Studies using serotonin reuptake inhibitors
In the last few years, an increasing number of studies on the effect of selective serotonin reuptake inhibitors (SSRIs) on FGIDs have been published. Using a double-blind randomized design, Kuiken and coauthors8 studied 40 patients with IBS who had no evidence of major depressive disorder. All patients underwent rectal sensitivity testing using balloon distention before and after a 6-week course of treatment with either fluoxetine(Drug information on fluoxetine) 20 mg/d or placebo. In addition, the investigators recorded abdominal pain scores, individual GI symptoms, subject’s global self-assessment, and psychological symptoms using the Symptom Check List (SCL)-90-R on entry and exit from the study.
They found that at study entry, IBS patients were more likely to show hypersensitivity to rectal distention. They noted that fluoxetine did not significantly alter the threshold for discomfort/pain relative to placebo either in hypersensitive patients or in patients who did not show hypersensitivity to balloon distention on entry. They also found no significant improvement in abdominal pain scores between the fluoxetine and placebo groups after 12 weeks of treatment. In the patients who were hypersensitive to balloon distention, fluoxetine significantly reduced the number of patients reporting significant abdominal pain (P = .04). Other GI symptoms, such as bloating, flatulence, urgency, incomplete evacuation, and global symptom relief were not significantly altered by fluoxetine compared with placebo. There was also no significant difference in psychological distress scores as measured by the SCL-90-R in the fluoxetine versus the placebo group. They concluded that fluoxetine did not reduce overall symptoms in patients with IBS.
Tabas and associates9 studied patients with IBS who were assessed regarding fiber intake. Group 1 consisted of 98 patients who were consuming less than 25 g/d of fiber. Group 2 consisted of 12 patients who were consuming a high-fiber diet (greater than 25 g/d). All patients were evaluated using the IBS Quality-Of-Life questionnaire and the Beck Depression Inventory. Bowel symptoms were recorded on study entry and exit. Group 1 was randomized to a high-fiber diet and group 2 was randomized to a double-blind placebo-controlled trial of paroxetine(Drug information on paroxetine) versus placebo. At the end of 12 weeks, patients in group 1 either self-reported improvement (n = 25) or failed to improve (n = 69) and were then allocated to paroxetine. The subjects, therefore, consisted of those that did not improve on fiber, as well as those who did improve on fiber. This was done to specifically study the impact of paroxetine on both populations who received fiber supplementation. This created a total study sample of 81 patients for the paroxetine portion of the trial. Of this group, 30 were randomized to paroxetine 20 mg/d and 36 received placebo.
In group 1, overall well-being improved in 26% of patients and all pain and bloating decreased in 22% and 26%, respectively, with the use of a highfiber diet alone. In group 2, overall well-being improved more with paroxetine than placebo (P = .01) but abdominal pain, bloating, and social functioning did not. Paroxetine significantly reduced food avoidance (P = .03). Work functioning was marginally better in the paroxetine group (P = .08). Interestingly, before unblinding, more paroxetine patients than placebo patients wanted to continue with their study medication (84% vs 37%; P < .001).
This study is interesting for a number of reasons. It demonstrated the clinical utility of using an SSRI for the treatment of IBS, and it showed that even in patients who had improved with higher fiber consumption, an antidepressant offered further advantage.
More recent studies
Building on the past, a number of new studies with SSRIs and tricyclic antidepressants have been conducted using contemporary methodology for the design of functional bowel treatment trials. Employing the more rigorous methodology derived from the recommendations of the Rome working teams has improved the quality of the results.
In a recent study, Creed and colleagues10 evaluated the cost effectiveness of psychotherapy versus paroxetine for the treatment of IBS. Patients in the National Health Service of the United Kingdom who were felt to have severe refractory IBS (n = 257) were randomized to either ongoing standard medical treatment, paroxetine 20 mg/d, or 8 hours of interpersonal psychodynamic psychotherapy. In this study, all patients in the standard medical treatment group completed the trial, while 31% of the psychotherapy group and 49% of the paroxetine group dropped out. Neither psychotherapy nor paroxetine were superior to standard medical treatment in reducing pain but both were significantly better in improving the physical aspects of health-related quality of life. There was no significant difference in the psychological component of health-related quality of life in either of the 3 treatment arms. None of the subjects showed any significant difference when compared to their pretreatment state. At the 1-year follow-up, the psychotherapy group had a significant reduction in overall health care costs compared with standard medical treatment, but the paroxetine group did not. These data suggest that for patients with severe IBS, both psychotherapy and paroxetine improve health-related quality of life. However, antidepressant treatment seems to be not as effective as psychotherapy for overall improvement in IBS symptoms and ability to reduce health care costs compared with standard medical treatment.
Drossman and associates11 conducted a recent landmark study on the use of antidepressant therapy for functional bowel disorders. They compared 431 patients randomized to 2 experimental arms. The first received either cognitive- behavioral therapy or an educational module. The second received desipramine 50 to 150 mg/d or placebo. In an intent-to-treat (ITT) analysis, behavior therapy was significantly better than the educational intervention, with responder rates of 70% versus 37%, respectively. Here the number needed to treat (NNT) was 3.1 for cognitive behavioral therapy. Desipramine was not superior to placebo in an ITT analysis. However, in a per-protocol analysis, analyzing individuals who had completed 12 weeks of desipramine treatment and not analyzing dropouts, desipramine was superior to placebo, with responder rates of 73% versus 49%, respectively (NNT = 5.2). Similar to the results found by Creed and associates, 10 psychotherapy was superior to antidepressant therapy, which, was superior to placebo treatment.
These 2 studies are helpful for a number of reasons. The first is that they demonstrate a role for both SSRIs and tricyclic antidepressants in the treatment of functional bowel disorders. In addition, they demonstrate that the major issue confronting the use of antidepressants in functional bowel disorders is not one of effectiveness but an issue of side effects and patient tolerance. The high dropout rates in the antidepressant arms in the studies by Creed and associates10 and Drossman and coworkers11 (49% and 28%, respectively) demonstrate the need for the clinician to be alert to side effects reported by patients and to deal with them aggressively, either by adjusting the dose of the medication or by changing to another antidepressant. Caution is suggested in using tricyclics in patients who have IBS with constipation because they may exacerbate the patient’s constipation symptoms.
Role of the psychiatrist
Psychiatrists should be comfortable and competent as primary clinicians for patients being treated for FGIDs with antidepressants, as well as acting as consultants to nonpsychiatric colleagues. Primary care physicians and gastroenterologists are not as skilled at understanding the pharmacology of various antidepressant agents. Anticholinergic, antihistaminic, and noradrenergic effects of the various antidepressants can be prescribed advantageously to individual patients. The psychiatrist clearly is in a unique role to provide this type of guidance.
Likewise, the adverse events associated with various antidepressant agents—such as sexual dysfunction associated with SSRIs, as well as rare but dangerous side effects such as serotonin syndrome—make it clear that the involvement of a psychiatrist, who would be familiar with these effects, would be beneficial. Finally, the psychiatrist has the ability to diagnose comorbid psychiatric disorders in the patient who presents with FGIDs. The high prevalence of anxiety and mood disorders in patients with FGIDs make the psychiatrist a vital contributor to patient care.12 Collaborative care, where the psychiatrist and the nonpsychiatric physician care for patients with FGIDs has been demonstrated to be quite effective. For psychiatrists to be effective participants in the care of patients with FGIDs, they need to understand the basic nature of these disorders and their attendant comorbidities, as well as the role of psychopharmacologic and behavioral treatment.
In addition to psychopharmacologic approaches, psychotherapy has also been shown to be individually effective when treating patients with functional bowel disorders. A number of studies have shown a significant improvement in functional bowel symptoms in patients exposed to a variety of psychotherapeutic approaches, including cognitive behavioral therapy and interpersonal therapy, as well as hypnosis directed toward bowel symptoms. It is important for physicians to recognize that behavioral tools at their disposal can also be highly effective in treating these patients.13
The usefulness of antidepressants for the treatment of functional bowel disorders has been reasonably well established. The recent meta-analyses by Jackson and associates6 and others, show that antidepressants are safe and effective for the management of functional bowel disorders. In addition to IBS, investigators over the last 15 years have shown the benefit of antidepressants therapy for noncardiac chest pain,14 functional vomiting,15 and functional dyspepsia.16 The more contemporary studies using high quality methodology further demonstrate the usefulness of both SSRIs and tricyclic antidepressants in this setting. Clearly, trials of newer antidepressants such as duloxetine(Drug information on duloxetine) and mirtazapine(Drug information on mirtazapine) should be considered for patients with FGIDs. A trial of escitalopram(Drug information on escitalopram) is under way for the treatment of IBS.
Side-effect profiles in patients with FGIDs also need to be more intensely studied to help optimize patient-drug matching. The use of pharmacogenomics and better definitions of functional bowel disorders will clearly help in doing this.
Dr Olden is a professor of medicine and psychiatry at the University of South Alabama in Mobile. He has indicated that he is a consultant for Novartis, Sucampo Pharmaceuticals, Takeda Pharmaceuticals, and Axcan Pharma Inc; he is also a recipient of grant support from Novartis.