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Keywords:

  • anxiety;
  • cognitive factors;
  • irritable bowel syndrome;
  • panic disorder

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Aim

The present study examined the effect of irritable bowel syndrome (IBS), cognitive appraisal of IBS, and anxiety sensitivity on anticipatory anxiety (AA) and agoraphobia (AG) in patients with panic disorder (PD).

Methods

We examined 244 PD patients who completed a set of questionnaires that included the Rome II Modular Questionnaire to assess the presence of IBS, the Anxiety Sensitivity Index (ASI), the Cognitive Appraisal Rating Scale (CARS; assessing the cognitive appraisal of abdominal symptoms in four dimensions: commitment, appraisal of effect, appraisal of threat, and controllability), and items about the severity of AA and AG. The Mini International Neuropsychiatric Interview was used to diagnose AG and PD.

Results

After excluding individuals with possible organic gastrointestinal diseases by using ‘red flag items,’ valid data were obtained from 174 participants, including 110 PD patients without IBS (PD/IBS[–]) and 64 with IBS (PD/IBS[+]). The PD/IBS[+] group had higher AA and higher comorbidity with AG than the PD/IBS[–] group. In the PD/IBS[+] group, the controllability score of CARS was significantly correlated with AA and ASI. Multiple regression analysis showed a significant effect of ASI but not of controllability on AA in PD/IBS[+] subjects.

Conclusion

This study suggested that the presence of IBS may be related to agoraphobia and anticipatory anxiety in PD patients. Cognitive appraisal could be partly related to anticipatory anxiety in PD patients with IBS with anxiety sensitivity mediating this correlation.

THE CORRELATION BETWEEN panic disorder (PD) and irritable bowel syndrome (IBS) has attracted much attention.[1-6] PD shares various symptoms with IBS, such as autonomic symptoms, anticipatory anxiety, depression, and avoidant behavior due to fear of symptoms.[5] In addition, PD patients have been shown to have a high prevalence of IBS.[1-5] For example, PD patients reportedly have a higher prevalence of IBS than patients with other psychiatric diseases.[6]

Studies have shown that the presence of IBS might be related to the development or severity of PD.[5, 7-12] Most PD patients develop IBS before PD, and IBS might be associated with the severity of anticipatory anxiety, agoraphobia, and panic attacks in PD patients.[5, 7] Based on the brain–gut axis, the hypersensitivity and increased motility of the colon observed in patients with IBS[8] might increase the activity of the locus coeruleus,[9, 10] which would then activate noradrenergic neurons, such as those neurons in the locus coeruleus, inducing fear and anxiety and subsequently the onset of PD.[11, 12] In addition, cognitive factors may play an important role in panic/IBS comorbidity and the severity of PD symptoms in PD patients with IBS. Maunder[13] has suggested that the experience of uncontrollable somatic symptoms, which is common in IBS patients and leads to avoidant behaviors, acts as a provocative factor for PD in patients with mild or subclinical PD-like symptoms who had otherwise not been identified as suffering from PD. We have previously reported that the cognition of abdominal symptoms may intensify anxiety in individuals with IBS.[14] The manner in which PD patients with IBS appraise their abdominal symptoms (e.g. that abdominal symptoms are uncontrollable or have a negative impact) may therefore be related to the severity of their PD-related symptoms.

Another factor that might affect anxiety-related symptoms in PD and IBS is anxiety sensitivity. Anxiety sensitivity is an enduring, trait-like tendency; it is believed that anxiety and its symptoms are harmful to the body or mental state. This tendency may be a psychological vulnerability factor for PD. PD patients were reported to have high scores for anxiety sensitivity.[15] Anxiety sensitivity has also been suggested as a possible cognitive mechanism that governs fear behavior.[16] In addition, individuals with IBS have also been reported to have high scores for anxiety sensitivity.[14, 17] We have observed that anxiety sensitivity is related to the cognition of abdominal symptoms and anxiety in individuals with IBS.[14]

Thus, we hypothesized that: (i) PD patients with IBS would have high anxiety sensitivity and severe anxiety-related symptoms, including anticipatory anxiety and agoraphobia, compared with those without IBS; and (ii) anxiety-related symptoms would be exacerbated by maladaptive cognition of IBS symptoms, which might be affected by anxiety sensitivity in PD patients with IBS.

As described above, PD and IBS may be mutually reinforcing through a duplicated mechanism of aggravation; therefore, it is clinically useful to investigate the correlation between cognitive factors, such as the manner in which PD patients with IBS appraise their abdominal symptoms and the symptoms and cognitions associated with PD. Thus far, little information is available regarding the psychological process related to the aggravation of anxiety-related symptoms in PD patients with IBS. Hence, we investigated: (i) the difference in anxiety sensitivity and anxiety-related symptoms (anticipatory anxiety and agoraphobia) according to the presence/absence of IBS in PD patients; and (ii) how the cognition of IBS is related to the severity of anxiety sensitivity, anticipatory anxiety, and agoraphobia in PD patients with IBS.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Participants

A total of 244 PD outpatients who attended a psychosomatic and psychiatric clinic participated in this study. PD was diagnosed according to DSM-IV criteria[18] and clinical records. An interview that used the Mini International Neuropsychiatric Interview (MINI) was also conducted to diagnose most of the patients. The participants were mainly prescribed antidepressants, such as paroxetine (10–40 mg/day), fluvoxamine (25–250 mg/day), and imipramine (10–150 mg/day), and/or anxiolytics, such as ethyl loflazepate (0.5–2.0 mg/day) and lorazepam (0.5–3 mg/day), regardless of the presence of IBS. After excluding individuals with red-flag items to exclude organic gastrointestinal diseases, valid data were obtained from 174 participants (55 men and 119 women). Interviews that used the MINI were conducted with 151 patients among the 174. The mean age of the participants was 37.7 ± 9.2 years. The participants included 110 PD patients who did not meet the criteria for IBS (63%; PD/IBS[–]) and 64 PD patients with IBS (37%; PD/IBS[+]). The duration of PD among the participants was 10.9 ± 10.5 years. The groups did not differ significantly in the duration of PD. The onset of IBS preceded PD in 28 patients (44% in PD/IBS[+]) while the onset of PD preceded IBS in 17 patients (27% in PD/IBS[+]). Simultaneous onset was found in 15 patients (23% in PD/IBS[+]). The chronological correlation was unknown in four patients (6% in PD/IBS[+]). There is no significant difference between the frequency of IBS preceding PD and that of PD preceding IBS in the PD/IBS[+] group.

Measures

MINI

The MINI[19] was designed as a brief structured interview for major axis I psychiatric disorders in the DSM-IV. We used this interview to confirm the presence of agoraphobia in the participants of this study.

Rome II Modular Questionnaire (only items related to IBS)

The Rome II diagnostic criteria for gastrointestinal disorders are widely used. IBS and its subtypes were defined according to the Rome II Modular Questionnaire.[20, 21] The presence of IBS was confirmed if participants had abdominal pain or discomfort at least once a week during at least 3 weeks in the last 3 months and had at least two of the three following symptoms: (i) pain or discomfort that improved or stopped after a bowel movement; (ii) a change in the number of bowel movements when the pain or discomfort started; and (iii) either softer or harder stools than usual when the pain or discomfort started.

Red-flag items

Seven red-flag items, based on the American Gastroenterological Association's guidelines for IBS, were used to distinguish organic from functional gastrointestinal diseases. Individuals reporting any of these red-flag items were excluded from this study. The items included unexplained weight loss, a history of organic bowel disease, a history of digestive surgery, being awakened by abdominal pain during night sleep, fever or arthralgia, blood in the stool, and anemia.

Anxiety Sensitivity Index

The Anxiety Sensitivity Index (ASI)[22, 23] is a 16-item reliable and valid index of the tendency to believe that the physical sensations associated with anxiety are harmful and bear negative physical, social, or psychological consequences. The total score ranges from 16 to 80. Each item is rated on a scale of 1 [not at all] to 5 [strongly agree].

Cognitive Appraisal Rating Scale

The Cognitive Appraisal Rating Scale (CARS)[24] was used to measure IBS-related cognition, that is, how individuals with IBS usually rate themselves when they have symptoms of IBS. The CARS consists of four factors (commitment, appraisal of effect, appraisal of threat, and controllability) that are assessed by two items rated on a scale of 1–4. The total score ranges from 8 to 32 (score on each subscale ranges from 2 to 8). The ‘commitment,’ ‘appraisal of effect,’ ‘appraisal of threat,’ and ‘controllability’ subscales of the CARS correspond to ‘challenge,’ ‘harmful effect,’ ‘threat,’ and ‘controllability,’ respectively, in the construct advocated by Lazarus and Folkman.[25] ‘Commitment’ is an attempt to improve that situation, ‘appraisal of effect’ is thinking that the situation may have an influence on one, ‘appraisal of threat’ is a thought that the situation may threaten one's life, and ‘controllability’ is a thought that one could deal with the situation. The CARS was standardized for the Japanese population and has sufficient validity and reliability.[24] We thus considered CARS to be suitable for this study. We instructed only those participants who met the criteria for IBS to complete the CARS.

Items about anticipatory anxiety and agoraphobia

The anticipatory anxiety score was calculated by using two items for the frequency (rated from 0 [none] to 4 [at all times]) and degree (rated from 0 [none] to 4 [extremely severe]) of anticipatory anxiety for the past week. Agoraphobia score was calculated by using two items, namely, the frequency of avoidant behavior (rated from 0 [none] to 4 [at all times]) and the degree of interference, for the past week (rated from 0 [none] to 4 [extremely severe]). The score for each variable ranged from 0 to 8. The internal reliabilities (coefficient Alfa) of items for anticipatory anxiety and items for agoraphobia in data of the present study were 0.90 and 0.85, respectively. Regarding correlations between these scores and the ASI score as indicator of concurrent validity, the anticipatory anxiety score and the agoraphobia score positively correlated with the ASI score (rs = 0.48, P < 0.001; rs = 0.24, P = 0.06, respectively, Spearman rank correlation coefficient).

Procedure

The researchers (physicians and clinical psychologists) conducted the interviews to confirm the presence or absence of agoraphobia in each participant. Participants then completed questionnaires containing the physical and psychological scales mentioned above.

Ethical considerations

The researchers provided a detailed explanation of the purpose of this study, the testing content, the protection of personal information, and other relevant information to the participants. The PD patients who agreed to participate in this study provided informed consent. The study was approved by the Ethical Committee of the Graduate School of Medicine, University of Tokyo.

Statistical analysis

Data analysis was performed using spss 17.0 (spss Japan, Tokyo, Japan). Nominal significance level was set at P < 0.05. Comparisons of the ASI, CARS, anticipatory anxiety, and agoraphobia scores between PD patients with and without IBS were performed with the Student's t-test. Comparison of the prevalence of agoraphobia between the two groups was performed with the χ2-test. The correlations among the variables, including ASI, CARS, anticipatory anxiety, agoraphobia, age, and PD duration in PD patients with IBS, were analyzed using Spearman's rank correlation coefficient. Multiple testing corrections between the CARS and other variables were performed using the Bonferroni test, with P < 0.013 (=0.05/4; statistically significant) after the correction. The effect of cognition of IBS on anticipatory anxiety score was examined by using multiple regression analysis. For this regression analysis, we selected the variables correlated with anticipatory anxiety as the explanatory variables.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Comparisons of anxiety sensitivity, anticipatory anxiety, and agoraphobia by the presence of IBS

The PD/IBS[+] patients had significantly higher anticipatory anxiety scores than the PD/IBS[–] group (Table 1). No significant difference was observed in the severity of agoraphobia and anxiety sensitivity between PD/IBS[+] and PD/IBS[–]. However, the PD/IBS[+] group had a significantly higher prevalence of agoraphobia than the PD/IBS[–] group (Table 2).

Table 1. Severities of anticipatory anxiety, agoraphobia, and anxiety sensitivity according to the presence/absence of IBS
 PD/IBS[+]PD/IBS[–]t value
Mean score ± SDMean score ± SD
  1. *P < 0.05.

  2. ASI, Anxiety Sensitivity Index; IBS, irritable bowel syndrome; PD, panic disorder; PD/IBS[+], patients with PD and IBS; PD/IBS[–], patients with PD who did not meet the criteria for IBS.

Anticipatory anxiety2.39 ± 2.191.73 ± 1.70t (172) = 2.01*
Agoraphobia11.77 ± 7.908.37 ± 6.551.91
ASI total46.42 ± 13.0742.94 ± 11.701.75
Table 2. Prevalence of agoraphobia by the presence of IBS
 PD/IBS[+]PD/IBS[–]
  1. χ2 [1] = 3.57; P < 0.05.

  2. IBS, irritable bowel syndrome; PD, panic disorder; PD/IBS[+], patients with PD and IBS; PD/IBS[–], patients with PD who did not meet the criteria for IBS.

Agoraphobia (+)3444
(–)2152

Correlations of anxiety sensitivity, anticipatory anxiety, and agoraphobia with IBS-related cognition in PD/IBS[+] patients

The ASI score was significantly positively correlated with appraisal of effect and appraisal of threat and significantly negatively correlated with controllability. Controllability was significantly negatively correlated with anticipatory anxiety (Table 3). ASI score was also significantly positively correlated with anticipatory anxiety (rs = 0.41; P < 0.01, not shown in the table). Correlations between controllability and anticipatory anxiety and between anxiety sensitivity and anticipatory anxiety remained statistically significant after applying the Bonferroni correction for multiple testing.

Table 3. Spearman rank correlation coefficients of anxiety sensitivity, anticipatory anxiety, and agoraphobia with subscales of the CARS in patients with PD and IBS
 CARS
CommitmentAppraisal of effectAppraisal of threatControllability
  1. *P < 0.05; **P < 0.01 uncorrected.

  2. ASI, Anxiety Sensitivity Index; CARS, cognitive appraisal rating scale; IBS, irritable bowel syndrome; PD, panic disorder.

Anticipatory anxiety0.170.180.23−0.35**
Agoraphobia0.110.210.13−0.14
ASI0.110.32*0.31*−0.27*

Age was correlated to anticipatory anxiety (rs = −0.30; P < 0.05) and controllability (rs = 0.26; P < 0.05, uncorrected). Duration of PD was not correlated with ASI, CARS, anticipatory anxiety, and agoraphobia scores.

Multiple regression was used to investigate the effect of the ASI and controllability score on the CARS, adjusting for both, on anticipatory anxiety score in the PD/IBS[+] group. ASI score was significantly related to anticipatory anxiety score (P < 0.001) but controllability and age were not (Table 4).

Table 4. Effects of ASI and the controllability score of CARS on anticipatory anxiety score in patients with PD and IBS
 B
  1. *P < 0.05.

  2. ASI, Anxiety Sensitivity Index; CARS, cognitive appraisal rating scale; IBS, irritable bowel syndrome; PD, panic disorder.

Age−0.14
ASI0.46*
Controllability−0.16
R20.32
Adjusted R20.28

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

PD patients with IBS (PD/IBS[+]) had higher anticipatory anxiety scores than those without IBS (PD/IBS[–]). The prevalence of agoraphobia was also higher in PD/IBS[+] patients than PD/IBS[–] patients, while severity of agoraphobia did not differ significantly between them. No significant difference was observed in anxiety sensitivity between PD/IBS[+] and PD/IBS[–] patients. In the PD/IBS[+] patients, lower ‘controllability’ was correlated with more severe anticipatory anxiety. When anxiety sensitivity, which was correlated with controllability, was adjusted for in multiple regression, however, the effect of controllability on anticipatory anxiety was not significant. On the other hand, anxiety sensitivity was significantly associated with anxiety sensitivity in the analysis.

Regarding the first purpose of the study, which was to investigate differences in anxiety sensitivity and anxiety-related symptoms according to the presence/absence of IBS in PD patients, the high prevalence of agoraphobia and severe anticipatory anxiety in PD/IBS[+] patients corresponded with the results of previous studies, which have observed the development of severe PD in the presence of IBS.[5, 7-12] Although the underlying mechanism of the correlation between severe anticipatory anxiety and high prevalence of agoraphobia in PD patients with IBS could not be fully clarified in the present study, these observations might provide a new direction for future studies that aim to develop more effective cognitive interventions for PD patients with IBS.

No significant difference was observed in anxiety sensitivity between PD/IBS[+] and PD/IBS[–] patients. Previous research works[14, 17] reported strong anxiety sensitivity in patients with IBS. These studies have also observed high anxiety sensitivity in PD patients.[15, 26, 27] The lack of a significant difference in anxiety sensitivity between PD/IBS[+] and PD/IBS[–] individuals might therefore indicate the absence of an interactive effect of PD and IBS on anxiety sensitivity.

The second purpose of this study was to investigate how the cognition of IBS is related to the severity of anxiety sensitivity, anticipatory anxiety, and agoraphobia in PD patients with IBS. We hypothesized that anxiety-related symptoms would be exacerbated by maladaptive cognition of IBS symptoms, which might be affected by anxiety sensitivity in PD patients with IBS. The present study found that lower controllability of abdominal symptoms was significantly correlated with the severity of anticipatory anxiety. However, when anxiety sensitivity, which was associated with controllability, was controlled for in multiple regression analysis, the correlation between the two did not remain statistically significant. In contrast, anxiety sensitivity was significantly associated with anticipatory anxiety when controllability was controlled for in multiple regression analysis. These suggest that the correlation between cognitive appraisal (or uncontrollability) of abdominal symptoms and anticipatory anxiety in PD/IBS[+] patients may be affected by the severity of anxiety sensitivity. These results could partly, although not fully, support our hypothesis. In a previous study in individuals with IBS, no significant correlation was observed between controllability of abdominal symptoms and anxiety.[14] The correlation between controllability of abdominal symptoms and anticipatory anxiety found in the present study might therefore be characteristic of PD patients or of PD-related anxiety.

The correlation between anxiety sensitivity and IBS-related cognitions were not significant after Bonferroni correction. Therefore, careful consideration is needed when interpreting the results of the correlation analysis.

The frequency of the patients with IBS preceding PD (44%) was higher than that of patients with the reverse (27%) and those with simultaneous onset of PD and IBS (23%) but the difference was not statistically significant. This might be consistent with a previous study that found that panic symptoms were more likely to follow IBS symptoms[5] although IBS symptoms were reported to be more likely to follow most psychiatric diseases.[28] This result could highlight the importance of PD prevention in individuals with IBS. A previous review[13] has suggested that the experience of feeling uncontrollable somatic symptoms, which is common in IBS and leads to avoidant behaviors, could act as a provocative factor for PD in patients with subclinical PD-like symptoms. We expect that interventions for the uncontrollability of abdominal symptoms could improve bowel motility in patients with IBS through physiological changes, including normalization of hypothalamic–pituitary–adrenal axis activity.[29] The improved bowel motility following the intervention might moderate the hyperactivity of the noradrenergic neurons in locus coeruleus,[9, 10] leading to alleviation of fear, anxiety, and subsequent onset of PD.[11, 12]

Although this study provided new insights, it has a number of limitations. First, the medications may have affected these results as the participants of this study were being treated for PD. Moreover, medications that are effective in treating both PD and IBS may improve PD and IBS symptoms, which could also have affected the results of the present study. Thus, future studies in newly diagnosed patients without a history of treatment for PD or IBS may find more accurate correlations between cognitive factors and anxiety symptoms in PD patients with IBS. Second, although Rome II investigates the symptoms during the past 1 year, the Rome II Modular Questionnaire examines the symptoms over a 3-month period, a much shorter period than that required by Rome II. A study that examined the general population by using Rome II survey criteria[20, 21] suggested that it may over-diagnose the disorder because of the shortened timeframe.[17] Moreover, Rome II has been revised to Rome III.[30] Therefore, it is necessary to evaluate the symptoms over a sufficient period of time and use the revised diagnostic criteria in a future study. Third, the present study did not use IBS patients without PD as another control group. The addition of this group may determine the characteristics of PD/IBS comorbidity that lead to high anticipatory anxiety and high comorbidity with agoraphobia. Fourth, while the internal consistency reliability of the items about agoraphobia was sufficient, correlation between the score and the ASI as indicator of concurrent validity did not reach a significant level. Further evaluation of the concurrent validity of the agoraphobia items may be recommended.

Conclusion

This study suggests that PD patients with IBS have more severe anticipatory anxiety and a higher prevalence of agoraphobia. Anxiety sensitivity in PD patients with IBS was correlated with the appraisal of abdominal symptoms while the cognition that their abdominal symptoms are uncontrollable was correlated with anticipatory anxiety. Cognitive appraisal could be partly related to anticipatory anxiety, with anxiety sensitivity mediating this correlation in PD patients with IBS. These observations might provide a new direction in future studies that contribute to the development of more effective cognitive intervention for PD patients with IBS.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This study was supported by Grants-in-Aid for Scientific Research on Priority Areas: ‘Comprehensive Genomics’ and ‘Applied Genomics’ (no. 17019029; no. 21300242) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The copyright of the Japanese version of the Rome II Modular Questionnaire is held by Drs S. Fukudo and M. Kanazawa. We thank them for granting permission to our group to use this questionnaire. None of the authors has anything to disclose.

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  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
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