以研究反应的预测因素、改善的持续时间、频率、时间过程和随后复发的预测因素（AIM 3）。影响：S-CitAD将为临床医生和支付者提供有关现实世界中可用的，立即可用的治疗AD躁动的方法的实用信息。S-CitAD研究结果还将为后续治疗开发奠定基础，提供该顺序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。