Antidepressant Therapy for Functional Dyspepsia

功能性消化不良的抗抑郁治疗

• 批准号: 7923485
• 负责人: NICHOLAS J TALLEY
• 金额: $ 39.95万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923485
• 关键词: Acceleration; Affect; American; Amitriptyline; Analgesics; Antidepressive Agents; Anxiety; Chronic; Clinical; Data; Disease; Dose; Double-Blind Method; Dyspepsia; Escitalopram; Exposure to; Follow-Up Studies; Functional disorder; Gastric Emptying; Gastroenterology; Genetic; Genetic Polymorphism; Genotype; Glutaminase; Heterotrimeric GTP-Binding Proteins; Hypersensitivity; Morbidity - disease rate; Motor; Natural History; Nutrient; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Physiological; Physiology; Placebo Control; Placebos; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Relaxation; Satiation; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonin; Severities; Solid; Stomach; Subgroup; Symptoms; Testing; Treatment outcome; Tricyclic Antidepressive Agents; Twin Studies; Uncontrolled Study; United States; Upper arm; base; depression; disability; drinking; evidence base; imaging modality; improved; novel; psychologic; response; reuptake; serotonin transporter; treatment response; week trial

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) 影响多达五分之一的人，会严重损害生活质量，而且费用非常高昂；治疗结果各不相同，而且往往不令人满意。 FD 中已发现胃运动和感觉障碍以及精神共病，但尚不清楚这些因素是否影响结果。最近有证据表明存在遗传成分；我们的试验数据（现已发表在《胃肠病学》上）表明异三聚体 G 蛋白多态性可能与 FD 相关。抗抑郁药通常用于 FD，并且似乎有效，但这不是基于证据的，而且反应也存在差异；目前还没有关于三环类抗抑郁药或选择性血清素再摄取抑制剂（SSRI）治疗功能性消化不良的充分随机对照试验。 我们在 FD 中假设：1) 在调整精神科共病后，在 12 周试验结束时，阿米替林（一种三环药物）和艾司西酞普兰（一种 SSRI）在总体症状缓解方面优于安慰剂。此外，与安慰剂组相比，在停止治疗后 6 个月时，总体症状缓解者的比例将显着增加。 2) 抗抑郁治疗期间，胃固体排空加速、餐后饱腹感减少和胃容量变化增加将是 FD 短期和长期有益结果的显着正向预测因子。相反，结果的负面预测因素将是胃排空减慢、餐后饱腹感增加和餐后胃容量变化减少。 3) 与短或杂合多态性相比，5-羟色胺转运蛋白长纯合多态性将预测对艾司西酞普兰和阿米替林的症状反应显着较差，而GNbeta3 CC多态性将预测与TT或TC基因型相比对两类抗抑郁药治疗的症状反应明显更好。 我们的目标是进行一项平行组、双盲、随机、安慰剂对照双模拟、动力充足的三臂多中心试验，以确定：1) 抗抑郁治疗（低剂量三环阿米替林 50 mg 或标准剂量艾司西酞普兰 10 mg）是否比安慰剂更有效缓解 FD。我们还将确定抗抑郁治疗是否可以减少 FD 患者的残疾并改善生活质量，以及停止治疗后临床反应是否持续超过 6 个月。 2）抗抑郁治疗是否改变胃排空（运动功能障碍）和营养饮料测试（胃过敏和/或胃调节测试），以及生理学改变的亚组是否与治疗结果相关。我们将在一项子研究中直接确定抗抑郁药是否会改变胃调节受损（通过 99mTc-SPECT）和对营养饮料测试的症状反应。 3) 血清素再摄取转运蛋白和异源三聚体 G 蛋白的多态性是否可以预测接受抗抑郁药物治疗的功能性消化不良患者的结果。 我们的研究将提供关于两种主要抗抑郁药物治疗 FD 疗效的首个对照数据，以及可预测此类疗法对 FD 有益效果的临床、生理和遗传因素的首个数据。