Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: a Multicenter, Randomized Controlled Study Nicholas J
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Gastroenterology 2015;149:340–349 Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study Nicholas J. Talley,1,2 G. Richard Locke,1 Yuri A. Saito,1 Ann E. Almazar,1 Ernest P. Bouras,3 Colin W. Howden,4 Brian E. Lacy,5 John K. DiBaise,6 Charlene M. Prather,7 Bincy P. Abraham,8 Hashem B. El-Serag,8 Paul Moayyedi,9 Linda M. Herrick,1 Lawrence A. Szarka,1 CLINICAL AT Michael Camilleri,1 Frank A. Hamilton,10 Cathy D. Schleck,11 Katherine E. Tilkes,1 and Alan R. Zinsmeister11 1Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; 2Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; 3Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida; 4Gastroenterology, Northwestern University, Chicago, Illinois; 5Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; 6Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; 7Gastroenterology, St Louis University, St Louis, Missouri; 8Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; 9Gastroenterology, McMaster University, Hamilton, Ontario, Canada; 10Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and 11Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota Keywords: Functional Dyspepsia; Abdominal Pain; Functional See editorial on page 270. Gastrointestinal Disorder; Antidepressant. BACKGROUND & AIMS: Antidepressants are frequently pre- unctional dyspepsia (FD) is a common functional scribed to treat functional dyspepsia (FD), a common disorder gastrointestinal disorder characterized by upper characterized by upper abdominal symptoms, including F abdominal discomfort or pain and symptoms of meal- discomfort or postprandial fullness. However, there is little related fullness or satiety.1 The condition has symptoms evidence of the efficacy of these drugs in patients with FD. We similar to other conditions, including gastroesophageal performed a randomized, double-blind, placebo-controlled trial fl to evaluate the effects of antidepressant therapy on symptoms, re ux, peptic ulcer disease, or irritable bowel syndrome gastric emptying (GE), and meal-induced satiety in patients (IBS). However, dyspepsia symptoms typically do not with FD. METHODS: We performed a study at 8 North Amer- improve with proton pump inhibitor therapy and are not ican sites of patients who met the Rome II criteria for FD chronologically associated with bowel habits. The patho- and did not have depression or use antidepressants. Patients genesis remains unclear, but abnormalities in gastric motor (n ¼ 292; 44 ± 15 years old, 75% were female, 70% with and sensory function and, more recently, low-grade 2,3 dysmotility-like FD, and 30% with ulcer-like FD) were duodenal inflammation, have been identified. Research randomly assigned to groups given placebo, 50 mg amitripty- studies have shown that diagnosing FD can be difficult. line, or 10 mg escitalopram for 10 weeks. The primary end Diagnostic testing usually includes upper endoscopy as well point was adequate relief of FD symptoms for 5 weeks of the as testing for Helicobacter pylori. FD symptoms often last 10 weeks (of 12). Secondary end points included GE time, interfere with school and work, and weight loss can occur maximum tolerated volume in Nutrient Drink Test, and FD- due to dietary restrictions.4À7 related quality of life. RESULTS: An adequate relief response FD symptom management remains challenging. Treat- was reported by 39 subjects given placebo (40%), 51 given ment can include dietary modifications, antiemetics, anti- amitriptyline (53%), and 37 given escitalopram (38%) (P ¼ .05, spasmodics, prokinetics, and analgesics.8 Options are quite after treatment, adjusted for baseline balancing factors varied and are applied based on predominant symptom. including all subjects). Subjects with ulcer-like FD given Although antidepressants, including tricyclic antidepressants > amitriptyline were 3-fold more likely to report adequate re- (TCAs) and selective serotonin reuptake inhibitors (SSRIs),9 ¼ fi lief than those given placebo (odds ratio 3.1; 95% con dence have been used for IBS, their efficacy in FD management interval: 1.1À9.0). Neither amitriptyline nor escitalopram is uncertain. Antidepressant data in FD are limited to 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 Abbreviations used in this paper: CI, confidence interval; EGD, esoph- ¼ fi À agogastroduodenoscopy; FD, functional dyspepsia; GE, gastric emptying; ratio 0.4; 95% con dence interval: 0.2 0.8). Both antide- IBS, irritable bowel syndrome; MTV, maximum tolerated volume; NDI, pressants improved overall quality of life. CONCLUSIONS: Nepean Dyspepsia Index; OR, odds ratio; SSRIs, serotonin reuptake in- Amitriptyline, but not escitalopram, appears to benefit some hibitors; TCAs, tricyclic antidepressants. patients with FD, particularly those with ulcer-like (painful) FD. © 2015 by the AGA Institute Patients with delayed GE do not respond to these drugs. 0016-5085/$36.00 ClinicalTrials.gov ID: NCT00248651. http://dx.doi.org/10.1053/j.gastro.2015.04.020 August 2015 Antidepressant Trial in Functional Dyspepsia 341 4 smaller studies utilizing amitriptyline, venlafaxine, and changed from 5 sites to 8 sites to facilitate recruitment. No sertraline.10À13 It is postulated that antidepressants might be changes in trial outcomes were made. The study ended based efficacious through reduction of psychological symptoms on funding period. All authors had access to the study data and (eg, anxiety or depression), central analgesic actions,14 or reviewed and approved the final manuscript. reduction of affective arousal and sleep restoration.15,16 Both TCAs and SSRIs have been shown to differently alter orocecal 17,18 Study Participants transit times and gastric accommodation. Enrollment was during October 2006 through October Despite ongoing clinical use, uncertainty remains 2012. The last patient was randomized November 2012 and ’ fi regarding antidepressants clinical ef cacy and mechanism completed 6-month post-treatment follow-up August 2013. of treatment response in FD. The aim of this multicenter, Inclusion criteria were age 18À75 years, Rome II criteria for FD randomized placebo-controlled trial was to assess whether (Table 1),20 and a normal upper endoscopy within 5 years. FD 12 weeks of therapy with amitriptyline or escitalopram was subtype was determined from a structured interview con- more efficacious than placebo in the relief of FD symptoms ducted at the baseline visit, and then defined as ulcer-like or and in improving quality of life. Our secondary aim was to dysmotility-like. If the participant had not had an esoph- CLINICAL AT assess whether gastric emptying (GE) and meal-induced agogastroduodenoscopy (EGD) within 5 years, one was per- satiety were altered by treatment with a TCA or SSRI, and formed before randomization in our trial. Exclusion criteria whether changes in gastric physiology were associated with were symptom resolution with antisecretory therapy (proton treatment outcome. In addition, we aimed to determine if pump inhibitor use for other reasons that did not resolve FD efficacy persisted 6 months after treatment was ceased. symptoms were allowed), current antidepressant, or nonste- roidal anti-inflammatory drugs use, history of esophagitis or ulcer disease or other organic upper gastrointestinal disease, Methods current drug or alcohol abuse, current or planned pregnancy, Study Overview major abdominal surgery, or major physical illness. Individuals with a Hospital Anxiety Depression Scale score 11 on the À This National Institutes of Health (DK065713) funded, depression scale were excluded. Patients older than age 50 multicenter, randomized double-blind parallel group trial years underwent an electrocardiogram. Women of childbearing (Clinicaltrials.gov ID: NCT00248651) comparing 12 weeks of years were administered a urine pregnancy test. Each site- amitriptyline, escitalopram, and matching placebo pills is specific investigator or coordinator recruited and enrolled summarized in Figure 1. Institutional Review Board approval participants. was obtained at each site. Written informed consent was ob- tained from each subject. Mayo Clinic Rochester monitored each site, centralized data storage, and analyzed the data. Data Baseline Washout and Safety Monitoring Board and National Institutes of Health Subjects had a 2- to 4-week baseline assessment period members monitored the study bimonthly and monthly, before randomization based on patient, staff, and research respectively. The trial design has been reported previously.19 equipment availability for study testing. Validated symptom Only results of the clinical primary aims will be reported. Af- diaries were completed during this period.21 Subjects were ter trial commencement, to facilitate recruitment, the study was required to have at least moderate FD symptoms on the Figure 1. Study design. There was a screening period of 0À4 weeks before randomization on day 1. Two on-site visits were required before randomization, with a third visit if a gastric accommo- dation study was per- formed (Mayo Clinic sites only). Study visits were monthly during the treat- ment phase. Weekly as- sessments were performed by phone during the treat-