Antidepressant Therapy for Functional Dyspepsia

描述(由申请人提供)： 功能性消化不良(FD)在美国每五个人中就有一个受到影响，可能会严重影响生活质量，而且成本非常高；治疗结果多种多样，往往不令人满意。胃运动和感觉障碍，以及精神疾病的并存，已经在FD中被发现，但尚不清楚这些因素是否会影响结果。最近有证据表明有遗传成分；我们的初步数据(现已发表在《胃肠病学》杂志上)表明，异源三聚体G蛋白多态可能与FD有关。抗抑郁药通常在FD中被开出，似乎有效，但这不是基于证据，反应是可变的；还没有足够的随机对照试验用三环类抗抑郁药或选择性5-羟色胺再摄取抑制剂(SSRI‘s)治疗功能性消化不良。 我们在FD中假设：1)阿米替林(三环类)和爱司匹兰(一种SSRI)在12周试验结束时在整体症状缓解方面将优于安慰剂，并对精神疾病的共同发病率进行了调整。此外，与安慰剂组相比，在停止治疗6个月后，全球症状应答者的比例将显著增加。2)固体胃排空加快、餐后饱腹感减少和抗抑郁治疗后进餐时胃容量变化增加是FD近期和远期疗效的显著正向预测指标。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)与短型或杂合型相比，5-羟色胺转运体长纯合子多态对艾司匹兰和阿米替林的疗效显著降低，而GNbeta3CC多态对两种抗抑郁药物的疗效预测均显著好于TT或TC基因型。 我们的目标是在一项平行分组的双盲、随机、安慰剂对照、充分有效的三臂多中心试验中确定：1)抗抑郁治疗(小剂量三环阿米替林50 mg或标准剂量艾司匹林10 mg)在缓解FD方面是否比安慰剂更有效。我们还将确定抗抑郁治疗是否减少了FD的残疾并提高了生活质量，以及在停止治疗后，临床反应是否持续了6个月以上。2)抗抑郁治疗是否改变了胃排空(运动功能障碍)和营养饮料试验(胃过敏和/或胃适应试验)，以及生理改变的亚组是否与治疗结果有关。我们将在一项子研究中直接确定抗抑郁剂是否改变了胃调节受损(通过99mTC-SPECT)和营养饮料测试的症状反应。3)5-羟色胺再摄取转运体和异三聚体G蛋白基因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预后。 我们的研究将提供两类主要抗抑郁药物在FD中的疗效的第一个对照数据，以及可能预测此类疗法在FD中的有益效果的临床、生理和遗传因素的第一个数据。

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.