antidepressants in irritable bowel syndrome l.
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Antidepressants in Irritable Bowel Syndrome. Alan Chiemprabha, M.D. Case Presentation. Mrs X is a 44 y.o.w.f with a PMHx significant for htn, tobacco abuse, anxiety, hyperlipidemia who presented to the OPD Medicine Clinic to establish a new PCP.

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case presentation
Case Presentation
  • Mrs X is a 44 y.o.w.f with a PMHx significant for htn, tobacco abuse, anxiety, hyperlipidemia who presented to the OPD Medicine Clinic to establish a new PCP.
  • The patient has not seen a physician for several years and presents now because of worsening chronic, intermittent lower abdominal pain associated with three loose bowel movements each day for the last two months.
  • Fam Hx - negative for early CADz, cancer, gi dz
  • Soc HX - 1 ppd tob, no etoh, divorced, lives with 2 sons
  • Meds - xanax prn
  • ROS - poor sleep, depressed mood, occ crying spells, no weight loss/early satiety/bloody or melanotic stools/fevers/night sweats/night time abd pain/suicidal ideation.
  • Exam - normal vitals, mildly obese, unremarkable heent, cv, chest, abd, ext, pelvic, breast, rectal (heme -)
irritable bowel syndrome
A chronic noninflammatory disease characterized by abdominal pain, altered bowel habits consisting of diarrhea, constipation or both, bloating and disturbed defecation associated with significant disability and health care costs.

More strict definitions include:

Manning Criteria Rome Criteria

Mild IBS (70%) - cared for by pcp; little or no functional impairment

Moderate IBS (25%) - exacerbations disrupt daily activities

Severe IBS (5%) - severe, unrelenting pain associated with

Irritable Bowel Syndrome
manning criteria
Manning criteria
  • Originally 15 symptoms were thought to be typical of IBS - 6 were found to be significantly more common in IBS.
  • Abdominal pain relieved by defecation
  • Looser stools with onset of pain
  • More frequent stools with onset of pain
  • Abdominal distention
  • Passage of mucus
  • Sensation of incomplete evacuation
rome criteria
Rome Criteria
  • At least 3 weeks of continuous or recurrent symptoms of the following in the preceding 3 months:
  • Abdominal pain or discomfort relieved with defecation, or associated with a change in frequency of stool, or associated with a change in consistency of stool
  • Two or more of the following, at least on one fourth of the occasions or days: altered stool: frequency, form, passage, passage of mucous, or bloating or feeling of abdominal distention
epidemiology health care burden
affects 5-12% men

affects 13-19% women

U.S. incidence rate in non-whites unclear

half present between the ages of 30 and 50

decreasing prevalence with increasing age (>60)

symptoms wax and wane

accounts for 3 million physician visits per year in the U.S.

accounts for 12 percent of primary care visits and 25-50 percent of gastroenterology referrals

IBS patients miss more work, utilize health care services more frequently, and incur higher healthcare costs on a yearly basis (primarily around the index year)

Epidemiology/Health Care Burden
  • Abnormal motility - no consensus; persons with IBS have increased motility in response to environmental or enteric stimuli.
  • Enhanced visceral sensitivity - to painful distentions, to normal intestinal function, increased somatic referral.
  • CNS Modulation - the brain-gut axis; link of higher cortical…visceral afferents…and visceral motor.
  • Psychosocial dysfunction - increased frequency of psychiatric diagnoses and abuse history in IBS patients.
  • Make a positive symptomatic diagnosis using the the Rome Criteria + absence of Red Flags/Alarm Sx
  • Talley et al.2 Manning criteria: sensitivity 58%; specificity 74% in discriminating IBS from organic gi disease. Manning criteria - less useful in clinical settings but is still useful in epidemiologic studies.
  • Vanner et al.1 Rome Criteria + absence of Red Flags: sensitivity 63%; specificity 100%. Validated in long-term outcome studies by Owens et al.20
  • Perform routine diagnostic studies and risk stratify the patient for organic disease to determine of additional diagnostic studies are needed.
diagnosis cont d red flags


Weight Loss

Progressive Pain

Awakening Pain

Sleeplessness secondary to pain

Abnormal physical exam

Large Volume Diarrhea

Bloody Stools

Nocturnal Diarrhea

Greasy Stools

Diagnosis cont’d: Red Flags
diagnosis cont d
Diagnosis cont’d
  • Initial diagnostics should include: CBC, Chemistry panel, LFT’s
  • Consider further diagnostics if symptoms persist despite the general treatment protocol.
  • For diarrhea-predominant subtypes: stool for quantitative volume, O&P, enteric pathogens, fecal fat, leukocytes, TSH, sigmoidoscopy and biopsy, small bowel biopsy.
  • For constipation-predominant subtypes: colonic transit studies to (verify presence and degree of constipation) and anorectal manometry.
general treatment approach
General Treatment Approach
  • 1. Good Patient-Physician Relationship
  • 2. Continued Education and Reassurance
  • 3. Dietary Modification
  • 4. Symptom Monitoring by Patient - mod
  • 5. Symptom Targeted Pharmacotherapy - mod
  • 6. Psychological Therapy - mod to sev
  • 7. Psychotropic Pharmacotherapy - mod to sev
  • 8. 5 HT 3 Antagonists and Newer Agents - mod to sev
symptom targeted pharmacotherapy
Symptom-Targeted Pharmacotherapy
  • For predominant Abdominal Pain and Bloating: levsin (an anticholinergic, hyoscyamine 0.125 mg tid), bentyl (an anticholinergic, dicyclomine 10-20 mg tid) and mebeverine (in Europe) to decrease sigmoid motility in response to meals.
  • For predominant Diarrhea: prn kaopectate and imodium (an opiod, loperamide 2-4mg tid)
  • For predominant Constipation: increase dietary fiber, metamucil (psyllium product), prn laxatives and stool softeners (avoid chronic use of stimulant laxatives).
psychological therapy
Psychological Therapy
  • Psychological therapy including: 1. Cognitive-behavioral treatment 2. Insight-oriented therapy 3. Relaxation/stress management treatment
  • Psychological therapy has been shown in RCT’s to reduce anxiety and decrease GI symptoms, mainly abdominal pain and diarrhea.
  • It seems to be most effective in those patients who relate their exacerbations of IBS to stressors, have typical IBS sx as opposed to chronic pain, and < 50 y.o.
heefner et al 10 methods
Heefner et al.10 - Methods
  • Drug: Desipramine 150mg qhs 2 months
  • Methods: Double, Blind, Placebo Controlled, RCT
  • 44 pts with IBS randomized into 2 groups of 22, one receiving drug, the other placebo. Treatment lasted 2 mo.
  • Outcome measures: Patient-rated symptom scale for (0-3) depression, abdominal pain, bowel movement irregularities, interference with daily life, and the Zung-self rated depression scale.
heefner et al 10 results
Heefner et al.10 - Results
  • 14/22 taking drug completed the study, 17/22 taking placebo completed the study (31/44).
  • Similar improvements in both drug and placebo groups for patient-rated depression, abdominal pain, and bowel movements.
  • Trend towards statistical significance in the Zung Self-Rating Depression Scale in pre and post drug group (not comparing drug to placebo).
  • Statistically sig improvement interference with daily life (p<0.05).
heefner et al 10 conclusions
Heefner et al.10 - Conclusions
  • Desipramine 150 mg qhs helps to significantly improve patient- perceived IBS-interference with daily life when compared to placebo but is not significantly different from placebo with regard to other patient-perceived symptoms of IBS.
steinhart et al 11 methods
Steinhart et al.11 - Methods
  • Drug: Amitriptyline 50mg qhs 4 weeks
  • Double-blind, placebo-controlled, cross-over, RCT
  • 14 pts with IBS were randomized to 2 groups one beginning with Amitrip 50mg qhs, the other with placebo, and crossed over to the other treatment after a 2 wk washout period. Each treatment lasted 4 wks.
  • Outcome Measures: Pts and interviewers rated pt IBS severity on a 4 point scale (I-IV) 5 times during the study with these daily measures summed at the end of the study.
steinhart et al 11 results
Steinhart et al.11 - Results
  • Trend towards statistical significance (p=0.08) in the sum of daily symptom severity ratings when comparing drug to placebo.
  • Statistically significant improvement in the drug group when comparing the pretest daily symptom ratings and that of the group receiving the drug.
steinhart et al 11 conclusions
Steinhart et al.11 - Conclusions
  • Treatment with Amitriptyline 50mg qhs showed a significant improvement (p=.0035) in the sum of daily symptom severity ratings when comparing the drug pretest group to the drug group but only a trend towards statistically significant improvement (p=0.08) in sums of daily symptom ratings when compared to placebo.
myren et al 1982 12 methods
Myren et al. 1982 12 - Methods
  • Drug: Trimipramine 50mg qd 4 weeks
  • Double-blind, placebo-controlled, RCT
  • 61 patients with IBS; 1 week washout then randomized to trimipramine or placebo for 4 weeks.
  • Outcome measures: Patient-rated scores registered by a physician on a 10cm analog scale before and after 28 days of treatment for obstruction, nausea, vomiting, belching, headache, sleeplessness, tiredness, anxiety, and depression.
myren et al 1982 12 results
Myren et al. 1982 12 - Results
  • Significant reductions in complaint scores were seen for both trimipramine and placebo.
  • Statistically significant reduction in mucus in stool when comparing trimipramine pre-treatment to post-treatment (p<0.003).
  • “Significantly Higher” reductions in scores for vomiting, sleeplessness, and depression in the trimipramine group (no p value given).
  • No statistically significant differences given to distinguish trimipramine from placebo.
myren et al 1982 12 conclusions
Myren et al. 1982 12 - Conclusions
  • Trimipramine 50mg qd significantly decreases mucus in stools when compared to pretreatment.
  • Otherwise, trimipramine is not significantly different from placebo for obstruction, nausea, vomiting, belching, headache, sleeplessness, tiredness, anxiety, and depression.
myren et al 1984 13 methods
Myren et al. 1984 13 - Methods
  • Drug: Trimipramine 50mg qhs (A), 10mg qam + 40 mg qhs (B), 35 mg qhs (C), or 10 mg tid for 6 weeks (D), or placebo (E).
  • Double-blind, placebo-controlled, RCT
  • 428 pts randomized to five different groups (A-E) to one of the above dosings of trimipramine or placebo for 6 weeks.
  • Outcome measures: Pt-rated (1x/week) and physician-rated (before and at end of study) 10cm analog scale for abdominal pain, oppression, nausea, vomiting, acid eructions, headache, sleeplessness, tiredness, anxiety, depression, and mucus and blood in stool.
myren et al 1984 13 results
Myren et al. 1984 13 - Results
  • Treatment groups A, B, and C had statistically significant reductions in analog scale values of abdominal pain, acid eructions, and nausea (A and B, p<0.010; C, p<0.05). A statistically significant improvement in the degree of depression (A-D) (p<0.01) and in “total effect of treatments” (p<0.05) occurred in the trimipramine groups when compared to placebo. No statistically significant differences were observed between the groups receiving different doses of trimipramine.
myren et al 1984 13 conclusions
Myren et al. 1984 13 - Conclusions
  • Trimipramine at doses of 35 mg qhs - 50 mg qhs for 6 weeks is significantly better than placebo at improving some IBS symptoms (abdominal pain, acid eructions, and nausea) (A and B, p<0.01; C, p<0.05).
  • Trimipramine at all study doses is significantly better than placebo in treating degree of depression scores (p<0.01) and “total effect of treatments” (p<0.05).
greenbaum et al 14 methods
Greenbaum et al.14 - Methods
  • Drugs: Desipramine titrated to 150mg qhs and atropine titrated to 1.2 mg qhs
  • Double-blind, placebo-controlled, cross-over RCT
  • 41 pts with IBS underwent a 4wk observation period followed by three 6 week test periods during which pts randomly assigned to receive one of the six possible sequences of the test agents.
greenbaum et al 14 methods cont d
Greenbaum et al.14 - Methods Cont’d
  • Variables assessed biweekly with questionnaires were the following: # of bm’s/week, # of loose bm’s/week, pain index (0-6 scale), constipation (0-4 scale), diarrhea (0-4 scale), retrospective global assessment, desipramine levels.
  • Also, before the study and at the end of each test period pts were evaluated by two psychologists using the Hamilton Depression Rating Scale (to follow changes in depressive sx) and the Brief Psychiatric Rating Scale (to follow mental status).
greenbaum et al 14 results
Greenbaum et al.14 - Results
  • 28 of 41 pts completed the study. 19 were diarrhea-predominant, 9 were constipation-predominant.
  • Diarrhea-predominant subgroup had a statistically significant reduction in the number of stools per week (p<0.02), pain index (p<0.0025), diarrhea (p<0.005), and (in the total group) improvement in the mean Brief Psychiatric Rating Scale compared to placebo (p<0.02). No differences in the # of loose stools/wk and HDRS.
  • Appeared to be a greater benefit in Retrospective Global Improvement with Desipramine (p=?).
greenbaum et al 14 conclusions
Greenbaum et al.14 - Conclusions
  • Desipramine titrated to 150mg qhs over a 6 week period is significantly better than placebo in the diarrhea-predominant subgroup at improving some IBS symptoms (pain, #stools/wk, diarrhea).
  • Appeared to have a greater beneficial effect on pt’s perception of global improvement.
  • There was no statistically significant difference between desipramine and placebo in depressive symptoms.
greenbaum et al 14 conclusions cont d
Greenbaum et al.14 - Conclusions cont’d
  • In constipation-predominant pts the effect was unclear given the small N.
  • This study contrasts the results by Heefner et al. In which desipramine did not show a statistical difference in depressive sx, pain, and bm’s
tanum and malt 15 methods
Tanum and Malt 15 - Methods
  • Drug: Mianserin titrated up to 120mg in 7wks then tapered to no pills by the end of the 8th week
  • 47 patients with FGD (functional gastrointestinal disorder including 60% IBS and 40% NUD) were left for randomization to drug and placebo groups after excluding for organic gi dz, renal, hepatic, respiratory, endocrine, rheumatic, cardiovascular, cerebrovascular, or psychiatric dz (including dementia, sz do, schizophrenia, mood/affective do, anxiety do, alc/drug abuse) and after a 1 wk washout period and 1wk single-blind placebo run-in period to exclude early placebo responders.
tanum and malt 15 methods cont d
Tanum and Malt 15 - Methods cont’d
  • Outcome Measures: Pts were assessed weekly the first 2 weeks then biweekly thereafter using 3 instruments:
  • 1. CGI - clinical global impression to assess changes in abdominal pain (7 to 1) in pts; performed by the primary investigator.
  • 2. VAS - visual analog scale; patient-rated pain (VAS-Pain) and 2 target symptoms associated with the abdominal pain (VAS-TSR1&2).
  • 3. DISS - Disability scale used to assess change in functional disability (0-10) for work, social, and family life.
tanum and malt 15 results
Tanum and Malt 15 - Results
  • 45/47 pts completed the study. Statistically significant improvements were seen for the mianserin group for all outcome variables (CGI, VAS-Pain, VAS-TSR, and DISS) at almost all time intervals.
  • For the placebo-treated patients the CGI, VAS-Pain, VAS-TSR, and DISS assessments remained almost unchanged from baseline.
  • There was no significant difference in response to treatment between IBS and NUD pts.
tanum and malt 15 conclusions
Tanum and Malt 15 - Conclusions
  • Mianserin titrated to a dose of 120 mg qd in this study population showed a statistically significant improvement for all outcome variables at almost all time intervals for pain severity, pain symptoms, and measures of disability.
jackson et al 9 methods
Jackson et al.9 - Methods
  • Meta-Analysis of Functional Gastrointestinal Disorders (IBS and NUD)
  • Search of:
  • Medline (1966 to December 1998)
  • PsycLit (1974 to December 1998), and
  • EMBASE (1974 to December 1998)
  • Cochrane Library and Database
  • Federal Research in Progress
jackson et al 9 methods cont d
Jackson et al.9 - Methods cont’d
  • Studies were screened for inclusion based on: randomization, placebo control, at least one group receiving an antidepressant, and measurable outcomes reported.
  • Studies were assessed for publication bias and heterogeneity.
  • 11 trials met all inclusion and exclusion criteria (8 for IBS and 3 for NUD)
jackson et al 9 results
Jackson et al.9 - Results
  • For dichotomous outcome variables abdominal pain improvement or “response to treatment” the
  • Odds Ratio with therapy is 4.2
  • Pooled Risk Difference is .32
  • NNT 3.2
  • For continuous outcome data since the studies did not use a common pain scale, pain scores were transformed to a standard meaure with antidepressant medication associated with an improvement of 0.9 SD units.
  • No publication bias found for either variable.
jackson et al 9 conclusions
Jackson et al.9 - Conclusions
  • Antidepressants reduce symptoms in Functional Gastrointestinal Disorder (both IBS and NUD).
  • For the dichotomous outcome of improvement in pain/symptoms the Odds Ratio = 4.2
  • For the continuous outcome variable of abdominal pain scores a quantitative measure: the mean improvement or standardized mean difference for those receiving treatment compared to those not receiving treatment was 0.9 SD.
  • However...
adverse events
Adverse Events
  • Heefner et al.- 3/8 drug, 1/5 placebo experienced -nausea, dizziness, palpitations, or pvc’s
  • Steinhart et al. - not discussed
  • Myren et al. 1982 - not discussed
  • Myren et al. 1984 - tiredness had trend towards statistical significance at 2 wks; not significant by end of study
  • Greenbaum et al. - 9 pts with anxiety, tremulousness, palpitations, sweating, xerostomia, and constipation. Dose reductions alleviated 6, 3 dropped from study.
  • Tanum et al. - 2 pts dropped out because of persistent sedation, vertigo, and “inner tension.”
take home points
Take Home Points
  • Heefner et al. - desipramine helps with patient perceived quality of life but not with other IBS sx.
  • Steinhart et al. - amitriptyline shows a trend towards statistical significance with the sum of daily symptom severity ratings.
  • Myren et al. ‘82 - trimipramine has no clear benefit over placebo with regard to IBS sx with exception of mucus in stool.
  • Myren et al. ‘84 - trimipramine is significantly better than placebo at treating abdominal pain, acid eructions, nausea, depressive sx, and total effect of treatments.
take home points50
Take Home Points
  • Greenbaum et al. - Desipramine is significantly better than placebo at improving abdominal pain, # of stools/wk, and diarrhea.
  • Tanum et al. - Mianserin is significantly better than placebo at improving abdominal pain, symptoms associated with abdominal pain, and functional disability in a particular population of IBS pts.
  • Jackson et al. - Antidepressants appear to be useful in IBS for improvement in pain/symptoms and appear to improve pain to a significant degree
take home points statistically significant symptom improvement by study
Take Home Points - statistically significant symptom improvement by study
  • Abdominal Pain -Myren 1984, Greenbaum, Tanum, Jackson
  • quality of life measures- Heefner, Steinhart (symptom severity scale included ibs affects on work), Myren 1984, Tanum
  • # of stools - Greenbaum
  • # of loose stools - none
  • diarrhea - Greenbaum
  • depressive symptoms - Myren 1984, for other either not significantly different from placebo or was not assessed.
take home points52
Take Home Points
  • Make a positive symptomatic diagnosis of Irritable Bowel Syndrome using the Rome Criteria and the absence of Red Flags/Alarm Symptoms to avoid unnecessary diagnostic workup.
  • Pursue additional diagnostic workup if warranted based upon risk stratification, or if the patient develops alarm symptoms.
  • Initiate the general treatment approach for IBS patients and reassess in 3-6 weeks. 1. Phys-Pat relationship 2. Education and Reassurance. 3. Dietary Modification 4. Symptom monitoring by patient. 5. Symptom-Targeted Pharmacotherapy.
take home points53
Take Home Points
  • Drossman et al. 22 states that “prescription medication is not routine recommended because
  • 1. IBS is a chronic disorder.
  • 2. Most drugs have side effects….and
  • 3. An initial placebo effect may influence patients to continue drugs indefinitely even if they are not effective. However, if a symptom exacerbation is distressing enough or impairs daily function, a drug targeted at that symptom can be prescribed for a limited time.”
take home points54
Take Home Points
  • If the patient has IBS refractory to the general treatment measures, then the pt likely has severe IBS.
  • Screen the patient for psychosocial stressors, depression, and history of sexual/physical abuse. If the patient has any of the above, aid the patient with maximizing social support systems. Consider referral to psychiatry or psychology for psychological therapies. If the patient has minor depression or IBS symptoms with predominant abdominal pain, consider the addition of an antidepressant. If a patient has major depression, treat their depression.
  • For severe IBS, consider referral to a pain control program and frequent follow-up with set time limits.
take home points55
Take Home Points
  • Much of the best available evidence for antidepressants to treat IBS is from the 1980’s.
  • Although the evidence for the use of antidepressants in IBS is not conclusive, evidence suggests a role for antidepressants for certain symptoms in IBS: abdominal pain, impaired quality of life/impaired daily function, and depressive symptoms (With the suggestion by Greenbaum’s study that antidepressants are more helpful in the diarrhea-predominant).
  • Other than case reports, there is no significant evidence supporting the use of SSRI antidepressants in IBS.
take home points56
Take Home Points
  • Based on the best available evidence, antidepressant therapy should likely be limited to those IBS patients with abdominal pain refractory to general treatment measures, impaired functional status secondary to their disease, and those IBS patients with major depression.
  • Treatment with antidepressants should be continued for at least 4-6 weeks and continued for 3-12 months. If the patient does not respond to treatment it should be discontinued, and consider a trial with a different med. If the patient responds, it should be tapered to the lowest effective dose.
take home points57
Take Home Points
  • Further placebo-controlled, double-blinded, RCT’s need to be performed with larger numbers, longer durations of therapy, and with better blinding to further assess the utility of antidepressants in IBS.
  • Given their lower side-effect profile and antiserotinergic properties it would be interesting to see if SSRI’s could prove useful in treating IBS symptoms.
case presentation58
Case Presentation
  • Upon completion of the physical exam, I asked the patient if she felt depressed. She answered,”Yes, lately.” I asked her why she felt depressed, and she burst into tears revealing that she had been raped twice, once when she was a teenager and once about ten years ago.
  • After counseling the patient on rape support groups, I started the patient on an antidepressant and referred the patient to psychiatry for additional counseling/psychotherapy. The patient’s antidepressant was titrated by psychiatry and the patient has a much improved mood and minimal IBS sx for 1 year.
closing remarks
Closing Remarks
  • The physician selected could not have been more to his (Simon Bolivar’s) liking. Hercules Gastelbondo was an immense, placid old man, anointed with contentment, whose skull was radiant with total baldness and who possessed the patience of a drowned man, which in itself alleviated the suffering of others…He prescribed chocolate cream with melted cheese for disturbances of the bile, he advised lovemaking during the languors of digestion…and he smoked endless wagon driver’s cigars, which he rolled with rag paper and prescribed to his patients for all sorts of equivocations of the body. The patients themselves said he never effected a complete cure but entertained them instead with his florid eloquence. He would break into plebeian laughter.
  • ‘Other doctors lose as many patients as I do,’ he would say. ‘But with me, they die happier.’”
  • The General in His Labyrinth. Alfred A. Knopf, 1990, p214-215.
alan sandwich hug from my niece and nephew on my birthday
“Alan Sandwich Hug” from my niece and nephew on my birthday
  • Special thanks to:
  • Joel Bruggen, M.D.
  • Amanda Ebright, M.D.