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Psychosomatics 43:451-455, December 2002
© 2002 The Academy of Psychosomatic Medicine

Does a Preexisting Anxiety Disorder Predict Response to Paroxetine in Irritable Bowel Syndrome?

Prakash S. Masand, M.D., Sanjay Gupta, M.D., Thomas L. Schwartz, M.D., David Kaplan, M.D., Subhdeep Virk, M.D., Ahmad Hameed, M.D., and Kari Lockwood, R.N.

Presented in part at the 154th annual meeting of the American Psychiatric Association, New Orleans, May 5–10, 2001. Received September 6, 2001; revision received April 5, 2002; accepted April 16, 2002. From the Department of Psychiatry, Duke University Medical Center; Olean General Hospital, Olean, N.Y.; State University of New York Upstate Medical University, Syracuse, N.Y.; and Syracuse Gastroenterological Associates, Syracuse, N.Y. Address reprint requests to Dr. Masand, Department of Psychiatary, Duke University Medical Center, Duke South Box 3391, Durham, NC 27710; masan001{at}mc.duke.edu (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Irritable bowel syndrome (IBS) is the most common disorder in patients seen by gastroenterologists. Twenty subjects with IBS diagnosed with the Rome criteria were treated for 12 weeks with 20–40 mg/day of paroxetine (mean dose=31 mg/day). At baseline, 10 patients had a lifetime history of an anxiety disorder, and 10 patients did not have such a history. Both groups had similar improvement in abdominal pain, constipation, diarrhea, incomplete emptying, and bloating/ abdominal distension. Paroxetine was very well tolerated.

Key Words: Irritable bowel syndrome • Anxiety disorder • paroxetine • Comorbidity • SSRIs

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Irritable bowel syndrome (IBS) is a gastrointestinal syndrome of unknown etiology characterized by abdominal pain and discomfort and altered bowel habits. A number of nongastrointestinal symptoms may be associated with IBS, including sleep disorders,1 pain syndromes,2 and sexual dysfunction.3

Mayer 4 has hypothesized a multicomponent conceptual model of IBS, comprising physiological, behavioral, cognitive, and emotional factors. Cognitive factors (e.g., coping style, illness behavior) play a prominent role in health care-seeking behavior.5 Emotional factors include the presence of a comorbid mood or anxiety disorder.

Anxiety disorders are common in IBS. The estimated prevalence for individual anxiety disorders is 7%–28% for panic disorder, 4%–58% for generalized anxiety disorder, and 7%–26% for social anxiety disorder.6–11

Conversely, patients with anxiety disorders frequently have comorbid IBS. In a chart survey of 41 consecutive patients with panic disorder who were seen in an anxiety clinic, 44% had prominent gastrointestinal symptoms.12 Noyes et al.13 reported that five (16.7%) of 30 patients with panic disorder met criteria for IBS, compared with none of a group of age- and sex-matched healthy subjects who had been recruited through the news media. Tollefson et al.14 found that 37% of a group of patients with generalized anxiety disorder had IBS, compared to 11% of an age- and sex-matched comparison group of medical center employees. In a study by Kaplan et al.,15, 19 (46.3%) of 41 patients with panic disorder had IBS, compared to one (2.5%) of 40 age- and sex-matched comparison patients who were seeking treatment for other medical reasons in a general physician's office. In addition, Masand et al.16 reported that 13 (41.9%) of 31 patients with alcohol use disorder met criteria for IBS, compared to one (2.5%) of 40 comparison patients who were seeking treatment for other medical reasons in a general physician's office.

The co-occurrence of IBS and anxiety disorders may be suggestive of an etiologic overlap of biopsychosocial and/or neurophysiologic factors. In a survey of patients with IBS and comparison subjects,17 recent life stresses were significantly associated with altered bowel habits (experienced by 73% of IBS patients versus 54% of comparison subjects) and abdominal pain (84% of IBS patients versus 64% of comparison subjects). IBS patients may also manifest enhanced perception of visceral stimuli18 and neuroendocrine abnormalities, notably increases in plasma and urinary epinephrine levels, consistent with sympathetic activation.19,20

The gastrointestinal tract responds to stimuli in part by activating the locus ceruleus, which is involved in fear and arousal states. Preliminary studies of agents that reduce locus ceruleus firing have been shown to relieve IBS symptoms.13,21 Serotonin (5-hydroxytryptamine, 5-HT) plays a prominent role both in the physiology of the gut and in the pathophysiology of anxiety disorders. 5-HT is found in gut enterochromaffin cells and in myenteric interneurons and is believed to mediate sensory and reflex responses to gastrointestinal stimuli.22 Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, have demonstrated efficacy across the spectrum of anxiety disorders, including panic disorder,23 social anxiety disorder,24 generalized anxiety disorder,25 and obsessive-compulsive disorder.26 The study reported here examined the use of paroxetine in IBS patients with and without comorbid anxiety disorders.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Twenty subjects with IBS (seven male patients and 13 female patients, mean age=42.8 years), 10 with a lifetime history of comorbid anxiety disorder and 10 without anxiety disorder, were enrolled. IBS was defined by using the Rome I criteria (Appendix 1). 27 Total duration of IBS was 7.15 years (range=0.5–30). At baseline all patients were administered a clinician version of the Structured Clinical Interview for DSM-IV (SCID). The anxiety disorders present in the anxiety group were specific phobia (N=5), panic disorder without agoraphobia (N=3), panic disorder with agoraphobia (N=1), social anxiety disorder (N=3), and posttraumatic stress disorder (N=1). In addition, major depressive disorder, dysthymia, and adjustment disorder were present in one patient each.


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APPENDIX 1. Rome I Diagnostic Criteria for Irritable Bowel Syndromea



The study was approved by the institutional review board at the participating institutions. All patients provided informed consent and underwent a physical examination and laboratory evaluations including complete blood count, blood chemistry, and fecal occult blood test. The patients also underwent a flexible sigmoidoscopy to confirm the diagnosis of irritable bowel syndrome. In addition, the 21-item Hamilton Depression Rating Scale, Clinical Global Impression (CGI), and Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale28 were administered at each follow-up visit.

Subjects were treated for 12 weeks with 20 mg of paroxetine in the morning. The dose was increased to 40 mg/day after 4 weeks in patients with a partial response to 20 mg. The mean dose of paroxetine was 31 mg/day.

Patients' self-rated symptom improvement was monitored on a daily basis throughout the study period by using a telephone-based interactive voice response system. The psychometric validity of the interactive voice response system in administering diagnostic and symptom rating scales by telephone has been evaluated in several studies. The interactive voice response system has been compared to the clinician-administered SCID.29 Interactive voice response systems have also been used to administer the Hamilton Depression Rating Scale,30 the Hamilton Anxiety Rating Scale,31 and the Zung Depression Scale.32

For dichotomous variables (i.e., abdominal pain, constipation, diarrhea, incomplete emptying, and bloating), response was defined as >=50% improvement from baseline to the last study week in the total or mean number of days the patient had the symptom. For continuous variables (i.e., severity and/or frequency and general level of stress), improvement was defined as >=50% reduction from the baseline week to the last study week in the total or mean severity score. Remission was defined as >=70% improvement over baseline.

The proportion of patients who experienced a response or remission (>=50% or >=70% improvement) was compared between anxiety groups by using Fisher's exact test. The mean change in the number of bowel movements between the first and last study week was assessed by using the t test.


  RESULTS

 
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 INTRODUCTION
 METHOD
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DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Overall, 13 (65%) of 20 subjects reported >=50% improvement in abdominal pain, 14 (70%) in pain severity, and 11 (55%) in pain frequency. For constipation, nine (69%) of 13 patients experienced >=50% change in frequency and eight (62%) had reduction in severity. For diarrhea, eight (57%) of 14 patients experienced improvement in frequency and reduction in severity. For incomplete emptying, nine (53%) of 17 patients improved in frequency and 10 (59%) had a reduction in severity.

Data were then analyzed according to the presence or absence of an anxiety disorder. Eight (80%) of 10 IBS patients with anxiety disorder and five (50%) of 10 patients without anxiety disorder experienced >=50% improvement in abdominal pain. Pain frequency was improved in seven (70%) and four (40%) patients with and without anxiety disorder, respectively.

For the more stringent criterion of remission (>=70% improvement), seven (70%) patients with anxiety disorder experienced improvement in abdominal pain, severity, and frequency, compared with two (20%) patients without anxiety disorder (p=0.07, Fisher's exact test).

For constipation, five (71%) of seven patients with anxiety disorder and four (67%) of six patients without anxiety disorder experienced >=50% improvement. Severity of constipation was alleviated in five (71%) and three (50%) patients with and without anxiety disorder, respectively. This improvement in constipation seemed somewhat unexpected in patients treated with an agent that binds to anticholinergic receptors in vitro; however, it is common to find differences between what is apparent in vitro and what occurs in clinical settings. The improvement in constipation may be mediated, in part, by other receptors, such as 5-HT3, 5-HT2A, and cholecystokinin. Diarrhea frequency and diarrhea severity were improved in five (71%) of seven anxiety disorder patients and three (43%) of seven patients without anxiety disorder. For patients reporting a sensation of incomplete emptying, improvement was found in five (63%) of eight anxiety disorder patients and four (44%) of nine patients with no anxiety disorder. Severity of incomplete emptying was alleviated in five (63%) patients with anxiety disorder and five (56%) patients without anxiety disorder. Six (60%) of 10 patients with anxiety disorder and five (50%) of 10 patients without anxiety disorder experienced improvement in frequency of bloating/distension. Severity of bloating/distension was improved in six (60%) patients in each of the two groups.

Figure 1 shows the level of improvement on the CGI for patients with and without anxiety disorder. Overall, five of nine patients (56%) with anxiety disorder reported feeling very much improved or much improved (>=4 consecutive days of feeling better), compared with three of eight patients (38%) without anxiety disorder. There was minimal improvement in general level of stress (one [10%] of 10 patients in each of the two groups). Improvement in IBS symptoms with paroxetine was independent of comorbid anxiety disorder. There was no significant difference between the two groups with respect to improvement on any IBS symptom. Moreover, there was no significant difference in any symptom domain according to the subtype of IBS (constipation or diarrhea predominance).



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FIGURE 1. Self-Ratings on the Clinical Global Impression Scale After a 12-Week Trial of Paroxetine for Patients With Irritable Bowel Syndrome, by Presence or Absence of Coexisting Anxiety Disorder


Paroxetine was generally well tolerated. The most common adverse effects on the UKU Side Effect Rating Scale were sleepiness/sedation, asthenia/lassitude/increased fatigue, and reduced salivation.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Early studies on the potential effectiveness of antidepressants in patients with IBS reported that trimipramine was efficacious in alleviating IBS-associated abdominal pain, nausea, sleeplessness, and depression.33,34 A recent meta-analysis examined data obtained from 12 randomized, placebo-controlled trials of antidepressants in IBS.35 Study medications included the tricyclic antidepressants amitriptyline, clomipramine, trimipramine, doxepin, desipramine, and the antiserotonin agent mianserin. The summary odds ratio for improvement with antidepressant therapy was 4.2; the average standardized mean improvement in pain was equal to 0.9 standard deviation units. In reviewing the 5-year clinical experience with antidepressants in outpatients with IBS (N=138), Clouse et al.36 reported improvement in 89% and complete remission of bowel symptoms in 61% of patients. Median doses to achieve remission were less than those used to obtain an antidepressant effect. The presence/absence of psychological symptoms was not predictive of treatment remission.

In the present open-label study, the effectiveness of the selective serotonin reuptake inhibitor paroxetine was comparable in IBS patients with and without a coexisting anxiety disorder. Although paroxetine was somewhat more effective in alleviating abdominal pain, pain frequency, and pain severity in patients with anxiety disorder than in those without anxiety disorder, the differences were not statistically significant. The lack of statistical significance may be due to disparity in the severity and recency of the anxiety disorders in the anxiety disorder group or due to the small number of patients in the study. Alternatively, these preliminary data indicate that the beneficial effects of paroxetine in IBS may not be due solely to antidepressant or anxiolytic effects and also suggest the need for further study to determine the mechanisms of effect.

The underlying mechanisms of paroxetine in relieving gastrointestinal symptoms are unknown but may be attributable in part to the activity of this agent at the 5-HT3 receptor. Some investigators have suggested that the beneficial effect of serotonergic and noradrenergic antidepressants in IBS may be partly due to these agents' antinociceptive (analgesic) effect, which is independent of their antidepressant effect.37 This hypothesis requires further examination in a larger, placebo-controlled trial to determine if pain scores improve more significantly than other IBS symptom clusters in IBS patients with and without coexisting psychiatric illness who are treated with paroxetine.

Strengths of our study included the use of Rome criteria for the diagnosis of IBS, as well as use of a detailed medical workup, including flexible sigmoidoscopy, to confirm the diagnosis of IBS. The psychiatric diagnoses were made by using a structured psychiatric interview, and depressive symptoms were monitored with the Hamilton depression scale to control for depression as a confounding variable. In addition, the automated telephone interactive voice response system helped avoid recall biases associated with retrospective methods for reporting symptoms, such as patient-rated symptom diaries submitted to researchers weekly or biweekly. In our study, patients completed 86% of all required daily calls.

Limitations of the study included a lack of placebo control, the small number of study patients, and inclusion of patients with comorbid psychiatric diagnoses. Our ability to show a true drug effect was somewhat limited by the absence of a placebo control. In a study conducted in a larger study population, the confidence that the results were not due to chance alone could be increased and perhaps statistical differences would be apparent. In our study, the presence of comorbid psychiatric diagnoses in the study patients could have been a confounding factor that skewed the results. The results should be interpreted cautiously, as the study was a preliminary, uncontrolled, open trial with a small number of participants. Randomized, double-blind, placebo-controlled studies are needed to verify our findings.


  CONCLUSIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The results of this open-label study suggest that paroxetine is effective in alleviating abdominal pain, constipation, and diarrhea associated with IBS. This improvement does not appear to be due to the medication's anxiolytic effects but to some undetermined effect on gastrointestinal functioning. Placebo-controlled studies examining the efficacy of paroxetine in IBS are required. Additional research is needed to ascertain the nonpsychiatric effects of paroxetine in patients with other functional gastrointestinal disorders.


  ACKNOWLEDGMENTS

 
Supported in part by GlaxoSmithKline.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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