Antidepressant Therapy for Functional Dyspepsia

描述（由申请人提供）： 功能性消化不良（FD）在美国影响多达五分之一的人，可以大大损害生活质量，并且非常昂贵;治疗结果是可变的，并且通常不令人满意。胃运动和感觉障碍，精神共病，已确定在FD，但它是未知的，如果这些因素影响的结果。最近有证据表明遗传成分;我们的初步数据（现已发表在Gastroenterology）表明异源三聚体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，并且反应是可变的;没有足够的三环类抗抑郁药或选择性5-羟色胺再摄取抑制剂（SSRI）在功能性消化不良中的随机对照试验。 我们在FD中假设：1）阿米替林（一种三环类药物）和艾司西酞普兰（一种SSRI）在12周试验结束时的总体症状缓解方面上级安慰剂，调整了精神病合并症。此外，与安慰剂组相比，停止治疗后6个月时总体症状应答者的比例将显著更大。2)在抗抑郁治疗中，固体胃排空加速、餐后饱腹感减少和餐后胃容积变化增强将是FD有益的短期和长期结局的显著阳性预测因子。相反，结果的阴性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)5-羟色胺转运体长纯合子多态性与短或杂合子多态性相比，预测对艾司西酞普兰和阿米替林的症状反应显著较差，而GN β 3 CC多态性与TT或TC基因型相比，预测对两种抗抑郁药治疗的症状反应显著更好。 我们的目标是在一个平行组，双盲，随机，安慰剂对照双模拟，充分把握度的三臂多中心试验，以确定：1）抗抑郁药治疗（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地缓解FD。我们还将确定抗抑郁治疗是否能减少功能障碍并改善FD患者的生活质量，以及停止治疗后临床反应是否持续6个月以上。2)抗抑郁药治疗是否改变胃排空（运动功能障碍）和营养饮料试验（胃过敏和/或胃调节试验），以及生理学改变的亚组是否与治疗结局相关。我们将在子研究中直接确定抗抑郁药是否改变胃调节受损（通过99 mTc-SPECT）和对营养饮料试验的症状反应。3)5-羟色胺再摄取转运蛋白和异源三聚体G蛋白多态性是否可预测功能性消化不良患者接受抗抑郁药治疗的结局 我们的研究将提供关于两种主要抗抑郁药物类在FD中的疗效的第一个对照数据，以及关于临床、生理和遗传因素的第一个数据，这些因素可能预测这种治疗在FD中的有益效果。

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.