Citalopram Decreases CSF AB: A Randomized Dose Finding Trial

描述(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，并预计在未来几十年内随着人口老龄化而急剧增加，除非能够制定预防措施。在修订的申请中，我们响应PAR-11-100阿尔茨海默病试点临床试验，概述了一项试点临床试验，以回答关键问题，然后进行更大规模的最终预期试验。我们将建立脑脊液药物疗效的衡量标准，并细化目标人群。我们有初步证据表明，选择性5-羟色胺再摄取抑制剂(SSRI)抗抑郁药与人脑中低Aβ斑块相关。我们通过测量SSRI抗抑郁药对AD转基因小鼠Aβ水平的影响，研究了这种减少淀粉样斑块负担的可能机制。在体内，三种常见的SSRI抗抑郁药能显著降低脑细胞外Aβ水平25%。此外，SSRI西酞普兰的慢性治疗4个月显著减少了42.3%和50.7%的海马区和皮质斑块负荷。我们将对从华盛顿大学ADRC招募的54名认知正常的参与者进行分层、随机的安慰剂对照试验，年龄在65-80岁(临床痴呆评定量表，[CDR]=0)。参与者将接受全面的临床评估和PET淀粉样蛋白成像。在随机化之前，他们将根据APOE4状态进行分层。参与者将被随机(每组18人)接受安慰剂、20毫克西酞普兰或40毫克西酞普兰的急性治疗。参与者将接受非放射性13C6-亮氨酸注射和脑脊液采样，并在我们的临床研究单位停留36小时期间评估Aβ产生。为了获得每组18名参与者的可分析数据，我们将招募n=60名受试者，考虑到之前的Silk研究中经历的10%的辍学率。我们将确定：1)SSRI给药是否导致脑脊液Aβ生成减少(目标1)；2)西酞普兰20 mg和40 mg剂量是否导致Aβ减少(目标2)；以及3)探讨载脂蛋白E状态或年龄是否对Aβ减少(目标3)有影响。意义：如果西酞普兰与Aβ生成的显著减少有关，我们将利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是否降低Aβ斑块形成的比率。虽然此类试验的设计考虑了许多因素，但鉴于SSRI是FDA批准的耐受性最好的神经活性药物类别之一，并且可以很容易地在临床试验中进行测试，因此对预防AD的潜在意义将是迅速和巨大的。

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 Aβ 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 Aβ levels in a transgenic mouse model of AD. Three common SSRI antidepressants acutely reduced brain extracellular Aβ 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 Aβ 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 Aβ production (Aim 1); 2) whether a dose of citalopram 20 mg as well as citalopram 40 mg dose results in Aβ reduction (Aim 2); and 3) explore whether there is an effect of APOE status or age on Aβ reduction (Aim 3). Significance: If citalopram is associated with a substantial reduction in Aβ generation, we wil use this data to plan a prospective clinical trial to test whether chronic use of SSRI reduces the rate of Aβ 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.