Antidepressant Therapy for Functional Dyspepsia

功能性消化不良的抗抑郁治疗

• 批准号: 6969791
• 负责人: NICHOLAS J TALLEY
• 金额: $ 62.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969791
• 关键词: G protein; amitriptyline; antidepressants; behavioral medicine; clinical research; clinical trials; gastrointestinal disorder chemotherapy; gastrointestinal imaging /visualization; gastrointestinal sign /symptom; genetic polymorphism; genetic susceptibility; human subject; human therapy evaluation; patient oriented research; psychopharmacology; psychophysiology; quality of life; serotonin inhibitor; stomach emptying

DESCRIPTION (provided by applicant): Functional dyspepsia (FD) affects up to one in five people in the United States, can substantially impair quality of life and is very costly; treatment outcomes are variable and often unsatisfactory. Gastric motor and sensory disturbances, and psychiatric co-morbidity, have been identified in FD but it is unknown if these factors influence outcome. There is recent evidence for a genetic component; our pilot data (now published in Gastroenterology) suggest that a heterotrimeric G protein polymorphism may be associated with FD. Antidepressants are commonly prescribed in FD and appear efficacious, but this is not evidence based and the response is variable; there have been no adequate randomized controlled trials with tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRI's) in functional dyspepsia. We hypothesize in FD that: 1) Amitriptyline (a tricyclic) and escitalopram (an SSRI) will be superior to placebo in terms of global symptom relief at the end of a 12 week trial, adjusting for psychiatric co-morbidity. Moreover, the proportion of global symptom responders will be significantly larger at 6 months after cessation of therapy, compared with the placebo group. 2) Acceleration of solid gastric emptying, reduction of postprandial satiation and enhanced gastric volume change with a meal on antidepressant therapy will be significant positive predictors of beneficial short and long-term outcome in FD. Conversely, negative predictors of outcome will be slowed gastric emptying, increased postprandial satiation and reduced postprandial gastric volume change. 3) The serotonin transporter long homozygous polymorphism will predict a significantly poorer symptom response to escitalopram and amitriptyline compared with the short or heterozygous polymorphisms, while the GNbeta3 CC polymorphism will predict a significantly better symptom response to both classes of antidepressant therapy compared to TT or TC genotype. We aim in a parallel group, double-blind, randomized, placebo-controlled double dummy, adequately powered three-arm multi-center trial to determine: 1) Whether antidepressant therapy (low dose tricyclic amitriptlyline 50 mg or standard dose escitalopram 10 mg) is more efficacious than placebo in relief of FD. We will also determine if antidepressant therapy reduces disability and improves quality of life in FD, and whether after cessation of therapy, clinical response persists over 6 months. 2) If gastric emptying (motor dysfunction) and the nutrient drink test (a test of gastric hypersensitivity and/or gastric accommodation) is altered by antidepressant therapy, and whether subgroups with altered physiology are associated with treatment outcome. We will directly determine in a sub-study if impaired gastric accommodation (by 99mTc-SPECT) and the symptom response to a nutrient drink test is altered by an antidepressant. 3) If polymorphisms of the serotonin reuptake transporter and the heterotrimeric G protein predict outcome in patients with functional dyspepsia receiving an antidepressant. Our study will provide the first controlled data on the efficacy of the two major antidepressant drug classes in FD, and the first data on clinical, physiological and genetic factors that may predict a beneficial effect of such therapy in FD.

描述（由申请人提供）： 在美国，功能性消化不良（FD）最多影响五分之一，可能会大大损害生活质量，并且非常昂贵。治疗结果是可变的，而且通常不令人满意。在FD中已经确定了胃运动和感觉障碍以及精神病的合并症，但未知这些因素是否影响结果。最近有证据表明遗传成分。我们的试点数据（现已发表在胃肠病学上）表明，异源性G蛋白多态性可能与FD有关。抗抑郁药通常在FD中规定，并且看起来有效，但这不是基于证据的，响应是可变的。在功能性消化不良中，没有使用三环抗抑郁药或选择性5-羟色胺再摄取抑制剂（SSRI）的足够随机对照试验。 我们在FD中假设：1）阿米替林（三环）和依他普兰（SSRI）在一项为期12周的试验结束时的全球症状缓解方面将优于安慰剂，并调整精神病的共生率。此外，与安慰剂组相比，在停止治疗后6个月后，全球症状反应者的比例将显着更大。 2）固体胃排空的加速，餐后饱食的减少以及抗抑郁药治疗的胃量变化增强将是FD中有益的短期和长期结果的重要积极预测指标。相反，结果的负面预测因素将减慢胃排空，餐后饱食的增加以及餐后胃体积变化减少。 3）与短或杂合多态性相比，血清素转运蛋白转运蛋白长期纯合多态性将预测症状的反应明显较差，对依他普里和阿米替林的症状反应明显较差，而GNBETA3 CC多态性则可以预测对两种类别的抗抑郁剂治疗或TCC与TTC的症状相比，将预测症状对两种类别的症状都可以更好地预测。 我们的目标是在平行组中，双盲，随机，安慰剂对照双虚拟，足够的三臂多中心试验，以确定：1）抗抑郁治疗（低剂量的三环脉络膜50 mg或标准剂量Escitalopram 10 mg）比fd serbo的效率更高。我们还将确定抗抑郁治疗是否会减少残疾并改善FD的生活质量，以及在停止治疗后，临床反应持续了6个月。 2）如果胃排空（运动功能障碍）和养分饮料测试（胃力超敏反应和/或胃可容纳的测试）会因抗抑郁治疗而改变，以及生理改变的亚组是否与治疗结果有关。我们将直接在子研究中直接确定胃置受损（99mtc-spect）以及对营养饮料测试的症状反应会被抗抑郁药改变。 3）如果5-羟色胺再摄取转运蛋白和异三聚体G蛋白的多态性可预测患有抗抑郁药的功能性消化不良患者的结果。 我们的研究将提供有关FD两种主要抗抑郁药类别的功效的第一个受控数据，以及有关临床，生理和遗传因素的第一个数据，这些数据可能预测了这种治疗在FD中的有益作用。