Katherine E. Tilkes

Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study.

BACKGROUND & AIMS Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 ± 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651.

810 The Functional Dyspepsia Treatment Trial (Fdtt) Key Results

G A A b st ra ct s and charges associated with either treatment strategy. Results: A total of 84 patients were randomized to the home (n=42) and hospital (n=42) groups. There was no difference between the patients randomized to the home and hospital groups with regards to age, gender, HAP and Imrie scores, clinical symptoms, laboratory, or biliary findings (Table 1). No patients developed organ failure, pancreatic necrosis, or died in either group. Only 3 patients required readmission to the hospital within 30 days, 1 (2.3%) from the home and 2 (4.8%) from the hospital groups (p=NS). None of the home-monitored patients required hospitalization in the 5-7 day follow-up after discharge. The duration of the abdominal pain and time to resumption of an oral diet were similar in both groups (p=NS) (Table 2). Significant cumulative cost savings were observed in the 42 patients in home monitoring group. Conclusion: Patients with mild non-alcoholic AP can be safely treated at home with regular visits by a nurse. Widespread adoption of this practice could result in large cost savings. Table 1. Demographic and clinical characteristics of the groups

Polymorphisms of 5-HTT LPR and GNβ3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial

Objectives:The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNβ3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNβ3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy.Methods:Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNβ3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods.Results:GNβ3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy–Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNβ3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43).Conclusions:GNβ3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

Effects of antidepressants on gastric function in patients with functional dyspepsia

Background:Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood.Aims:Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology.Methods:This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS).Results:In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS–PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02).Conclusions:Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.

1017 The Functional Dyspepsia Treatment Trial (FDTT): 5-HTT LPR and Gn β3 825C>T Are Not Pharmacogenetic Markers for FD Antidepressant Treatment Response

The Functional Dyspepsia Treatment Trial (FDTT): 5-HTT LPR and Gnβ3 825C>T Are Not Pharmacogenetic Markers for FD Antidepressant Treatment Response Yuri A. Saito, Ann E. Almazar, Giles R. Locke, Ernest P. Bouras, Colin W. Howden, Brian E. Lacy, John K. DiBaise, Charlene M. Prather, Bincy Abraham, Hashem El-Serag, Paul Moayyedi, Lawrence A. Szarka, Linda M. Herrick, Katherine E. Tilkes, Cathy D. Schleck, Alan R. Zinsmeister, Nicholas J. Talley

Tu1845 In Functional Dyspepsia, Are Meal-Related Symptoms Linked to Less Drinking Capacity?

Background: Serotonin (5-HT) signaling in the small intestine is involved in motor, sensory and secretory pathways. Studies of neuroendocrine cell mapping in functional dyspepsia (FD), characterized by upper gastrointestinal motor and sensory disturbances, are scarce although it has been previously noted that there is no significant difference in numbers of 5HT cells in duodenum in post infectious FD vs. controls1. In patients with irritable bowel syndrome, another functional bowel disorder, a low density of duodenal neuroendocrine cells is also described2. Aim: To examine the content of neuroendocrine cells in the duodenum of subjects with FD, specifically the relative content of serotonin (5-HT) containing cells and to investigate a possible relationship between neuroendocrine cell numbers and FD subtypes. Methods: A random sample of an adult Swedish population (n = 1000) (the Kalixanda study) underwent upper endoscopy and biopsies taken from the duodenal bulb (D1) and the second part of duodenum (D2). From this study 23 subjects with FD were identified, 13 with postprandial distress syndrome (PDS), 10 with epigastric pain syndrome (EPS) and 12 healthy controls. Immunocytochemistry was performed for Chromogranin A (CGA) and 5-HT. Positive cells were quantified per mm2. Results: Cases and controls showed similar demographics. The number of CGA stained cells was significantly lower in FD patients both in D1 (p = 0.01) and D2 (p = 0.04) whereas there was no significant difference in 5-HT content. See figure. When EPS and PDS were studied separately, the number of CGA stained cells was significantly decreased in D1 in patients with EPS (p = 0.03). Conclusions: The number of duodenal neuroendocrine cells is decreased in FD compared with control subjects, but this is not due to a reduction in the number of 5-HT containing cells. It is possible that this reduction reflects reduced cellular densities of other hormones (e.g. somatostatin) which could result in a high secretion of gastric acid, with a change in motility or visceral sensitivity leading to dyspeptic symptoms in these cases. 1. Futagami S et al. Am J Gastroenterol. 2010 ;105:1835-42. 2. El-Salhy M et al. Scand J Gastroenterol. 2010 ;45:1435-9.

Mo1873 Menetrier's Disease Is Associated With an Increased Risk of Gastric Cancer: A Case-Control Study

G A A b st ra ct s malignancies (1.3%). FD was diagnosed in the remaining 3,426 (75.4%) patients with a female preponderance (odds ratio [OR], 1.41; 95% CI 1.23-1.62). The prevalence of FD declined with age (84.9% at age,40 years; 76.3% at 40-49, 75.2% at 50-59, 70.8% at 6069 and 64.6% above 70 years, P,.001). Using Rome III criteria, 68.7% of these FD cases were classified as epigastric pain syndrome (EPS); 8.7% as postprandial distress syndrome (PDS); and 22.6% as overlap condition. There was no significant relationship between Helicobacter pylori infection and any type of FD (23.5%, 23.3% and 24.1%, respectively, P= .9). Other GI complaints were heartburn accounting for 2.4%, globus pharyngeus 11.1%, bloating 41.7%, diarrhea 7.3% and constipation 20.9%. Concomitant heartburn was more frequently occurred in subjects with EPS (OR, 1.31; 95% CI 1.04-1.65). Individuals with PDS were more likely to report coexisted bloating (OR, 4.24; 95% CI 3.25-5.52), diarrhea (OR, 1.66; 95% CI 1.13-2.44) and constipation (OR, 1.49; 95% CI 1.14-1.96). The frequency of irritable bowel syndrome (IBS) among FD patient was 8.3% (95% CI 7.4-9.3%). The overlap between FD and IBS was associated with female sex (OR, 1.38; 95% CI 1.05-1.82) and the presence of PDS (OR, 1.84; 95% CI 1.29-2.63). The use of proton pump inhibitors longer than 3 months tends to be associated with FD-IBS overlap but the difference did not reach statistical significance (OR, 1.28; 95% CI 0.99-1.64, P=.051). Conclusion: FD is the most common cause of dyspeptic symptoms in our patient population. Overlap of FD and reflux symptoms is commonly seen in individuals with EPS whereas FD-IBS overlap is often observed in those with PDS. The association between these conditions could provide valuable insights into pathophysiology of functional GI disorders.

Mo1171 Disordered Eating Behaviors in Functional Dyspepsia Patients

G A A b st ra ct s volume of gas evacuated after a standard meal (262±22 and 265±25 mL, respectively), and reported more abdominal symptoms (5.8±0.3 vs 0.4±0.2 mean discomfort/pain score, respectively; p=<0.0001). In both groups, the flatulogenic diet increased the number of gas passages (44.4±5.3 and 21.7±2.9 daytime passages, respectively), gas production (656±52 and 673±78 mL, respectively) and abdominal symptoms (7.9±0.3 and 2.8±0.4 discomfort/ pain, respectively) as compared to baseline (p<0.05 vs for all), and uncovered differences in gut microbiota between groups (26% patients vs 60% healthy subjects harbouring Methanobrevibacter smithii p=0.037). CONCLUSION. Patients complaining of flatulence have a poor tolerance of intestinal gas, without increment in production. Diet has a major impact on gut flora, gas production, and abdominal symptoms both in healthy subjects and in flatulent patients.