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.