Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study

Nicholas J. Talley; G. Richard Locke; Yuri A. Saito; Ann E. Almazar; Ernest P. Bouras; Colin W. Howden; Brian E. Lacy; John K. Dibaise; Charlene M. Prather; Bincy P. Abraham; Hashem B. El-Serag; Paul Moayyedi; Linda M. Herrick; Lawrence A. Szarka; Michael Camilleri; Frank A. Hamilton; Cathy D. Schleck; Katherine E. Tilkes; Alan R. Zinsmeister

doi:10.1053/j.gastro.2015.04.020

Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study

Nicholas J. Talley, G. Richard Locke, Yuri A. Saito, Ann E. Almazar, Ernest P. Bouras, Colin W. Howden, Brian E. Lacy, John K. Dibaise, Charlene M. Prather, Bincy P. Abraham, Hashem B. El-Serag, Paul Moayyedi, Linda M. Herrick, Lawrence A. Szarka, Michael Camilleri, Frank A. Hamilton, Cathy D. Schleck, Katherine E. Tilkes, Alan R. Zinsmeister

Research output: Contribution to journal › Article › peer-review

268 Scopus citations

Abstract

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 â‰¥ 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.

Original language	English (US)
Pages (from-to)	340-349.e2
Journal	Gastroenterology
Volume	149
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2015.04.020
State	Published - Aug 1 2015

Keywords

Abdominal Pain
Antidepressant
Functional Dyspepsia
Functional Gastrointestinal Disorder

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2015.04.020

Cite this

Talley, N. J., Richard Locke, G., Saito, Y. A., Almazar, A. E., Bouras, E. P., Howden, C. W., Lacy, B. E., Dibaise, J. K., Prather, C. M., Abraham, B. P., El-Serag, H. B., Moayyedi, P., Herrick, L. M., Szarka, L. A., Camilleri, M., Hamilton, F. A., Schleck, C. D., Tilkes, K. E., & Zinsmeister, A. R. (2015). Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study. Gastroenterology, 149(2), 340-349.e2. https://doi.org/10.1053/j.gastro.2015.04.020

Talley, NJ, Richard Locke, G, Saito, YA, Almazar, AE, Bouras, EP, Howden, CW, Lacy, BE, Dibaise, JK, Prather, CM, Abraham, BP, El-Serag, HB, Moayyedi, P, Herrick, LM, Szarka, LA, Camilleri, M, Hamilton, FA, Schleck, CD, Tilkes, KE & Zinsmeister, AR 2015, 'Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study', Gastroenterology, vol. 149, no. 2, pp. 340-349.e2. https://doi.org/10.1053/j.gastro.2015.04.020

@article{f402a9e44d7a4c0c9606a1b16ba12070,

title = "Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study",

abstract = "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 {\^a}‰¥ 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.",

keywords = "Abdominal Pain, Antidepressant, Functional Dyspepsia, Functional Gastrointestinal Disorder",

author = "Talley, {Nicholas J.} and {Richard Locke}, G. and Saito, {Yuri A.} and Almazar, {Ann E.} and Bouras, {Ernest P.} and Howden, {Colin W.} and Lacy, {Brian E.} and Dibaise, {John K.} and Prather, {Charlene M.} and Abraham, {Bincy P.} and El-Serag, {Hashem B.} and Paul Moayyedi and Herrick, {Linda M.} and Szarka, {Lawrence A.} and Michael Camilleri and Hamilton, {Frank A.} and Schleck, {Cathy D.} and Tilkes, {Katherine E.} and Zinsmeister, {Alan R.}",

note = "Funding Information: Because the pathophysiology of FD remains poorly understood and a variety of treatment classes are available, health care providers do face uncertainty in selecting therapies for patients with FD. Options used in practice with limited or no data include antispasmodics, analgesics, over-the-counter remedies, as well as antidepressants to treat visceral hypersensitivity. 8 This multicenter randomized, double-blind, placebo-controlled trial comparing placebo, amitriptyline, and escitalopram in FD subjects lends support to the use of TCAs—but not SSRIs—for this common disorder. Those receiving amitriptyline had a 2-fold increased odds of reporting adequate relief than those receiving escitalopram. The improvement in FD symptoms did not directly correlate with baseline gastric physiology or changes in GE or satiation. Amitriptyline appears to derive its benefit predominantly through improving abdominal pain. Despite the smaller number of ulcer-like FD subjects, those with ulcer-like FD receiving amitriptyline were 3-fold more likely to report symptom relief than those receiving placebo, without similar findings in those with dysmotility-like FD. This is consistent with studies showing amitriptyline is beneficial in pain syndromes, including IBS and neuropathic pain. 9,35 This differential treatment effect supports the division of FD into a pain or meal-related satiety subtype. Our findings complement the NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, in which nortriptyline was not helpful in improving idiopathic gastroparesis symptoms, including nausea, meal-related satiety, fullness, anorexia, and bloating. 36 In our trial, FD patients with normal GE at baseline treated with amitriptyline reported statistically significant improvement in abdominal pain and postprandial distress. Our study suggests that in patients with upper abdominal discomfort with a normal endoscopy, clinicians could usefully subtype the FD based on the Rome criteria. Among individuals with pain-predominant FD, a tricyclic antidepressant might be considered in the management algorithm. GE need not be performed unless nausea/vomiting are present and gastroparesis needs to be excluded. Notably FD patients with mild delay in GE or dysmotility-like FD had only a 30% and 46% response rate to amitriptyline, respectively; a tricyclic antidepressant could be considered in these subsets if depression coexists or if FD-related quality of life is poor. Although bowel irregularity was present in more than half of patients with FD, particularly dysmotility-type FD, concurrent IBS was present in only a minority. Treatment response to antidepressant therapy did not differ between patients with FD alone and FD-IBS, suggesting the presence of additional gastrointestinal symptoms does not decrease the likelihood of response to antidepressant therapy. Although our study suggests that patients with FD are more likely to respond to tricyclic antidepressants, firm conclusions regarding the role of tricyclic antidepressants in FD management—and specifically its role in management of various FD subtypes and additional outcomes—cannot be made due to the relatively modest sample size and the resulting borderline P value of .05 with the study{\textquoteright}s a priori primary end point. The limited power was primarily due to difficulty with recruitment. Despite intensive efforts, only 292 of the planned 400 were randomized. Identifying individuals with a known diagnosis of FD (and not reflux disease), who did not meet exclusion criteria—including response to antisecretory therapy, current depression or psychiatric disease, or current antidepressant use for any reason, who were willing to participate in this intensive trial—was challenging. It is perhaps debatable whether the study outcome was truly positive. We would argue that the findings are positive in favor of amitriptyline use in FD management because the results appear to follow drug mechanisms with TCAs positively impacting those with painful FD and normal GE. In addition, the mean symptom score on the NDI improved in those who received antidepressants, as did overall FD-related quality of life and specific aspects of FD-specific quality of life improved among those receiving antidepressants. Nonetheless, although more than half of the FD patients receiving TCAs reported adequate relief of FD symptoms, clearly the remainder did not. In other words, TCAs can help FD symptoms improve, but will not resolve all symptoms in all FD patients. Side effects were noted in a quarter of the participants, including those on placebo. Although FD patients have reported antidepressant intolerance, 37 this study found that the antidepressant side effect experience was quite heterogeneous, although gastrointestinal and neurologic symptoms were more common globally on active treatment. However, there were no common gastrointestinal symptoms among treatment groups. Only dizziness was a common neurologic symptom, particularly in the escitalopram group. This symptom heterogeneity might reflect underlying sensitivity and vigilance rather than drug-related adverse events. Although SSRIs might be perceived to be better tolerated than TCAs, we did not find this. One potential drawback of the study design is that it includes the requirement of a normal EGD, but only within the past 5 years, raising the question that individuals with an alternative explanation for symptoms might have been included. Reassuringly, 80% of the participants had an EGD within 1 year of study recruitment. As a prior study has shown that the yield from EGD in functional dyspepsia is low in the absence of alarm features 38 and a meta-analysis in FD found that endoscopy was not superior to empiric acid suppression in terms of outcomes, the likelihood of misclassification of FD appears low. 39 The greatest strength of this study is that although it might have been slightly underpowered to evaluate FD subgroups, it remains one of the largest and most ambitious studies of FD performed to date. Clinical trials evaluating symptom-based functional gastrointestinal disorders can be challenging when a number of end points exist (eg, adequate relief, global symptoms). This study utilized “adequate relief” as its primary outcome, which has been used and accepted in other functional gastrointestinal trials, such as IBS. 23,40 Although Rome III criteria were not applied because the study began before their publication, the current data suggest epigastric pain syndrome and ulcer-like dyspepsia cover similar domains. This study{\textquoteright}s execution and interpretation of results were regularly overseen by the National Institutes of Health and the Data and Safety Monitoring Board. Although a number of outcomes were collected in this comprehensive study, only predesignated aims and analyses are reported in this article. In conclusion, in this large, multicenter, randomized, double-blind, placebo-controlled clinical trial, amitriptyline appeared beneficial in FD, particularly in those with ulcer-like FD. Although adverse events were common, there was no overall difference between the 3 arms (except in neurologic symptoms, with highest rates in the escitalopram arm) suggesting that with provider counseling and support, TCAs will be generally well tolerated at low doses. The results do not support the use of escitalopram in FD. Publisher Copyright: {\textcopyright} 2015 by the AGA Institute.",

year = "2015",

month = aug,

day = "1",

doi = "10.1053/j.gastro.2015.04.020",

language = "English (US)",

volume = "149",

pages = "340--349.e2",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "2",

}

TY - JOUR

T1 - Effect of amitriptyline and escitalopram on functional dyspepsia

T2 - A multicenter, randomized controlled study

AU - Talley, Nicholas J.

AU - Richard Locke, G.

AU - Saito, Yuri A.

AU - Almazar, Ann E.

AU - Bouras, Ernest P.

AU - Howden, Colin W.

AU - Lacy, Brian E.

AU - Dibaise, John K.

AU - Prather, Charlene M.

AU - Abraham, Bincy P.

AU - El-Serag, Hashem B.

AU - Moayyedi, Paul

AU - Herrick, Linda M.

AU - Szarka, Lawrence A.

AU - Camilleri, Michael

AU - Hamilton, Frank A.

AU - Schleck, Cathy D.

AU - Tilkes, Katherine E.

AU - Zinsmeister, Alan R.

N1 - Funding Information: Because the pathophysiology of FD remains poorly understood and a variety of treatment classes are available, health care providers do face uncertainty in selecting therapies for patients with FD. Options used in practice with limited or no data include antispasmodics, analgesics, over-the-counter remedies, as well as antidepressants to treat visceral hypersensitivity. 8 This multicenter randomized, double-blind, placebo-controlled trial comparing placebo, amitriptyline, and escitalopram in FD subjects lends support to the use of TCAs—but not SSRIs—for this common disorder. Those receiving amitriptyline had a 2-fold increased odds of reporting adequate relief than those receiving escitalopram. The improvement in FD symptoms did not directly correlate with baseline gastric physiology or changes in GE or satiation. Amitriptyline appears to derive its benefit predominantly through improving abdominal pain. Despite the smaller number of ulcer-like FD subjects, those with ulcer-like FD receiving amitriptyline were 3-fold more likely to report symptom relief than those receiving placebo, without similar findings in those with dysmotility-like FD. This is consistent with studies showing amitriptyline is beneficial in pain syndromes, including IBS and neuropathic pain. 9,35 This differential treatment effect supports the division of FD into a pain or meal-related satiety subtype. Our findings complement the NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, in which nortriptyline was not helpful in improving idiopathic gastroparesis symptoms, including nausea, meal-related satiety, fullness, anorexia, and bloating. 36 In our trial, FD patients with normal GE at baseline treated with amitriptyline reported statistically significant improvement in abdominal pain and postprandial distress. Our study suggests that in patients with upper abdominal discomfort with a normal endoscopy, clinicians could usefully subtype the FD based on the Rome criteria. Among individuals with pain-predominant FD, a tricyclic antidepressant might be considered in the management algorithm. GE need not be performed unless nausea/vomiting are present and gastroparesis needs to be excluded. Notably FD patients with mild delay in GE or dysmotility-like FD had only a 30% and 46% response rate to amitriptyline, respectively; a tricyclic antidepressant could be considered in these subsets if depression coexists or if FD-related quality of life is poor. Although bowel irregularity was present in more than half of patients with FD, particularly dysmotility-type FD, concurrent IBS was present in only a minority. Treatment response to antidepressant therapy did not differ between patients with FD alone and FD-IBS, suggesting the presence of additional gastrointestinal symptoms does not decrease the likelihood of response to antidepressant therapy. Although our study suggests that patients with FD are more likely to respond to tricyclic antidepressants, firm conclusions regarding the role of tricyclic antidepressants in FD management—and specifically its role in management of various FD subtypes and additional outcomes—cannot be made due to the relatively modest sample size and the resulting borderline P value of .05 with the study’s a priori primary end point. The limited power was primarily due to difficulty with recruitment. Despite intensive efforts, only 292 of the planned 400 were randomized. Identifying individuals with a known diagnosis of FD (and not reflux disease), who did not meet exclusion criteria—including response to antisecretory therapy, current depression or psychiatric disease, or current antidepressant use for any reason, who were willing to participate in this intensive trial—was challenging. It is perhaps debatable whether the study outcome was truly positive. We would argue that the findings are positive in favor of amitriptyline use in FD management because the results appear to follow drug mechanisms with TCAs positively impacting those with painful FD and normal GE. In addition, the mean symptom score on the NDI improved in those who received antidepressants, as did overall FD-related quality of life and specific aspects of FD-specific quality of life improved among those receiving antidepressants. Nonetheless, although more than half of the FD patients receiving TCAs reported adequate relief of FD symptoms, clearly the remainder did not. In other words, TCAs can help FD symptoms improve, but will not resolve all symptoms in all FD patients. Side effects were noted in a quarter of the participants, including those on placebo. Although FD patients have reported antidepressant intolerance, 37 this study found that the antidepressant side effect experience was quite heterogeneous, although gastrointestinal and neurologic symptoms were more common globally on active treatment. However, there were no common gastrointestinal symptoms among treatment groups. Only dizziness was a common neurologic symptom, particularly in the escitalopram group. This symptom heterogeneity might reflect underlying sensitivity and vigilance rather than drug-related adverse events. Although SSRIs might be perceived to be better tolerated than TCAs, we did not find this. One potential drawback of the study design is that it includes the requirement of a normal EGD, but only within the past 5 years, raising the question that individuals with an alternative explanation for symptoms might have been included. Reassuringly, 80% of the participants had an EGD within 1 year of study recruitment. As a prior study has shown that the yield from EGD in functional dyspepsia is low in the absence of alarm features 38 and a meta-analysis in FD found that endoscopy was not superior to empiric acid suppression in terms of outcomes, the likelihood of misclassification of FD appears low. 39 The greatest strength of this study is that although it might have been slightly underpowered to evaluate FD subgroups, it remains one of the largest and most ambitious studies of FD performed to date. Clinical trials evaluating symptom-based functional gastrointestinal disorders can be challenging when a number of end points exist (eg, adequate relief, global symptoms). This study utilized “adequate relief” as its primary outcome, which has been used and accepted in other functional gastrointestinal trials, such as IBS. 23,40 Although Rome III criteria were not applied because the study began before their publication, the current data suggest epigastric pain syndrome and ulcer-like dyspepsia cover similar domains. This study’s execution and interpretation of results were regularly overseen by the National Institutes of Health and the Data and Safety Monitoring Board. Although a number of outcomes were collected in this comprehensive study, only predesignated aims and analyses are reported in this article. In conclusion, in this large, multicenter, randomized, double-blind, placebo-controlled clinical trial, amitriptyline appeared beneficial in FD, particularly in those with ulcer-like FD. Although adverse events were common, there was no overall difference between the 3 arms (except in neurologic symptoms, with highest rates in the escitalopram arm) suggesting that with provider counseling and support, TCAs will be generally well tolerated at low doses. The results do not support the use of escitalopram in FD. Publisher Copyright: © 2015 by the AGA Institute.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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 â‰¥ 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.

AB - 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 â‰¥ 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.

KW - Abdominal Pain

KW - Antidepressant

KW - Functional Dyspepsia

KW - Functional Gastrointestinal Disorder

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U2 - 10.1053/j.gastro.2015.04.020

DO - 10.1053/j.gastro.2015.04.020

M3 - Article

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Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study

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