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Citalopram Provides Little or No Benefit in Nondepressed Patients With Irritable Bowel Syndrome

Published:September 18, 2009DOI:https://doi.org/10.1016/j.cgh.2009.09.008

      Background & Aims

      Data on the benefit of selective serotonin reuptake inhibitors (SSRIs) in irritable bowel syndrome (IBS) are conflicting. The longitudinal relationship between clinical symptoms and sensitivity to barostat-mediated rectal distension in IBS remains unclear. We assessed the benefit of citalopram and explored the relationships between symptoms, quality of life (QOL), and rectal sensitivity to barostat distension in non-depressed IBS patients.

      Methods

      Patients from primary, secondary, and tertiary care settings were randomly assigned to receive citalopram (20 mg/day for 4 weeks, then 40 mg/day for 4 weeks) or placebo in a study with double-masking and concealed allocation. Symptoms were assessed weekly, and IBS-QOL and rectal sensation by barostat were assessed at the beginning and end of the study.

      Results

      Patients receiving citalopram did not achieve a higher rate of adequate relief of IBS symptoms than patients receiving placebo (12/27 [44%] vs 15/27 [56%]; P = .59), regardless of IBS subtype. The odds ratio for weekly response with citalopram vs placebo was 0.80 (95% confidence interval, 0.61–1.04). Improvements in specific symptom and IBS-QOL scores were not superior for citalopram. Changes in IBS-QOL score and pressure eliciting pain showed a modest correlation (r = 0.33; 95% confidence interval, 0.03–0.57), but changes in symptoms and IBS-QOL scores or rectal sensitivity were not correlated substantially.

      Conclusions

      Citalopram was not superior to placebo in treating non-depressed IBS patients. Changes in symptoms were not substantially correlated with changes in rectal sensation assessed by barostat. Any benefit of citalopram in non-depressed IBS patients is likely to be modest at best.

      Abbreviations used in this paper:

      CI (confidence interval), CONSORT (Consolidated Standards of Reporting Trials), IBS (irritable bowel syndrome), QOL (quality of life), SD (standard deviation), SSRI (selective serotonin reuptake inhibitor)
      Irritable bowel syndrome (IBS) is a classic functional gastrointestinal disorder characterized by abdominal pain and altered defecation that is responsible for significant morbidity, decrement in quality of life, and burden of disease.
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      No therapy for IBS has an excellent response rate.
      • Brandt L.J.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • et al.
      An evidence-based systematic review on the management of irritable bowel syndrome.
      The pathophysiology of IBS is believed to involve alterations in gastrointestinal motility and sensation and in brain-gut interactions.
      • Drossman D.A.
      • Camilleri M.
      • Mayer E.A.
      • et al.
      AGA technical review on irritable bowel syndrome.
      Antidepressants often are used to treat functional gastrointestinal disorders and other chronic pain syndromes.
      • Brandt L.J.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • et al.
      An evidence-based systematic review on the management of irritable bowel syndrome.
      • Clouse R.E.
      • Lustman P.J.
      • Geisman R.A.
      • et al.
      Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience.
      • Jackson J.L.
      • O'Malley P.G.
      • Tomkins G.
      • et al.
      Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis.
      • Ford A.C.
      • Talley N.J.
      • Schoenfeld P.S.
      • et al.
      Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.
      • Verdu B.
      • Decosterd I.
      • Buclin T.
      • et al.
      Antidepressants for the treatment of chronic pain.
      Tricyclic antidepressants have been studied more thoroughly than the selective serotonin reuptake inhibitors (SSRIs) for the treatment of IBS.
      • Ford A.C.
      • Talley N.J.
      • Schoenfeld P.S.
      • et al.
      Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.
      • Drossman D.A.
      • Toner B.B.
      • Whitehead W.E.
      • et al.
      Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.
      Data on the effect of SSRIs in IBS are mixed.
      • Kuiken S.D.
      • Tytgat G.N.
      • Boeckxstaens G.E.
      The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.
      • Tabas G.
      • Beaves M.
      • Wang J.
      • et al.
      Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial.
      • Vahedi H.
      • Merat S.
      • Rashidioon A.
      • et al.
      The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study.
      • Tack J.
      • Broekaert D.
      • Fischler B.
      • et al.
      A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome.
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      Depression, anxiety, and other psychiatric diagnoses are prevalent in persons with functional gastrointestinal disorders.
      • Whitehead W.E.
      • Palsson O.
      • Jones K.R.
      Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?.
      The effect of antidepressants in functional gastrointestinal disorders does not appear to be explained by treatment of depression.
      Visceral hypersensitivity can be shown in laboratory studies in a significant fraction of patients with IBS and other functional gastrointestinal disorders.
      • Mertz H.
      • Naliboff B.
      • Munakata J.
      • et al.
      Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
      • Azpiroz F.
      • Bouin M.
      • Camilleri M.
      • et al.
      Mechanisms of hypersensitivity in IBS and functional disorders.
      • Camilleri M.
      Testing the sensitivity hypothesis in practice: tools and methods, assumptions and pitfalls.
      • Mayer E.A.
      • Bradesi S.
      • Chang L.
      • et al.
      Functional GI disorders: from animal models to drug development.
      Although abnormalities in visceral sensation have been proposed as contributors to symptoms, the relevance of sensitivity during experimental distension remains controversial.
      • Azpiroz F.
      • Bouin M.
      • Camilleri M.
      • et al.
      Mechanisms of hypersensitivity in IBS and functional disorders.
      • Camilleri M.
      Testing the sensitivity hypothesis in practice: tools and methods, assumptions and pitfalls.
      • Mayer E.A.
      • Bradesi S.
      • Chang L.
      • et al.
      Functional GI disorders: from animal models to drug development.
      The scant published data on the correlation between symptoms and visceral sensitivity suggest weak, if any, correlation,
      • Mertz H.
      • Naliboff B.
      • Munakata J.
      • et al.
      Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
      • Whitehead W.E.
      • Diamant N.
      • Meyer K.
      • et al.
      Pain thresholds measured by the barostat predict the severity of clinical pain in patients with irritable bowel syndrome.
      • Kuiken S.D.
      • Lindeboom R.
      • Tytgat G.N.
      • et al.
      Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome.
      • Izquierdo S.
      • Rey E.
      • Garcia Alonso M.
      • et al.
      Has the identification of rectal hypersensitivity any implication in the clinical outcome of irritable bowel syndrome?.
      • Zar S.
      • Benson M.J.
      • Kumar D.
      Rectal afferent hypersensitivity and compliance in irritable bowel syndrome: differences between diarrhoea-predominant and constipation-predominant subgroups.
      and there have been no detailed examinations of the longitudinal relationship between changes in symptoms and sensitivity to barostat-mediated distension.
      • Mayer E.A.
      • Bradesi S.
      • Chang L.
      • et al.
      Functional GI disorders: from animal models to drug development.
      We designed this study to examine the effect of the SSRI citalopram on symptoms and quality of life (QOL) in nondepressed patients with IBS. We also explored the longitudinal relationships between symptoms, QOL, and sensitivity to barostat-mediated distension.

      Materials and Methods

       General Study Design

      This prospective, randomized, placebo-controlled trial with double-masking and concealed allocation was approved by the Committee of Human Research of the University of California, San Francisco, and the Institutional Review Board of Kaiser Permanente Northern California. The trial design was guided by published recommendations
      • Drossman D.A.
      • Corazziari E.
      • Talley N.J.
      Rome II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus.
      and the Consolidated Standards of Reporting Trials (CONSORT) statement.
      • Moher D.
      • Schulz K.F.
      • Altman D.G.
      The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.
      Enrollment was open from 2001 to 2008.

       Hypotheses and Study Outcomes

      We hypothesized that citalopram treatment improves IBS symptoms in nondepressed patients with IBS more than placebo, and that changes in symptoms, QOL, and rectal sensitivity assessed by barostat are correlated significantly.
      The primary measure of response was achieving self-reported weekly “adequate relief” of IBS symptoms.
      • Mangel A.W.
      • Hahn B.A.
      • Heath A.T.
      • et al.
      Adequate relief as an endpoint in clinical trials in irritable bowel syndrome.
      • Camilleri M.
      • Chey W.Y.
      • Mayer E.A.
      • et al.
      A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome.
      • Camilleri M.
      • Northcutt A.R.
      • Kong S.
      • et al.
      Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.
      Overall response was defined as achieving adequate relief in at least 3 of the past 6 weeks. The primary measure of QOL was the change in IBS–QOL score from baseline to study end.
      • Drossman D.A.
      • Patrick D.L.
      • Whitehead W.E.
      • et al.
      Further validation of the IBS-QOL: a disease-specific quality-of-life questionnaire.
      Rectal sensitivity was measured as symptom level as a function of distending pressure. Sensation was scored on a scale of 0 to 10, where 0 equaled no inflation sensation, 1 to 5 equaled increasing painless sensation, and 6 to 10 equaled increasing pain, with 6 equaling threshold pain and 10 equaling the worst imaginable pain. Urgency was scored on a scale of 0 to 5, where 0 equaled no urgency and 1 to 5 equaled increasing urgency, with 1 equaling threshold urgency and 5 equaling the worst imaginable urgency.
      Secondary outcomes included changes in overall IBS symptom score, pain/discomfort score, number and consistency of daily bowel movements, urgency score, number of days per week with adequate relief, and satisfaction with these parameters.

       Study Participants

      Potentially eligible subjects were adult men or women ages 18 to 75 years who fulfilled the Rome II IBS criteria,
      • Drossman D.A.
      • Corazziari E.
      • Talley N.J.
      Rome II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus.
      were in good general health without conditions to explain abdominal pain and altered defecation, were not depressed, and could provide written informed consent. Exclusion criteria included a diagnosis of depression, taking antidepressant medication, or scoring 17 (borderline clinical depression) or higher on the Beck Depression Inventory; pregnancy; use of IBS medications including alosetron, tegaserod, antispasmodics, or anticholinergics; chronic pain medications including opiates within 4 weeks of entry; prior colon or rectal surgery; and major organ disease including diabetes. Fiber or loperamide use as needed was allowed.
      Eligible subjects had to have a normal sigmoidoscopy or colonoscopy within 5 years of enrollment and normal complete blood count and thyroid function studies, and subjects with diarrhea had to have negative stool studies for ova and parasites and normal colon biopsies. Women of child-bearing age were required to have a negative urine pregnancy test. Subjects were counseled to avoid pregnancy during the study and to use contraception.
      Subjects were drawn from primary, secondary, and tertiary care settings, including General Medicine and Gastroenterology clinics at the University of California, San Francisco, Kaiser Permanente Northern California, and community practices. At the University of California, San Francisco, recruitment efforts included fliers, letters to providers, on-site recruitment, and invitation letters approved by patients' physicians sent to patients with electronic entry diagnoses of “IBS” or “abdominal pain” with either “diarrhea” or “constipation.” For Kaiser Permanente Northern California, recruitment was based on invitation letters sent to patients with at least 2 electronic diagnostic entries for IBS, at least 1 visit within the past year, a colonoscopy or sigmoidoscopy within 5 years, and no entries for a psychiatric diagnosis or antidepressant prescription within 1 year. Community recruitment included letters to providers and posting of study information on the General Clinical Research Center web site and ClinicalTrials.gov (NCT00477165).
      Potentially eligible subjects were screened via telephone. Up to 3 attempts were made to telephone patients who were sent letters and did not return a refusal-to-participate postcard.

       Study Protocol

      After screening, during the initial study visit, written informed consent was obtained. Subjects completed the 21-item Beck's Depression Inventory. All enrolled subjects scored 16 or less (normal, 1–10; mild mood disturbance, 11–16). Subjects completed a questionnaire with the Rome II criteria and Supportive Symptoms of IBS,
      • Drossman D.A.
      • Corazziari E.
      • Talley N.J.
      Rome II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus.
      and were stratified into diarrhea-predominant IBS, constipation-predominant IBS, or alternating IBS.
      • Drossman D.A.
      • Corazziari E.
      • Talley N.J.
      Rome II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus.
      Urine pregnancy tests were obtained for women of child-bearing age. Screening daily symptom diaries were dispensed to score the secondary symptom outcomes on scales of 0 to 10.
      A second study visit occurred 1 week later (week 0). To continue participation, subjects had to score an average of pain/discomfort of 3 or greater during the screening week. All subjects who enrolled met this criterion. Subjects completed the IBS–QOL and the first barostat study. Questionnaires to be filled out on a weekly basis were dispensed to score whether weekly adequate relief was achieved, and the secondary symptom outcomes on scales of 0 to 10.
      Study medication or placebo was dispensed. The Investigational Drug Pharmacy prepared identical citalopram 20-mg and placebo capsules and generated 3 block-randomization lists, stratified by IBS subtype. For the first 4 weeks, 30 tablets were dispensed with instructions to take 1 capsule per day.
      At a third interim visit 4 weeks later (week 4), questionnaires and remaining capsules were collected, questionnaires were dispensed, and 60 tablets were dispensed with instructions to take 2 capsules per day.
      At a final visit 4 weeks later (week 8), questionnaires and capsules were collected. Subjects completed a second IBS–QOL questionnaire and barostat study.
      During the study, subjects were asked to call a research coordinator weekly to report completion of questionnaires. If the telephone call was not received, a research coordinator contacted the subject. Subjects were asked to call if they experienced side effects, which could lead to a dose reduction to 1 capsule per day.
      Medication adherence was determined by counting the remaining capsules and is reported as a percentage of capsules taken as directed.

       Barostat Study

      Polyethylene barostat bags of 500 mL were affixed to 18F nasogastric tubes. A bag was passed into the rectum, with tubing connected to the barostat (Distender Series II; G&J Electronics, Inc., Willowdale, Ontario, Canada), which was controlled by a computer that recorded bag pressure, volume, and corrected volume every second. After 5 minutes, the bag was unfurled with 100 mL of air and deflated. A distension sequence using the ascending method of limits was performed, with inflations lasting 45 seconds from 0 to up to 60 mm Hg, increasing by 3 mm Hg, and separated by 45-second deflations. Subjects rated sensation and urgency 30 seconds into each inflation. The study was stopped when subjects reported sensation of 8 or greater out of 10.

       Sample Size and Statistical Analysis

      The standardized mean improvement in pain with antidepressants in functional gastrointestinal disorders has been reported as 0.9 standard deviation (SD) units (95% confidence interval [CI], 0.6–1.2 SD units), with a summary odds ratio for improvement of 4.2 (95% CI, 2.3–7.9).
      • Jackson J.L.
      • O'Malley P.G.
      • Tomkins G.
      • et al.
      Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis.
      We estimated that to detect a standardized effect size of 0.9 in global symptoms with 2-sided α value of .05 and β value of .1, 54 subjects were needed; and that to detect an overall response to citalopram of 66% versus 30% with placebo (odds ratio for response, 4.5) with 2-sided α value of .05 and β value of .2, 60 subjects were needed.
      P values for comparing continuous variables were obtained by the Mann–Whitney test, and for dichotomous outcomes by the Fisher exact test. Mixed-effect models accounting for repeated measures within subjects were used to compare curves of symptom scores versus week and versus barostat pressure. The effect of treatment on adequate relief at weeks 3 to 8 was modeled by logistic regression, with a random subject effect included to account for nonindependence of responses from the same patient at different weeks. Volume versus distending pressure was defined as rectal compliance. The last observation was carried forward if distensions stopped at a given pressure for a given subject. The Pearson correlation coefficient was used to examine prespecified correlations between symptoms, IBS-QOL scores, and barostat parameters. The primary analyses were based on the intention to treat, with patients who withdrew being considered nonresponders. Exploratory per-protocol analyses were performed.

      Results

       Study Subjects and Adherence to Treatment

      A total of 234 potentially eligible subjects were identified. Of these, 180 were excluded and 54 (44 women) enrolled in the study, with 27 each randomized to citalopram and placebo (see Supplementary Figure 1). Demographic characteristics did not differ substantially between groups, and stratification at randomization yielded a balance of IBS subtypes between groups (Table 1). During the screening week, the median number of days with any pain and with pain scores of 3 or greater was 7.0 (interquartile range, 7.0–7.0) and 5.0 (interquartile range, 3.3–7.0), respectively. Nine subjects (6 women) withdrew from the study because of side effects, 7 in the citalopram group and 2 in the placebo group (P = .14) (Table 1).
      Table 1Demographic Characteristics of Study Subjects
      Placebo (N = 27)Citalopram (N = 27)TotalP value
      Mean age, y (SD) [range]51 (14) [30–75]53 (15) [27–75].60
      Sex.73
       Women23 (85%)21 (78%)44 (81%)
       Men4 (15%)6 (22%)10 (19%)
      Race.083
       Caucasian23 (85%)22 (82%)45 (83%)
       African American4 (15%)1 (4%)5 (9%)
       Asian0 (0%)4 (15%)4 (7%)
      Ethnicity.47
       Hispanic or Latino3 (11%)6 (22%)9 (17%)
       Not Hispanic or Latino24 (89%)21 (78%)45 (83%)
      IBS subgroup1.00
       Constipation11 (41%)10 (37%)21 (39%)
       Diarrhea11 (41%)12 (44%)23 (43%)
       Alternator5 (19%)5 (19%)10 (19%)
      Beck Depression Inventory score, mean (SD)5.9 (5.4)6.6 (5.1).47
      Discontinued treatment.14
       No25 (93%)20 (74%)45 (83%)
       Yes2 (7%)7 (26%)9 (17%)
      During weeks 1 through 4, the mean adherence to treatment was 97% (range, 86%–100%) for citalopram and 97% (range, 79%–100%) for placebo. During weeks 5 through 8, 1 patient in the citalopram group and 2 patients in the placebo group required dose reduction to 1 capsule per day. During weeks 5 through 8, the mean adherence to treatment was 96% (range, 86%–100%) for citalopram and 91% (range, 73%–100%) for placebo.

       Symptoms

      The overall response rate was 12 of 27 (44%) in the citalopram group and 15 of 27 (56%) in the placebo group (P = .59). The response rate was not superior for citalopram compared with placebo for any of the IBS subgroups (constipation-predominant, 5 of 10 vs 6 of 11; diarrhea predominant, 6 of 12 vs 6 of 11; alternators, 1 of 5 vs 3 of 5).
      There were no statistically significant differences between groups in the rates of adequate relief during any week by intention-to-treat analysis (Figure 1A). In a repeated-measures logistic regression model of adequate relief as a function of study week, assuming the citalopram effect builds linearly over time starting at week 3, the odds ratio for weekly response with citalopram versus placebo was 0.80 (95% CI, 0.614–1.035). The upper bound on the possible benefit of citalopram by study end was an odds ratio for response of 1.035
      • Clouse R.E.
      • Lustman P.J.
      • Geisman R.A.
      • et al.
      Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience.
      or 1.23. In per-protocol analysis with a logistic regression model of the same form, the odds ratio for weekly response with citalopram versus placebo was 0.91 (95% CI, 0.687–1.196) (Figure 1B).
      Figure thumbnail gr1
      Figure 1Weekly rates of adequate relief by (A) intention-to-treat analysis and (B) per-protocol analysis.
      Weekly symptom scores, satisfaction scores, and number of days with adequate relief did not differ substantially between groups during any week, as illustrated for weeks 4 and 8 in Table 2.
      Table 2Symptom and Satisfaction Scores at Weeks 4 and 8 of Treatment
      Week 4 mean (SD)Week 8 mean (SD)
      Placebo (N = 25)Citalopram (N = 22)P valuePlacebo (N = 25)Citalopram (N = 20)P value
      Overall IBS symptoms4.4 (2.4)4.0 (2.2).484.4 (3.0)3.3 (2.5).24
      Satisfaction with IBS symptoms4.6 (3.0)5.4 (2.7).425.4 (3.4)5.9 (3.4).71
      Days with adequate relief per week3.4 (2.1)3.6 (2.1).764.0 (2.3)4.0 (2.3).88
      Abdominal pain4.4 (2.5)4.2 (2.6).804.3 (3.0)3.7 (2.6).39
      Urgency3.3 (2.6)3.7 (2.6).603.2 (2.7)3.6 (2.5).56
      Number of bowel movements per week2.2 (3.2)2.2 (1.1).091.9 (1.6)2.3 (1.4).29
      Stool consistency6.0 (1.9)6.5 (2.0).386.1 (1.8)6.2 (2.0).79
      NOTE. Stool consistency was graded on the following scale: 0, solid and hard; 10, completely watery.

       Quality of Life

      The IBS-QOL overall score and subscores improved slightly over 8 weeks for both groups. However, there were no statistically significant differences in scores between groups at either week 0 or 8, or in the magnitude of the changes from week 0 to 8 (Table 3). For instance, the changes in overall IBS-QOL score for citalopram (6.3; 95% CI, −0.07 to 12.7) and placebo (7.6; 95% CI, 2.4–12.9) were not significantly different (P = .47).
      Table 3QOL Scores at Weeks 0 and 8 of Treatment
      Week 0 mean (SD)Week 8 mean (SD)
      Placebo (N = 27)Citalopram (N = 27)P valuePlacebo (N = 25)Citalopram (N = 20)P value
      Overall67 (23)71 (6).8574 (24)74 (18).85
      Body image70 (21)71 (20).8279 (22)75 (18).26
      Dysphoria65 (27)69 (21).7372 (29)73 (24).64
      Food avoidance56 (29)61 (23).6266 (27)60 (30).38
      Health worry58 (29)68 (21).2468 (27)74 (21).58
      Interference with activity67 (25)67 (20).8376 (27)68 (22).16
      Relationships72 (32)77 (17).7878 (26)83 (18).89
      Social reaction73 (26)79 (17).7779 (26)83 (21).73
      Sexual74 (32)77 (32).7177 (31)83 (28).62

       Rectal Sensitivity to Barostat-Mediated Distension

      There were no substantial differences in rectal compliance between groups at week 0 (P = .16) or week 8 (P = .24). At week 8, but not week 0, sensation but not urgency scores were slightly lower for the citalopram group than the placebo group (Figure 2).
      Figure thumbnail gr2
      Figure 2Mean rectal sensation as a function of distending pressure at the end of the study.

       Correlations Between Symptoms, Quality of Life, and Barostat Results

      The change in weekly overall IBS symptom score was not statistically significantly correlated with the change in the overall IBS–QOL score (r = −0.23; 95% CI, −0.50 to 0.07). There was a modest correlation between improvement in overall IBS–QOL score and increase in pressure eliciting threshold pain (r = 0.33; 95% CI, 0.03–0.57).
      No statistically significant correlation was observed between the absolute change in weekly pain score on a scale of 0 to 10 and the absolute change in pressures eliciting threshold pain measured in mm Hg (r = 0.05; 95% CI, −0.26 to 0.34) (Figure 3), or between absolute change in the weekly urgency score and absolute change in pressures eliciting threshold urgency (r = 0.01; 95% CI, −0.30 to 0.32). There were no statistically significant correlations between the absolute change in overall IBS symptom score and the absolute changes in pressures eliciting threshold pain (r = 0.12; 95% CI, −0.18 to 0.41) or urgency (r = −0.05; 95% CI, −0.34 to 0.26).
      Figure thumbnail gr3
      Figure 3Correlation between absolute changes in abdominal pain scores on a scale of 0 to 10 and absolute changes in rectal distension pressure threshold for pain measured in mm Hg.

      Discussion

      In this study, citalopram was not superior to placebo in achieving adequate relief of IBS symptoms, improving individual symptom scores, or improving QOL in nondepressed patients with IBS. Citalopram treatment had minimal impact on rectal sensitivity. In a comprehensive exploration of the longitudinal relationship between symptoms and sensitivity to barostat-mediated rectal distension, there were no statistically significant correlations between the changes in overall IBS symptoms and QOL, or IBS symptoms and rectal sensation assessed by barostat.
      Five previous studies have examined the effect of SSRIs on IBS symptoms, with conflicting results. Three studies of paroxetine,
      • Tabas G.
      • Beaves M.
      • Wang J.
      • et al.
      Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial.
      fluoxetine,
      • Vahedi H.
      • Merat S.
      • Rashidioon A.
      • et al.
      The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study.
      and citalopram
      • Tack J.
      • Broekaert D.
      • Fischler B.
      • et al.
      A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome.
      reported a modest benefit, whereas 2 studies of fluoxetine
      • Kuiken S.D.
      • Tytgat G.N.
      • Boeckxstaens G.E.
      The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.
      and citalopram
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      did not. A recent meta-analysis of these studies found a relative risk of persistent or unimproved IBS symptoms or abdominal pain of 0.62 (95% CI, 0.45–0.87) for SSRIs versus placebo, with significant heterogeneity between studies.
      • Ford A.C.
      • Talley N.J.
      • Schoenfeld P.S.
      • et al.
      Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.
      The meta-analysis used data from 113 SSRI-treated subjects and 117 controls. This was among the larger studies that addressed the effect of an SSRI in IBS, and we found evidence against a substantial benefit of citalopram, contrary to the findings of the meta-analysis.
      Differences in study designs and patient populations may account in part for the different results among the 6 trials. Kuiken et al
      • Kuiken S.D.
      • Tytgat G.N.
      • Boeckxstaens G.E.
      The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.
      enrolled 40 nondepressed IBS patients of all subtypes from a tertiary center in a 6-week study of fluoxetine or placebo. Tabas et al
      • Tabas G.
      • Beaves M.
      • Wang J.
      • et al.
      Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial.
      randomized 81 patients with IBS of all subtypes and without exclusion for depression to a high-fiber diet with paroxetine or placebo for 12 weeks. Vahedi et al
      • Vahedi H.
      • Merat S.
      • Rashidioon A.
      • et al.
      The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study.
      randomized 44 patients with constipation-predominant IBS to fluoxetine or placebo for 12 weeks, and excluded patients with severe depression. Tack et al
      • Tack J.
      • Broekaert D.
      • Fischler B.
      • et al.
      A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome.
      recruited 23 nondepressed IBS patients from a tertiary care center for a crossover trial comparing citalopram versus placebo. Talley et al
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      randomized 51 patients with IBS of all types without psychiatric illness to citalopram (17 subjects), imipramine, or placebo (16 subjects) for 12 weeks. Features of the trials in which some benefit was detected include the lack of exclusion for depression,
      • Tabas G.
      • Beaves M.
      • Wang J.
      • et al.
      Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial.
      inclusion of only constipation-predominant patients,
      • Vahedi H.
      • Merat S.
      • Rashidioon A.
      • et al.
      The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study.
      and a cross-over design with patients from tertiary care.
      • Tack J.
      • Broekaert D.
      • Fischler B.
      • et al.
      A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome.
      The specific drug, dose, and duration used in each trial could be important factors, but no clear pattern emerged. The study by Tack et al
      • Tack J.
      • Broekaert D.
      • Fischler B.
      • et al.
      A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome.
      is the only one that showed benefit for citalopram, whereas the study by Talley et al
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      reported identical response rates for citalopram and placebo, and our study found evidence against any substantial benefit of citalopram.
      The trials used different definitions for clinical response, and this may explain much of the conflict in the conclusions. We used adequate relief of IBS symptoms as the primary outcome. The same outcome was assessed by Talley et al.
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      In contrast, the other trials assessed global symptom response, overall well-being, or the effect on specific symptoms. However, in our trial we also assessed overall symptom response, change in specific symptoms, and QOL, and we saw little benefit of citalopram.
      Based on all available data, we conclude that there is only weak evidence that citalopram may be superior to placebo in achieving a stringent criterion of response in nondepressed patients with IBS. We recognize that our trial has the limitation of relatively small sample size, as do all previous studies in this area, but in our study citalopram was not numerically superior to placebo and the upper confidence bound provides evidence against any substantial benefit. Thus, the lack of significant benefit of citalopram cannot be explained exclusively by a type II error. A much larger trial with hundreds of patients per group would be needed to detect a relatively small difference in overall response,
      • Andresen V.
      • Montori V.M.
      • Keller J.
      • et al.
      Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials.
      as other investigators also have pointed out.
      • Kuiken S.D.
      • Tytgat G.N.
      • Boeckxstaens G.E.
      The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.
      Such a trial is challenging to perform. The formal rate of exclusion from our trial because of depression or antidepressant use greatly underestimates the number of patients who actually were excluded from our trial for these reasons because patients screened informally in clinics were never screened formally for inclusion. Although we cannot quantitate this effect, this presented a substantial recruitment challenge. Similar challenges have been recognized by other investigators.
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      A potential limitation is that we do not know whether patients could have been unblinded based on side effects.
      The relationship between clinical symptoms and sensitivity to barostat-mediated rectal distension has not been studied thoroughly.
      • Mayer E.A.
      • Bradesi S.
      • Chang L.
      • et al.
      Functional GI disorders: from animal models to drug development.
      Rectal sensitivity has been proposed as a potential biological marker for IBS,
      • Mertz H.
      • Naliboff B.
      • Munakata J.
      • et al.
      Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
      and effects on visceral sensitivity have been considered as ways to screen for promising pharmaceuticals.
      • Mayer E.A.
      • Bradesi S.
      • Chang L.
      • et al.
      Functional GI disorders: from animal models to drug development.
      We found no statistically significant correlations between changes in IBS symptoms and changes in barostat parameters. Although we acknowledge controversies pertaining to the optimal barostat protocol and the relevance of barostat data to clinical symptoms, our results suggest that changes in rectal sensitivity to barostat-mediated distension may not lead to improvements in clinical symptoms.
      We urge caution against overinterpreting the modest correlation between the changes in IBS–QOL score and the pressure eliciting threshold pain. This correlation is plausible if decreased rectal sensitivity were associated with decreased clinical symptoms, and in turn improved QOL. But we found evidence against substantial positive values for these other correlations.
      In conclusion, in this study citalopram was not superior to placebo in treating nondepressed patients with IBS, and changes in clinical symptoms were not correlated substantially with changes in rectal sensation. Considering all available evidence, any benefit of SSRIs compared with placebo in nondepressed patients with IBS is likely to be modest at best.

      Acknowledgments

      Trial Registration: ClinicalTrials.gov ID NCT00477165.

      Supplementary data

      Video Abstract

      References

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