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Cited by 96Inflammatory Bowel DiseaseGastrointestinal motility and disordersMicroscopic Colitis

Tricyclic Antidepressants for Management of Residual Symptoms in Inflammatory Bowel Disease

Open access
Iskandar, Heba N., Cassell, Benjamin, Kanuri, Navya, Gyawali, C. Prakash, Gutierrez, Alexandra, Dassopoulos, Themistocles, Ciorba, Matthew A., Sayuk, Gregory S.·2014·Journal of Clinical Gastroenterology
DOI 10.1097/mcg.0000000000000049PMC PMC4111227
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Abstract

BACKGROUND: Tricyclic antidepressants (TCAs) have efficacy in treating irritable bowel syndrome (IBS). Some clinicians use TCAs to treat residual symptoms in inflammatory bowel disease (IBD) patients already on decisive IBD therapy or with quiescent inflammation, although this strategy has not been formally studied. GOALS: The aim of this study was to examine the efficacy of TCA therapy in IBD patients with residual symptoms, despite controlled inflammation, in a retrospective cohort study. STUDY: Inclusion required initiation of TCA for persistent gastrointestinal symptoms. IBD patients had inactive or mildly active disease with persistent symptoms despite adequate IBD therapy as determined by their physician. Symptom response was compared with IBS patients. Established Likert scales were used to score baseline symptom severity (0=no symptoms, 3=severe symptoms) and TCA response (0=no improvement; 3=complete satisfaction). RESULTS: Eighty-one IBD [41.3±1.7 y, 56F; 58 Crohn's disease/23 ulcerative colitis (UC)] and 77 IBS (46.2±1.7 y, 60F) patients were initiated on a TCA therapy. Baseline symptom scores (IBD, 2.06±0.03; IBS, 2.12±0.04; P=0.15) and symptom response to TCA therapy (IBD, 1.46±0.09; IBS, 1.30±0.09; P=0.2) were similar in both the groups. At least moderate improvement (Likert score ≥2) on TCA was achieved by comparable proportions of patients (59.3% IBD vs. 46% IBS; P=0.09). Within IBD, response was better with UC than Crohn's disease (1.86±0.13 vs. 1.26±0.11, respectively, P=0.003). CONCLUSIONS: In a clinical practice setting, TCA use led to moderate improvement of residual gastrointestinal symptoms in IBD patients for whom escalation of IBD therapy was not planned. UC patients demonstrated higher therapeutic success. IBD symptom responses were similar to IBS patients.

Integrity signals

Registry

Crossref · 10.1097/mcg.0000000000000049

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Differences in tricyclic antidepressant response between Crohn's disease and ulcerative colitis were nonsignificant for added benefit at the second follow-up visit.

    “These differences in TCA response between CD and UC were nonsignificant for added benefit at the second follow-up visit with a mean response score of 1.31 ± 0.16 for CD and 1.47 ± 0.17 for UC, P = 0.76.”
    Quote in the paperNot a substantial claim
  • Findingown data

    83% of ulcerative colitis patients versus 50% of Crohn's disease patients had at least moderate symptomatic improvement on tricyclic antidepressants.

    “This translated into 83% of UC patients having at least a moderate symptomatic improvement on TCA, compared with 50% of CD patients (P = 0.01).”
    Quote in the paperSubstantial claim
  • Findingown data

    Depression was more commonly reported in inflammatory bowel disease patients.

    “Depression was more commonly reported in IBD patients.”
    Quote in the paperNot a substantial claim
  • Findingown data

    A total of 158 subjects, 81 with inflammatory bowel disease and 77 with irritable bowel syndrome, met eligibility criteria and formed the study groups.

    “A total of 158 subjects, 81 IBD patients (58CD/23 UC) and 77 IBS patients met the eligibility criteria and formed the study groups.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Mean baseline symptom severity scores were similar in the inflammatory bowel disease and irritable bowel syndrome groups.

    “Mean baseline symptom severity scores were similar in the 2 groups (IBD: 2.06 ± 0.03, IBS: 2.12 ± 0.04; P = 0.15).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 21
  • May combine two claims. 26
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Age differed slightly statistically but was clinically similar between the inflammatory bowel disease and irritable bowel syndrome groups.

    “Although age was slightly different statistically, it was clinically similar.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Sex distributions were not significantly different between the inflammatory bowel disease and irritable bowel syndrome groups.

    “Sex distributions were not significantly different between the 2 groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tricyclic antidepressant frequency and median dose were similar in both groups, and nortriptyline was favored over amitriptyline and desipramine.

    “The frequency and median dose of TCA use was similar in both the groups; nortriptyline was favored over amitriptyline and desipramine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The most frequent symptom reported was abdominal pain in both groups.

    “The most frequent symptom reported was abdominal pain in the 2 groups (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean response scores after tricyclic antidepressant treatment were similar in the inflammatory bowel disease and irritable bowel syndrome groups, indicating modest symptom improvement in both.

    “Mean response scores following treatment using the Likert response scale were also similar (IBD: 1.46 ± 0.09, IBS 1.30 ± 0.09 in IBD, P = 0.2), indicating modest symptom improvement in both the cohorts (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overall, 52% of inflammatory bowel disease patients and 62% of irritable bowel syndrome patients had at least moderate improvement over their symptom level at first follow-up.

    “Overall, 52% of IBD and 62% of IBS patients had at least a moderate improvement (score 2 or 3) over the level of symptoms at first follow-up (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the entire study population, functional diagnoses predicted poorer response to tricyclic antidepressants, whereas mood disturbance diagnoses did not affect therapeutic response.

    “Similarly, in our entire study population, functional diagnoses predicted poorer response to TCA therapy, whereas a mood disturbance diagnoses did not affect the therapeutic response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In multivariable logistic regression, ulcerative colitis patients responded significantly better than Crohn's disease patients, while abdominal pain and a comorbid functional diagnosis were associated with a lower likelihood of response.

    “UC patients responded significantly better than CD patients; presence of abdominal pain and presence of a comorbid functional diagnosis were associated with a significantly lower likelihood of response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At the second visit, 56% of Crohn's disease patients and 40% of ulcerative colitis patients had at least a further moderate symptom response.

    “At the second visit, 56% of CD group and 40% of UC group had at least a further moderate symptom response, P = 0.16.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Over two thirds of study patients had multiple follow-up visits after starting tricyclic antidepressant therapy.

    “Although by design all study patients had at least 1 follow-up visit after starting the TCA therapy, over two thirds had multiple follow-up visits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the inflammatory bowel disease subgroup multivariable analysis, only a diagnosis of ulcerative colitis was a significant predictor of treatment response; prior surgery and inflammatory bowel disease medication regimen were not significant predictors.

    “Only a diagnosis of UC was found to be a significant predictor of treatment response in this model (OR = 4.5, 95% confidence interval, 1.3-15.5, P = 0.02). Prior surgery and IBD medication regimen were not significant predictors of treatment response to TCAs in this cohort.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using the physician global assessment, 45.6% of the inflammatory bowel disease cohort were in clinical remission and the remainder had mild disease activity.

    “Using the PGA, 45.6% of the IBD cohort (51.7% CD, 34.8% UC, P = 0.17) were in clinical remission and the remainder had mild disease activity (Table 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Nausea and constipation were more prevalent in irritable bowel syndrome patients, and diarrhea was also more prevalent in irritable bowel syndrome patients.

    “Nausea and constipation were more prevalent in IBS patients, whereas diarrhea was more prevalent in IBS patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the first visit, 59.3% of inflammatory bowel disease patients and 46.0% of irritable bowel syndrome patients showed at least a moderate symptom response to tricyclic antidepressant therapy.

    “Upon further analysis of response, 59.3% of the IBD and 46.0% of the IBS patients showed at least a moderate symptom response (score ≥ 2) to TCA therapy at the first visit.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In that Australian service, the most common reason for antidepressant prescription was depression or anxiety, with very few prescribed for somatic complaints.

    “The most common reason for this prescription was depression or anxiety, with very few prescribed for somatic complaints.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given the mechanisms of benefit, irritable bowel syndrome therapies such as tricyclic antidepressants could be a reasonable adjunctive therapy for residual symptoms in inflammatory bowel disease.

    “Given these mechanisms of benefit, IBS therapies such as TCAs could constitute a reasonable adjunctive therapy for residual symptoms in IBD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tricyclic antidepressant therapy should not worsen inflammation and may reduce inflammation, as suggested by preclinical models.

    “However, TCA therapy should not worsen inflammation and may even reduce inflammation as evidence in preclinical models suggests.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Symptoms in inflammatory bowel disease may not always be linked to structural or inflammatory findings, supported by poor correlation between pain symptoms and inflammatory bowel disease activity indices.

    “Symptoms in IBD may not always be linked to structural or inflammatory findings, which are supported by the poor correlation between pain symptoms and IBD disease activity indices.16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Among 401 inflammatory bowel disease charts reviewed, 20.2% met inclusion criteria, 34.2% were excluded for lack of a second follow-up visit, and 45.6% were excluded by other criteria.

    “Among the total number of IBD patient charts reviewed (n = 401), 20.2% met inclusion criteria (n = 81), 34.2% were excluded because of a lack of a second follow-up visit at the time of chart review (n = 137), and 45.6% were excluded according to the criteria mentioned above (n = 183).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The conclusions were based on global symptom improvement, as quantitative improvement in specific symptoms could not be tracked using this grading system.

    “Our conclusions were based on global symptom improvement, as quantitative improvement in specific symptoms could not be tracked using this grading system.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

    Study design and conductown data

    Reasons for lack of a second follow-up included side effects, lack of efficacy, symptom resolution, unstated reasons, and no further contact.

    “Reasons for lack of inclusion for a second follow-up were discontinuation of TCA because of side effects (11% of IBD patients and 1.3% of IBS patients), lack of efficacy (3.7% of IBD patients, none of IBS patients), or because of symptom resolution (2.5% of IBD patients, none of IBS patients).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Because of the retrospective design, the study could not assess patients' symptoms directly and relied on provider notes for the outcome.

    “Because of our retrospective design, we could not assess patients symptoms directly; we relied on the provider's notes for our outcome.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both mood disorders and non-gastrointestinal functional diagnoses are common in irritable bowel syndrome patients.

    “Both mood disorders and non-GI functional diagnoses are common in IBS patients.27,28”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27]

      Not checked in the free run.

    • cites [28]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Occult inflammation represents another mechanistic explanation for residual symptoms in inflammatory bowel disease patients without structural abnormalities.

    “Occult inflammation represents another mechanistic explanation for residual symptoms in IBD patients without structural abnormalities.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Small-bowel involvement in Crohn's disease patients may have led to inflammation or mild structural abnormalities that routine testing did not detect.

    “Small-bowel involvement in CD patients may have led to inflammation or even mild structural abnormalities that were not detected by routine testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Irritable bowel syndrome occurs in approximately 10% to 15% of adults in North America.

    “IBS occurs in approximately10% to 15% of adults in North America.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    There is a need for agents to address residual symptoms in patients who do not require or are not candidates for further escalation of immunosuppression.

    “There is a need for agents to address these symptoms in patients who do not require, or are not candidates for, further escalation of immunosuppression.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Differences in tricyclic antidepressant choice, dosing variety, patient follow-up intervals, and available testing are inherent to this retrospective study.

    “Differences in TCA choice, dosing variety, patient follow-up intervals, and available testing are inherent to this retrospective study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Global improvement mechanisms may explain why the presence of pain was not a significant independent predictor of response to tricyclic antidepressants in the model.

    “We postulate that global improvement mechanisms may explain why the presence of pain in our study was not a significant independent predictor of response to TCA in our model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In this study, two trained physicians performed separate blinded grading of baseline symptoms and treatment response, yielding high interobserver agreement.

    “In this study, 2 trained physicians (H.N.I. and B.C.) performed separate blinded grading of baseline symptoms and treatment response, yielding high interobserver agreement with a κ = 0.79 for the baseline symptom severity score and a κ = 0.83 for the treatment response score.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a retrospective study of ulcerative colitis patients, 50% experienced pain, with coexisting mood disorders and female sex identified as significant predictors of pain, similar to functional bowel disorders.

    “In a retrospective study of UC patients, 50% of patients experienced pain, with coexisting mood disorders and female sex identified as significant predictors of pain, similar to functional bowel disorders.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The grading system includes subjective elements, but high interobserver agreement was seen in this study and others.

    “The grading system we used includes some subjective elements; however, high interobserver agreement was seen in our study and others.15,17,19”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15]

      Not checked in the free run.

    • cites [17]

      Not checked in the free run.

    • cites [19]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A study of inflammatory bowel disease patients in clinical remission found that Rome II symptoms correlated with increased calprotectin, suggesting that occult inflammation may drive symptoms.

    “A study evaluating IBD patients in clinical remission noted that Rome II symptoms correlated with increased calprotectin suggesting that occult inflammation may be driving these symptoms.3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These comorbidities are implicated in poorer response to therapy in irritable bowel syndrome patients and predict premature discontinuation of antidepressant therapies.

    “These comorbidities are implicated in poorer response to therapy in IBS patients and predict premature discontinuation of antidepressant therapies.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mood disorders are found more frequently in patients with inflammatory bowel disease than in the general population in several epidemiologic studies.

    “Furthermore, mood disorders are found more frequently in patients with IBD in several epidemiologic studies, when compared with the general population.29–31”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29]

      Not checked in the free run.

    • cites [30]

      Not checked in the free run.

    • cites [31]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The study relied on the physician global assessment, ensuring categorization was not restricted by test performance or findings; guidelines stress the importance of this global assessment, which correlates with Crohn's disease activity index scores.

    “As for disease severity, we relied on the PGA, ensuring that categorization was not restricted by the performance of, or specific findings on tests; nevertheless, guidelines for CD management stress the importance of this global assessment, which correlates with CD activity index scores.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Patient expectation of tertiary center physician recommendations could have increased the likelihood of a positive response.

    “However, patient expectation of tertiary center physician recommendations could have increased the likelihood of positive response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    This is a low-risk/high-benefit intervention in the right patient because tricyclic antidepressant effects can improve symptoms but are unlikely to mask a true inflammatory bowel disease flare.

    “We propose that this is a low-risk/high-benefit intervention in the right patient as TCA effects can improve symptoms but are unlikely to mask a true IBD flare.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study is strengthened by the presence of a control group of irritable bowel syndrome patients.

    “however, the study is strengthened by the presence of a control group of IBS patients.”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    Some clinicians use tricyclic antidepressants to treat residual symptoms in inflammatory bowel disease patients who are already on adequate inflammatory bowel disease therapy or who have quiescent inflammation, although this strategy has not been formally studied.

    “Some clinicians use TCAs to treat residual symptoms in inflammatory bowel disease (IBD) patients already on decisive IBD therapy or with quiescent inflammation, although this strategy has not been formally studied.”

  • The paper relies on this without support.

    Diarrhea and pain-predominant symptoms often remain in treated inflammatory bowel disease patients, and these features also make up the symptom profiles of irritable bowel syndrome patients who benefit from tricyclic antidepressant therapy.

    “Diarrhea and pain-predominant symptoms often remain in treated IBD patients; these same features also comprise the symptom profiles of IBS patients who benefit from TCA therapy.”

  • The paper relies on this without support.

    The authors have observed experiential success using tricyclic antidepressants to treat residual symptoms in inflammatory bowel disease patients at their institution.

    “In our institution, we have observed experiential success in using TCAs to treat this type of residual symptoms in IBD patients.”
3 of 3

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abdominal pain is described as both significant and nonsignificant

    Major

    The results say abdominal pain was significantly associated with a lower likelihood of response, but the discussion says it was not a significant independent predictor in the model.

  • Reported response-score errors cannot be SEMs

    Minor

    The paper says continuous variables are reported as mean ± SEM, yet it gives errors of 1.37 and 1.33 for group means on a response scale limited to 0-3. With groups of patients, SEMs that large are impossible on that scale.

2 of 2

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Authors
Iskandar, H. N., Cassell, B., Kanuri, N., Gyawali, C. P., Gutierrez, A., Dassopoulos, T., Ciorba, M. A., & Sayuk, G. S.
Affiliations
  • Emory University (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Iskandar, Heba N.
  • Cassell, Benjamin
  • Kanuri, Navya
  • Gyawali, C. Prakash
  • Gutierrez, Alexandra
  • Dassopoulos, Themistocles
  • Ciorba, Matthew A.
  • Sayuk, Gregory S.
ORCID
Venue
Journal of Clinical Gastroenterology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-05
Volume
48
Issue
5
Pages
423-429
ISSN
0192-0790 (ISSN-L)
DOI
10.1097/mcg.0000000000000049
PMC
PMC4111227
OpenAlex
W2021012097
Cited by
96
References
35
Citations by year
2026: 6 · 2025: 9 · 2024: 10 · 2023: 7 · 2022: 10 · 2021: 7 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 6 · 2014: 4
FWCI
6.11
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000448)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K08DK089016, K23DK084113, T32DK007130, P30DK052574)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Health Sciences › Medicine › Epidemiology › Microscopic Colitis
Keywords
tricyclic antidepressants, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, symptom response, antidepressant efficacy, symptom severity
MeSH terms
Adult, Antidepressive Agents, Tricyclic, Colitis, Ulcerative, Crohn Disease, Female, Humans, Male, Middle Aged, Retrospective Studies, Severity of Illness Index, Cohort Studies, Treatment Outcome, Irritable Bowel Syndrome

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