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（由应用程序提供）：阿尔茨海默氏病（AD）是一种破坏性的疾病，估计仅影响美国的500万患者，并且预计在未来几十年中，随着人口年龄的增长，除非可以采取预防措施。在修订后的应用中，我们对阿尔茨海默氏病前11-100杆的临床试验做出了回应，以概述一项试验临床试验，以在进行TOA大规模，确定性的前瞻性试验之前回答关键问题。我们将在CSF中建立药物效率的衡量标准，并完善目标人群。我们有初步的证据表明，选择性5-羟色胺再摄取抑制剂（SSRI）抗抑郁药与人脑中的A斑块较低有关。我们通过测量SSRI抗抑郁药对AD的转基因小鼠模型中A水平的影响，研究了淀粉样菌斑伯恩的可能机制。三种常见的SSRI抗抑郁药在体内急性降低了25％的细胞外A水平。此外，用SSRI，西妥位酰胺治疗慢性治疗4个月，显着降低了海马和皮质斑块分别燃烧了42.3％和50.7％。我们将对54名认知正常参与者（65-80岁）进行分层，随机的安慰剂对照试验（临床痴呆评级量表，[CDR] = 0），从华盛顿大学ADRC招募。参与者将进行全面的临床评估和PET淀粉样蛋白成像。在随机化之前，它们将按APOE4状态进行分层。参与者将与安慰剂，20 mg citalopram或40 mg citalopram随机分配（每组18）。参与者将在我们的临床研究部门36小时逗留期间，将接受非放射性活性13C6-亮氨酸给药和CSF采样。为了通过可分析的数据产生n = 18个参与者，我们将招募n = 60个受试者，从而允许在先前的丝绸研究中经历的10％辍学率。我们将确定：1）SSRI给药是否会导致CSF的生产减少（AIM 1）； 2）剂量的西妥位20毫克以及三妥位酰胺40毫克剂量是否会导致A降低（AIM 2）； 3）探索APOE状态还是年龄对A降低的影响（AIM 3）。意义：如果西妥位与A生成大幅度降低有关，我们将使用此数据来计划一项前瞻性临床试验，以测试长期使用SSRI是否会降低斑块形成的速率。尽管SSRI是经FDA批准的最佳神经活性药物类别之一，但在临床试验中很容易测试这种试验，但这种试验的设计是许多因素，因此预防AD的潜在意义将是快速且大。