Citalopram Decreases CSF AB: A Randomized Dose Finding Trial

西酞普兰减少 CSF AB：随机剂量探索试验

• 批准号: 8701208
• 负责人: YVETTE I SHELINE
• 金额: $ 39.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701208
• 关键词: Acute; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Antidepressive Agents; Appearance; Binding; Biological Assay; Brain; Chronic; Citalopram; Clinical; Clinical Research; Clinical Trials; Clinical dementia rating scale; Cognitive; Data; Development; Disease; Dose; Dropout; Elderly; Enrollment; FDA approved; Feasibility Studies; Future; Generations; Hippocampus (Brain); Hour; Human; Human Volunteers; Image; Impaired cognition; Individual; Kinetics; Label; Length; Leucine; Measures; Methods; Monitor; Mus; Outcome Measure; Participant; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacodynamics; Physiologic pulse; Pittsburgh Compound-B; Placebos; Population; Positron-Emission Tomography; Prevention; Prevention strategy; Preventive; Production; Randomized; Recruitment Activity; Retrospective Studies; Rodent; Sampling; Secondary Prevention; Selective Serotonin Reuptake Inhibitor; Senile Plaques; Spinal Puncture; Stable Isotope Labeling; Target Populations; Techniques; Testing; Transgenic Mice; United States; Universities; Washington; age related; amyloid imaging; base; clinically relevant; design; drug efficacy; experience; extracellular; high risk; human data; in vivo; inhibitor/antagonist; mouse model; pilot trial; pre-clinical; prospective; randomized placebo controlled trial; research clinical testing; secretase; sound; success; time use

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. In the revised application we respond to PAR-11-100 Alzheimer's Disease Pilot Clinical Trials to outline a pilot clinical trial to answer critical questions before proceeding toa larger scale, definitive prospective trial. We will establish measures of drug efficacy in CSF as well as refine the target population. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A¿ plaques in the human brain. We have investigated the possible mechanism for this reduction in amyloid plaque burden by measuring the effect of SSRI antidepressants on A¿ levels in a transgenic mouse model of AD. Three common SSRI antidepressants acutely reduced brain extracellular A¿ levels by 25% in vivo. Furthermore, chronic treatment with an SSRI, citalopram, for 4 months significantly reduced hippocampal and cortical plaque burden by 42.3% and 50.7%, respectively. We will conduct a stratified, randomized placebo controlled trial of 54 cognitively normal participants, age 65- 80, (Clinical Dementia Rating scale, [CDR] = 0) recruited from the Washington University ADRC. Participants will have undergone full clinical evaluation and PET amyloid imaging. Prior to randomization they will be stratified by APOE4 status. Participants will be randomized (18 per group) to acute treatment with placebo, 20 mg citalopram or 40 mg citalopram. Participants will receive non-radioactive 13C6-leucine administration and CSF sampling with assessment of A¿ production during a 36-hour stay in our clinical research unit. To yield n = 18 participants per group with analyzable data, we will recruit n = 60 subjects, allowing for the 10% dropout rate that has been experienced in prior SILK studies. We will determine: 1) whether SSRI administration results in reduced CSF A¿ production (Aim 1); 2) whether a dose of citalopram 20 mg as well as citalopram 40 mg dose results in A¿ reduction (Aim 2); and 3) explore whether there is an effect of APOE status or age on A¿ reduction (Aim 3). Significance: If citalopram is associated with a substantial reduction in A¿ generation, we wil use this data to plan a prospective clinical trial to test whether chronic use of SSRI reduces the rate of A¿ plaque formation. While many factors go into the design of such a trial, given that SSRIs are among the best-tolerated neuroactive drug classes approved by the FDA and could be readily tested in a clinical trial, the potential significance for AD prevention would be rapid and large.

描述（由申请人提供）：阿尔茨海默病 (AD) 是一种毁灭性的疾病，估计仅在美国就有 500 万患者受到影响，并且预计随着人口老龄化，这种疾病在未来几十年内将急剧增加，除非能够制定预防措施。在修订后的申请中，我们响应 PAR-11-100 阿尔茨海默氏病试点临床试验，概述了一项试点临床试验，以回答关键问题，然后再进行更大规模的、明确的前瞻性试验。我们将建立脑脊液药物疗效的衡量标准并进行完善。我们有初步证据表明选择性血清素再摄取抑制剂 (SSRI) 抗抑郁药与较低的 A¿我们通过测量 SSRI 抗抑郁药对 A¿ 的影响，研究了减少淀粉样斑块负担的可能机制。三种常见的 SSRI 抗抑郁药可显着降低 AD 转基因小鼠模型中的脑细胞外 A 水平。此外，长期使用 SSRI（西酞普兰）治疗 4 个月，海马和皮质斑块负荷分别显着降低 42.3% 和 50.7%。我们将对 54 名认知正常的患者进行分层、随机安慰剂对照试验。从华盛顿大学 ADRC 招募的年龄 65-80 岁的参与者（临床痴呆评级量表，[CDR] = 0）参与者将学习完整课程。临床评估和 PET 淀粉样蛋白成像之前，将根据 APOE4 状态对参与者进行分层（每组 18 名），接受安慰剂、20 mg 西酞普兰或 40 mg 西酞普兰急性治疗。给药和脑脊液采样并评估 A¿为了获得每组 18 名具有可分析数据的参与者，我们将招募 60 名受试者，考虑到之前 SILK 研究中出现的 10% 的退出率。将确定：1) SSRI 给药是否会导致 CSF A 减少生产（目标 1）；2) 西酞普兰 20 mg 剂量和西酞普兰 40 mg 剂量是否会产生 A¿减少（目标 2）；和 3）探讨 APOE 状态或年龄是否对 A¿减少（目标 3）：如果西酞普兰与 A¿ 的大幅减少有关。一代，我们将使用这些数据来计划一项前瞻性临床试验，以测试长期使用 SSRI 是否会降低 A 发生率虽然此类试验的设计涉及许多因素，但考虑到 SSRI 是 FDA 批准的耐受性最好的神经活性药物类别之一，并且可以在临床试验中轻松进行测试，因此对于 AD 预防的潜在意义将是迅速的。而且很大。