CITALOPRAM DECREASES CSF AB: A RANDOMIZED DOSE FINDING TRIAL

描述（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的疾病，估计仅在美国就影响500万患者，并且随着人口老龄化，除非可以开发预防措施，否则预计在未来几十年内将急剧增加。在修订后的申请中，我们回应PAR-11-100阿尔茨海默病试点临床试验，概述了一个试点临床试验，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。我们将在CSF中建立药物疗效指标，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）抗抑郁药与人类大脑中较低的A斑块有关。我们通过测定SSRI抗抑郁药对AD转基因小鼠模型中A水平的影响，研究了淀粉样斑块负荷减少的可能机制。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著降低42.3%和50.7%。我们将进行一项分层、随机安慰剂对照试验，纳入54名认知正常的参与者，年龄65- 80岁，（临床痴呆评定量表，[CDR] = 0），从华盛顿大学ADRC招募。参与者将接受全面的临床评估和PET淀粉样蛋白成像。随机化前，将按APOE 4状态对其进行分层。参与者将被随机（每组18人）接受安慰剂、20 mg西酞普兰或40 mg西酞普兰的急性治疗。受试者将在我们的临床研究单位停留36小时期间接受非放射性13 C6-亮氨酸给药和CSF采样，并评估A？产生。为了获得每组n = 18例具有可分析数据的受试者，我们将招募n = 60例受试者，考虑到既往SILK研究中发生的10%脱落率。我们将确定：1）SSRI给药是否导致CSF A？产生减少（目的1）; 2）西酞普兰20 mg和40 mg剂量是否导致A？减少（目的2）; 3）探索APOE状态或年龄是否对A？减少有影响（目的3）。重要性：如果西酞普兰与A？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是否会降低A？斑块形成率。虽然这种试验的设计涉及许多因素，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，并且可以在临床试验中进行测试，因此预防AD的潜在意义将是快速和巨大的。 公共卫生相关性：阿尔茨海默病（AD）是一种毁灭性的疾病，预计在未来几十年内将急剧增加，除非能够制定预防措施。在当前修订的应用程序中，我们回应PAR-11-100阿尔茨海默病试点临床试验，概述试点临床试验，以回答关键问题，然后再进行更大的 规模，明确的前瞻性试验。我们有初步证据表明，选择性5-羟色胺再吸收抑制剂（SSRI）抗抑郁药与人脑中淀粉样蛋白结合率较低有关。我们将对54名认知正常的参与者进行随机安慰剂对照试验，年龄65-80岁，（临床痴呆评定量表，[CDR] = 0），从华盛顿大学ADRC招募。参与者将被随机（每组18人）接受安慰剂、20 mg西酞普兰或40 mg西酞普兰的急性治疗。受试者将在我们的临床研究单位停留36小时期间接受非放射性13 C6-亮氨酸给药和CSF采样，并评估A？产生。我们将确定：SSRI给药是否导致CSF A <$生成减少（目标1）;西酞普兰20 mg剂量和西酞普兰40 mg剂量是否与A <$减少相关（目标2）;以及探索APOE 4状态和年龄是否影响A <$减少（目标3）。重要性：如果西酞普兰与A <$世代的大幅减少有关，我们将利用这些数据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 <$斑块形成率。虽然这种试验的设计涉及许多因素，但考虑到SSRIs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进行测试，因此预防AD的潜在意义很大。

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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating illness, projected to increase dramatically over the next decades unless preventive measures can be developed. In the current 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 to a larger scale, definitive prospective trial. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower amyloid binding in the human brain. We will conduct a 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 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. We will determine: whether SSRI administration results in reduced CSF A¿ production (Aim 1); whether citalopram 20mg dose as well as citalopram 40 mg dose are associated with A¿ reduction (Aim 2); and explore whether APOE4 status and age influence A¿ reduction (Aim 3). Significance: If citalopram is associated with a substantial reduction in A¿ generation, we will 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 large.