Functional GI Disorders: A Psychiatric Perspective

May 1, 2006

Evidence showing the effectiveness of psychopharmacologic and psychotherapeutic management of functional gastrointestinal disorders over standard medical treatment is increasing.

At first glance, it would seempeculiar to be discussing GIdisorders in a psychiatric publication.However, functional GI disorders(FGIDs) represent a unique subsetof GI disorders that have strong psychiatricimplications beyond mere psychiatriccomorbidity and/or psychosocialdistress, which are indeed frequentconcomitants of these disorders. Thereis increasing evidence that psychopharmacologicand psychotherapeuticmanagement of FGIDs are highly effectiveand, in many instances, surpass theefficacy of standard medical treatment.This article reviews the diagnostic criteriafor FGIDs and briefly discusses theirpresentation and medical evaluation.The role of the psychiatrist in treatingpatients with these disorders isdiscussed in greater detail, with anemphasis on psychopharmacologictreatment. In addition, the emerging andquite exciting literature supporting therole of psychotherapy and other behavioralinterventions in managing thesecomplex disorders and their psychosocialconcomitants, including psychiatriccomorbidity, will be discussed.

Epidemiology anddiagnostic criteria

FGIDs consist of a wide spectrum ofsyndromes, which cross over and, insome cases, overlap various anatomicareas of the luminal gut. Although irritablebowel syndrome (IBS) has traditionallybeen the most studied andwritten about, FGIDs constitute anumber of unique disorders, includingfunctional esophageal disorders (noncardiacchest pain, functional dysphagia,and globus sensation); functionaldyspepsia (pain, discomfort, nausea,and other symptoms above the navelin persons who do not meet the diagnosticcriteria for IBS); functionalabdominal pain syndrome; functionalabdominal bloating; functional diarrhea;functional disorders of the biliarytract, including Oddi sphincter; functionaldisorders of the anorectal area,such as pelvic floor dyssynergia; andproctalgia fugax. Functional disordersare somewhat unique in gastroenterologicpractice because they are diagnosedusing symptom-based criteria.

Building on the DSM model, internationalteams of physicians and otherscientists expert in the area of FCIDshave been gathering since 1988 on aregular basis in Rome to develop symptom-based criteria for the variousFGIDs. Similar to the DSM, as diagnosticcriteria have been developed andfield-tested, the Rome criteria haveevolved over time (Table).

The Rome working teams go beyondmerely formulating diagnostic criteria;they also address important clinical andresearch issues. For instance, the Romebook includes working-team reports onpediatric FGIDs, design for treatmenttrials for FGIDs, and discussions of thepsychosocial aspects of FGIDs.1 The factthat the psychosocial aspects of FGIDsreceive significant recognition in theRome process speaks to the importanceof these factors in properly diagnosingand treating FGIDs.

Psychopharmacologic treatment

The earliest reported use of antidepressantsfor GI disease was the use oftricyclic antidepressants for the treatmentof peptic ulcer disease.2 Tricyclicshave subsequently been replaced bymore effective therapy based on updatedknowledge of pathophysiology. Theeffectiveness of tricyclic antidepressantscan be influenced by their specificreceptor activity. For instance, highlyantihistaminic drugs, such as doxepinand imipramine, are helpful in promotingsleep. This could also influence theirability to produce analgesia. In the1970s and 1980s the analgesic propertiesof antidepressants were discovered.Antidepressant agents have beensuccessfully used for the managementof a wide variety of neuropathic painsyndromes such as diabetic peripheralneuropathy, postherpetic neuralgia,migraine headache, cancer-relatedpain, and other painful conditions. Anumber of meta-analyses have supportedthe usefulness of antidepressantsin these settings.3,4

Egbunike and Chaffee3 reviewed theliterature on antidepressants and chronicpain and described a number of interestingfindings. The first was that theanalgesic effect of the drugs tended tobe independent of their antidepressanteffect. Second, they found that the dosesof heterocyclic antidepressants used toachieve adequate analgesia seemed tobe lower than those considered effectivefor the treatment of patients withmood disorders. Finally, they noticedthat the onset of analgesia for neuropathicpain syndromes ranged from 1day to 10 weeks, with unpredictableresponse time. This is considerablyshorter than the time usually requiredto effectively treat patients with moodand anxiety disorders.

GI Disorders

The tricyclic antidepressants havealso been found to play a role in treatingthe visceral pain associated withFGIDs. In 1987 Greenbaum andcolleagues5 undertook a landmark studylooking at the efficacy and mechanismof action of antidepressants in functionalbowel disorders. In this study, 28 patientswith IBS completed a double-blindcrossover study using desipramineversus atropine versus placebo inrandom sequence. Atropine was usedas an active because the 0.4-mg dosewas able to simulate the antimuscariniceffect of desipramine. All patientsunderwent rectosigmoid manometry.In addition, all were administered theHamilton depression rating scale(HAM-D) and the Brief PsychiatricRating Scale (BPRS) to assess theirpsychiatric status both on entry and exitfrom the study. GI symptoms were alsorecorded.

Twenty-eight patients completed theentire protocol. Nine patients treatedwith desipramine complained of sideeffects that included anxiety, tremor,palpitations, sweating, xerostomia, andconstipation. During the atropine phaseof the protocol, 7 patients also had sideeffects, the most common being xerostomia,constipation, and palpitations.When GI symptoms were measured,there was a significant reduction in thenumber of stools per week in thedesipramine group compared with theplacebo group (P P P

Twenty-eight patients completed theentire protocol. Nine patients treatedwith desipramine complained of sideeffects that included anxiety, tremor,palpitations, sweating, xerostomia, andconstipation. During the atropine phaseof the protocol, 7 patients also had sideeffects, the most common being xerostomia,constipation, and palpitations.When GI symptoms were measured,there was a significant reduction in thenumber of stools per week in thedesipramine group compared with theplacebo group (P P P

Overall motility did not differ significantlybetween the 3 arms of the study,except in patients with diarrheapredominantIBS. In these patients,overall motility was decreased withdesipramine compared with atropine (P

The investigators concluded that thepositive effect of desipramine was independentof its antimuscarinic effect andbecause of the dosage used in thisstudy, the lack of correlation with bloodconcentrations, and the short durationof the trial, the antidepressant effect ofdesipramine was not responsible for theimprovement seen in the patients.Likewise, study data demonstrated alack of correlation between patientimprovement and any documentablechanges in GI motility.

This study was the first to empiricallydesignate the unique effect ofantidepressants on functional boweldisorders independent of any depressantand anticholinergic effects. Thelack of correlation between changes inpsychiatric status and changes in GImotility also spoke to the unique propertyof desipramine to improve globalwell-being in patients with functionalbowel disorders.

The literature has continued to movein a positive direction supporting theinitial findings of Greenbaum and associates.5 Jackson and coauthors6 undertooka meta-analysis of publishedrandomized controlled trials on the useof antidepressants for FGIDs. With theapplication of quality criteria, 11randomized placebo-controlled trialsof antidepressant therapy for FGIDswere identified in the literature. Theseincluded trials of amitriptyline, desipramine,doxepin, clomipramine, trimipramine,and mianserin (a serotoninreuptake blocker not available in theUnited States).

The authors concluded that the oddsof improvement in patients whoreceived antidepressant therapy forfunctional bowel disorders was 4 to 2.They calculated that an average of 3.2patients needed to be treated to improve1 patient symptom. They concludedthat the use of tricyclic antidepressantsas functional antidepressants was effective.However, based on the literaturereviewed, they could not concludewhether the effect was independent ofthe antidepressant effect of the drug.

In an attempt to further elucidate therole of antidepressants in functionalbowel disorders, in 2002 Brandt andcoworkers7 undertook a systematicreview of all pharmacotherapy for IBSusing evidence-based methodology.They concluded that tricyclic antidepressantsare not more effective thanplacebo in relieving global IBS symptoms.The investigators used a subjectglobal assessment as the methodologicgold standard to gauge effectiveness.The methodology was based on recommendationsfrom the Rome workingteams on FGIDs; however, most of thestudies reviewed by Brandt and associateswere performed before theserecommendations existed, so the resultingnegative view of tricyclic antidepressantsmay be unduly harsh.

 Manning Criteria
Abdominal pain that is relieved with abowel movement Pain associated with more frequentstools Sensation of incomplete evacuation Passage of mucus Abdominal distention
 Rome Criteria
Continuous or recurrent symptoms of: Abdominal pain, relieved with defecationor associated with change in frequencyor consistency of stool;
 Revised Rome Criteria
At least 12 weeks or more, which neednot be consecutive, in the preceding 12 months of abdominal discomfort or pain that has 2 out of 3 features: Relieved with defecation;

Studies using serotoninreuptake inhibitors

In the last few years, an increasingnumber of studies on the effect of selectiveserotonin reuptake inhibitors(SSRIs) on FGIDs have been published.Using a double-blind randomizeddesign, Kuiken and coauthors8 studied40 patients with IBS who had noevidence of major depressive disorder.All patients underwent rectal sensitivitytesting using balloon distentionbefore and after a 6-week course oftreatment with either fluoxetine 20 mg/dor placebo. In addition, the investigatorsrecorded abdominal pain scores,individual GI symptoms, subject'sglobal self-assessment, and psychologicalsymptoms using the SymptomCheck List (SCL)-90-R on entry andexit from the study.

They found that at study entry, IBSpatients were more likely to showhypersensitivity to rectal distention.They noted that fluoxetine did notsignificantly alter the threshold fordiscomfort/pain relative to placeboeither in hypersensitive patients or inpatients who did not show hypersensitivityto balloon distention on entry.They also found no significant improvementin abdominal pain scores betweenthe fluoxetine and placebo groups after12 weeks of treatment. In the patientswho were hypersensitive to balloondistention, fluoxetine significantlyreduced the number of patients reportingsignificant abdominal pain (P = .04).Other GI symptoms, such as bloating,flatulence, urgency, incomplete evacuation,and global symptom relief werenot significantly altered by fluoxetinecompared with placebo. There was alsono significant difference in psychologicaldistress scores as measured bythe SCL-90-R in the fluoxetine versusthe placebo group. They concludedthat fluoxetine did not reduce overallsymptoms in patients with IBS.

Tabas and associates9 studied patientswith IBS who were assessedregarding fiber intake. Group 1 consistedof 98 patients who were consumingless than 25 g/d of fiber. Group 2consisted of 12 patients who wereconsuming a high-fiber diet (greaterthan 25 g/d). All patients were evaluatedusing the IBS Quality-Of-Lifequestionnaire and the Beck DepressionInventory. Bowel symptoms wererecorded on study entry and exit. Group1 was randomized to a high-fiber dietand group 2 was randomized to adouble-blind placebo-controlled trial ofparoxetine versus placebo. At the endof 12 weeks, patients in group 1 eitherself-reported improvement (n = 25) orfailed to improve (n = 69) and werethen allocated to paroxetine. Thesubjects, therefore, consisted of thosethat did not improve on fiber, as wellas those who did improve on fiber. Thiswas done to specifically study theimpact of paroxetine on both populationswho received fiber supplementation.This created a total study sampleof 81 patients for the paroxetine portionof the trial. Of this group, 30 wererandomized to paroxetine 20 mg/d and36 received placebo.

In group 1, overall well-beingimproved in 26% of patients and all painand bloating decreased in 22% and26%, respectively, with the use of a highfiberdiet alone. In group 2, overall well-being improved more with paroxetinethan placebo (P = .01) but abdominalpain, bloating, and social functioningdid not. Paroxetine significantly reducedfood avoidance (P = .03). Work functioningwas marginally better in theparoxetine group (P = .08). Interestingly,before unblinding, more paroxetinepatients than placebo patients wantedto continue with their study medication(84% vs 37%; P

This study is interesting for a numberof reasons. It demonstrated the clinicalutility of using an SSRI for the treatmentof IBS, and it showed that evenin patients who had improved withhigher fiber consumption, an antidepressantoffered further advantage.

More recent studies

Building on the past, a number of newstudies with SSRIs and tricyclic antidepressantshave been conducted usingcontemporary methodology for thedesign of functional bowel treatmenttrials. Employing the more rigorousmethodology derived from the recommendationsof the Rome working teamshas improved the quality of the results.

In a recent study, Creed and colleagues10evaluated the cost effectivenessof psychotherapy versusparoxetine for the treatment of IBS.Patients in the National Health Serviceof the United Kingdom who were feltto have severe refractory IBS (n = 257)were randomized to either ongoingstandard medical treatment, paroxetine20 mg/d, or 8 hours of interpersonalpsychodynamic psychotherapy.In this study, all patients in the standardmedical treatment group completedthe trial, while 31% of thepsychotherapy group and 49% of theparoxetine group dropped out. Neitherpsychotherapy nor paroxetine weresuperior to standard medical treatmentin reducing pain but both were significantlybetter in improving the physicalaspects of health-related quality oflife. There was no significant differencein the psychological componentof health-related quality of life in eitherof the 3 treatment arms. None of thesubjects showed any significant differencewhen compared to their pretreatmentstate. At the 1-year follow-up, thepsychotherapy group had a significantreduction in overall health care costscompared with standard medical treatment,but the paroxetine group did not.These data suggest that for patients withsevere IBS, both psychotherapy andparoxetine improve health-related qualityof life. However, antidepressanttreatment seems to be not as effectiveas psychotherapy for overall improvementin IBS symptoms and ability toreduce health care costs compared withstandard medical treatment.

Drossman and associates11 conducteda recent landmark study on the use ofantidepressant therapy for functionalbowel disorders. They compared 431patients randomized to 2 experimentalarms. The first received either cognitive-behavioral therapy or an educationalmodule. The second receiveddesipramine 50 to 150 mg/d or placebo.In an intent-to-treat (ITT) analysis,behavior therapy was significantly betterthan the educational intervention, withresponder rates of 70% versus 37%,respectively. Here the number neededto treat (NNT) was 3.1 for cognitivebehavioral therapy. Desipramine wasnot superior to placebo in an ITT analysis.However, in a per-protocol analysis,analyzing individuals who hadcompleted 12 weeks of desipraminetreatment and not analyzing dropouts,desipramine was superior to placebo,with responder rates of 73% versus49%, respectively (NNT = 5.2). Similarto the results found by Creed and associates,10 psychotherapy was superior toantidepressant therapy, which, was superiorto placebo treatment.

These 2 studies are helpful for anumber of reasons. The first is that theydemonstrate a role for both SSRIs andtricyclic antidepressants in the treatmentof functional bowel disorders. In addition,they demonstrate that the majorissue confronting the use of antidepressantsin functional bowel disordersis not one of effectiveness but an issueof side effects and patient tolerance.The high dropout rates in the antidepressantarms in the studies by Creedand associates10 and Drossman andcoworkers11 (49% and 28%, respectively)demonstrate the need for theclinician to be alert to side effectsreported by patients and to deal withthem aggressively, either by adjustingthe dose of the medication or by changingto another antidepressant. Cautionis suggested in using tricyclics inpatients who have IBS with constipationbecause they may exacerbate thepatient's constipation symptoms.

Role of the psychiatrist

Psychiatrists should be comfortable andcompetent as primary clinicians forpatients being treated for FGIDs withantidepressants, as well as acting asconsultants to nonpsychiatric colleagues.Primary care physicians andgastroenterologists are not as skilledat understanding the pharmacologyof various antidepressant agents.Anticholinergic, antihistaminic, andnoradrenergic effects of the various antidepressantscan be prescribed advantageouslyto individual patients. Thepsychiatrist clearly is in a unique roleto provide this type of guidance.

Likewise, the adverse events associatedwith various antidepressantagents--such as sexual dysfunctionassociated with SSRIs, as well as rarebut dangerous side effects such as serotoninsyndrome--make it clear that theinvolvement of a psychiatrist, whowould be familiar with these effects,would be beneficial. Finally, the psychiatristhas the ability to diagnose comorbidpsychiatric disorders in the patientwho presents with FGIDs. The highprevalence of anxiety and mood disordersin patients with FGIDs make thepsychiatrist a vital contributor to patientcare.12 Collaborative care, where thepsychiatrist and the nonpsychiatricphysician care for patients with FGIDshas been demonstrated to be quite effective.For psychiatrists to be effectiveparticipants in the care of patients withFGIDs, they need to understand thebasic nature of these disorders and theirattendant comorbidities, as well as therole of psychopharmacologic andbehavioral treatment.

In addition to psychopharmacologicapproaches, psychotherapy has alsobeen shown to be individually effectivewhen treating patients with functionalbowel disorders. A number ofstudies have shown a significantimprovement in functional bowel symptomsin patients exposed to a varietyof psychotherapeutic approaches,including cognitive behavioral therapyand interpersonal therapy, as well ashypnosis directed toward bowel symptoms.It is important for physicians torecognize that behavioral tools at theirdisposal can also be highly effective intreating these patients.13

Conclusions

The usefulness of antidepressants forthe treatment of functional bowel disordershas been reasonably well established.The recent meta-analyses byJackson and associates6 and others,show that antidepressants are safe andeffective for the management of functionalbowel disorders. In addition toIBS, investigators over the last 15 yearshave shown the benefit of antidepressantstherapy for noncardiac chestpain,14 functional vomiting,15 and functionaldyspepsia.16 The more contemporarystudies using high qualitymethodology further demonstrate theusefulness of both SSRIs and tricyclicantidepressants in this setting. Clearly,trials of newer antidepressants such asduloxetine and mirtazapine should beconsidered for patients with FGIDs. Atrial of escitalopram is under way forthe treatment of IBS.

Side-effect profiles in patients withFGIDs also need to be more intenselystudied to help optimize patient-drugmatching. The use of pharmacogenomicsand better definitions of functionalbowel disorders will clearly helpin doing this.

Dr Olden is a professor of medicine and psychiatryat the University of South Alabama inMobile. He has indicated that he is a consultantfor Novartis, Sucampo Pharmaceuticals,Takeda Pharmaceuticals, and Axcan PharmaInc; he is also a recipient of grant supportfrom Novartis.

References:

References

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