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Psychosomatic Medicine 66:79-84 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Impact of Depressive Mood on Relapse in Patients With Inflammatory Bowel Disease: A Prospective 18-Month Follow-Up Study

Christian Mittermaier, MD*, Clemens Dejaco, MD*, Thomas Waldhoer, PhD, Anna Oefferlbauer-Ernst, MD, Wolfgang Miehsler, MD, Markus Beier, MD, Wolfgang Tillinger, MD, Alfred Gangl, MD and Gabriele Moser, MD

From the Department of Medicine IV, Division of Gastroenterology and Hepatology (C.D., A.O. W.M., M.B., W.T., A.G., G.M.), Department of Physical Medicine and Rehabilitation (C.M.), and Department of Epidemiology, Institute of Tumor Biology (T.W.), University Hospital of Vienna, Vienna, Austria.

Address correspondence and reprint requests to Dr. Clemens Dejaco, Division of Gastroenterology and Hepatology, Department of Internal Medicine IV, University Hospital, AKH, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: clemens.dejaco{at}akh-wien.ac.at


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: There is evidence of an interaction between psychological factors and activity of inflammatory bowel disease (IBD). We examined the influence of depressive mood and associated anxiety on the course of IBD over a period of 18 months in a cohort of patients after an episode of active disease.

METHODS: In this prospective, longitudinal, observational study, 60 patients (37 women and 23 men) with clinically inactive IBD (Crohn disease, n = 47, 78%; ulcerative colitis, n = 13, 22%) were enrolled after a flare of disease. Psychological status, health-related quality of life (HRQOL), and disease activity were evaluated at baseline and then every 3 months for a period of 18 months by means of clinical and biological parameters, the Beck Depression Inventory (BDI), the Spielberger State-Trait Anxiety Inventory, the Inflammatory Bowel Disease Questionnaire, the Perceived Stress Questionnaire, and the Rating Form of Inflammatory Bowel Disease Patients Concerns.

RESULTS: At baseline, depression (BDI >=13 points) was found in 17 of 60 (28%) patients. Thirty-two patients (59%) experienced at least one relapse during the 18 months of follow-up. Regression analysis showed a significant correlation between BDI scores at baseline and the total number of relapses after 12 (p < .01) and 18 months (p < .01) of follow-up. Furthermore, depression scores at baseline correlated with the time until the first recurrence of the disease (p < .05). Anxiety and low HRQOL were also related with more frequent relapses during follow-up (p < .05 and p < .01, respectively).

CONCLUSIONS: Psychological factors such as a depressive mood associated with anxiety and impaired HRQOL may exert a negative influence on the course of IBD. Therefore, assessment and management of psychological distress should be included in clinical treatment of patients with IBD.

Key Words: inflammatory bowel disease, • depressive mood, • anxiety, • disease activity, • health-related quality of life.

Abbreviations: BDI = Beck Depression Inventory;; CAI = colitis activity index;; CD = Crohn disease;; CDAI = Crohn disease activity index;; ESR = erythrocyte sedimentation rate;; HRQOL = health-related quality of life;; IBD = inflammatory bowel disease;; IBDQ = Inflammatory Bowel Disease Questionnaire;; PSQ = Perceived Stress Questionnaire;; RFIPC = Rating Form of Inflammatory Bowel Disease Patient Concerns;; STAI = Spielberger State-Trait Anxiety Inventory;; UC = ulcerative colitis.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Inflammatory bowel disease (IBD), including both Crohn disease (CD) and ulcerative colitis (UC), is a chronic disabling disorder of unknown multifactorial cause. It is characterized by episodes of exacerbations and remissions. Because the course of disease is unpredictable and there is no realistic hope for cure in patients with CD, treatment must focus on prevention of complications, induction and maintenance of remission, and improvement and preservation of quality of life. The onset of IBD mainly occurs in young people; therefore, questions of quality of life and of coping strategies with the disease are particularly important. Kordy et al. (1) showed that an active and problem-oriented coping style has positive effects on the duration of a flare of disease. There are several reports on the interaction between psychological factors and activity of IBD (2–6). Most studies assessed a possible relationship between stress and disease activity but yielded contradictory results (7–10). However, many patients attach importance to psychological factors, particularly stress, as contributory to the onset and course of the disease (11,12).

There is increasing evidence that depressive mood exerts negative effects on the course of several chronic diseases. In cardiac patients, depression may predict the occurrence of cardiac events and mortality (13,14). A high score of depression is linked to a reduced chance of survival in patients with breast cancer (15). Psychological distress can lead to increased disease severity (16) and disability (17,18) in patients with rheumatoid arthritis. In diabetic patients with depression, glycemic control was significantly more difficult to manage compared with those without depression (19). Considering these reports on different clinical conditions, the question arises whether depressive mood may be a risk factor in IBD.

The primary aim of our prospective study was to examine the relationship between depressive mood and the course of IBD over a period of 18 months in a cohort of patients in remission after an episode of active disease, assuming that depression may be a risk factor for relapse. Secondary, we also evaluated the influence of other psychological factors, such as anxiety and perceived stress and of disease specific quality of life on the course of disease. It is the first study with a continuous long-term follow-up of IBD patients with clinic visits every 3 months, including assessment of clinical, biological, and psychological parameters and health-related quality of life (HRQOL).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Patients
Sixty patients (37 women and 23 men; median age, 31 years; range, 19–59 years) with IBD (CD, n = 47, 78%; UC, n = 13, 22%) who attended the gastroenterology outpatient clinic for IBD at the University of Vienna were enrolled consecutively into this prospective longitudinal observational study after they had achieved remission within 8 to 12 weeks after an acute flare. Patients were followed up by assessing disease activity, HRQOL, and psychological status every 3 months for a period of 18 months. All patients gave informed consent to participate in this study.

Eligibility criteria were as follows:

  1. (1) Patients with IBD diagnosed by generally accepted clinical, endoscopic, histologic, and/or radiologic criteria, age 18 to 65 years.
  2. (2) Patients in remission 8 to 12 weeks after a flare defined by the CD activity index (CDAI) (20) or by the colitis activity index (CAI) (21).
  3. (3) Intention to remain in the region of Vienna for the upcoming 18 months.
  4. (4) Sufficient knowledge of the German language to understand and answer the questionnaires.
  5. (5) Informed consent.

Patients with known or evident psychiatric diseases, patients undergoing psychopharmacotherapy, and stoma patients were excluded.

Protocol
Evaluation of disease activity during follow-up was performed every 3 months for a total of 18 months by physicians (C.M., W.T., and C.D.) who were unaware of the psychological state of the patients at the time of baseline examination. At baseline, patients had to have been in remission (CDAI <150 or CAI <5) for at least 4 weeks. Systemic steroids, immunosuppressants, and 5-aminosalycilates were allowed in maintenance or decreasing doses to preserve remission (Table 1). Medication was prescribed according to the recommendations of the German consensus conferences (22,23).


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  		TABLE 1. Sociodemographic and Disease-Related Data at Baseline, Summarized for All Patients and Separately Outlined for Depressed and Nondepressed Subjects
 
A relapse was defined by clinical criteria and by a CDAI of 150 points or higher or by an increase of 70 points for patients with CD (24), or by a CAI of 6 points or higher for patients with UC (21). To ensure that a relapse indicated by elevated CDAI or CAI counts did not simply reflect a symptom reporting behavior rather than actual disease exacerbation, we also assessed laboratory parameters like leukocytes, platelets, C-reactive protein, orosomucoid, erythrocyte sedimentation rate (ESR), and hemoglobin at clinical visits during a flare. In the case of symptoms indicating a relapse, patients were told to come to the outpatient clinic or, if a visit was not possible, to phone their physician at the hospital. Any initiation of immunosuppressants or steroids during follow-up was considered a recurrence of disease activity.

Because the psychological status at baseline may be influenced by previous relapses, disease activity within the year before enrollment was examined retrospectively by reviewing the patients’ charts. The number of disease flares was summarized for each patient. Possible risk factors for relapse, such as the use of nonsteroidal anti-inflammatory drugs and oral contraceptives and smoking in CD (25), were also recorded before study entry.

Evaluation of Psychological Status
Psychological status was assessed by using the following questionnaires:

  1. (1) Beck Depression Inventory (BDI) (26), a widely used, well validated 21-item self-report inventory that assesses severity of depressive symptoms. Depression was assumed when the BDI score was 13 points or higher. It has been shown that a cutoff point of 13 or higher provided an optimal balance between sensitivity (0.85) and specificity (0.88) in differentiating depressed and nondepressed patients (27).
  2. (2) Spielberger State-Trait Anxiety Inventory (STAI) (28) to assess state and trait anxiety. State anxiety (STAI1) indicates anxiety related to the present moment, whereas trait anxiety (STAI2) indicates a stable dimension of personality.
  3. (3) Inflammatory Bowel Disease Questionnaire (IBDQ) (29), a disease-specific symptom-based self-report measure of quality of life with a 32-item scale that covers symptoms, physical functioning, and psychological state.
  4. (4) Perceived Stress Questionnaire (PSQ) (30), a self-report measure for perceived stress in two versions, with the recent form (PSQ-V) covering the past month and the general form (PSQ-G) covering the past 2 years.
  5. (5) Rating Form of Inflammatory Bowel Disease Patient Concerns (RFIPC) (31), a self-report measure of disease-related concerns and worries that covers 25 potential issues related to IBD.

For data analysis, patients were divided into two groups (depressed and nondepressed subjects) according to their BDI score (>=13 vs. <13 points) at baseline.

Statistical Analysis
Data were analyzed by using the Statistical Analysis System WAMASTAT (32), developed at the University of Vienna and derived from SAS (SAS/STAT 1999, User’s Guide, Version 8; SAS Institute, Cary, NC). Because data are not distributed symmetrically, values are expressed as medians (interquartile range). The relationships between BDI scores and disease-related and sociodemographic data were analyzed using the Wilcoxon test, the Mann-Whitney U test, or the {chi}2 test as appropriate. The relation between psychometric, sociodemographic, and disease-related data at baseline and the total number of relapses during follow-up and during the year before enrollment were examined by the Kendall correlation coefficient {tau}. In addition, we estimated a Poisson regression model with "total number of relapses" as the dependent variable, and BDI scores, numbers of flares within the previous year, medication at baseline, and smoking status as independent variables. To assess the influence of baseline disease activity in patients with CD on the course of disease, a further regression analysis adding CDAI to the mentioned independent variables was performed. Medication and smoking status were treated as categorical and therefore were entered via dummy variables. Proc genmod with the option pscale for accounting for overdispersion was used for estimation. For comparison, the statistical level of significance was set at p <.05. A Kaplan-Meier curve showing the relapse-free survival of patients from the depressed and the nondepressed group was calculated. The curves were compared by the Cox F test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
All 60 patients who entered the protocol were included for analyses regarding correlation of disease-related and psychometric variables at baseline with the total number of relapses within 1 year before enrollment. Two patients with UC who had undergone colectomy and consequently had no remaining symptoms of UC were excluded from the 12-month and 18-month follow-up analyses. Four patients (two with CD and two with UC) were lost to follow-up, one after 12 months and the other three after 15 months. Five of these six patients presented with depressive mood (BDI score >=13 points) at baseline (median BDI score, 14; interquartile range, 13–15). Survival analyses were calculated for all patients, censored within 18 months follow-up or at the time that they were lost. Fifty-four patients were included in the 18-month follow-up analysis. Ten of them entered the study after they had experienced their first acute flare of IBD.

Sociodemographic and disease-related data of all patients are shown in Table 1, psychometric data and HRQOL at baseline in Table 2.


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  		TABLE 2. Psychometric Data and HRQOL at Baselinea
 
Thirty-two patients (59%) experienced at least one relapse during the 18 months of follow-up. Evaluation of biological parameters revealed significantly elevated CRP and orosomucoid counts during flares compared with baseline values in remission (p <.01). No correlation was found for ESR, leukocytes, and hemoglobin (data not shown).

Psychometric Scores, Disease-Related Data, and Relapse Rates
The correlation of disease-related and psychometric variables at baseline with the total number of relapses within 1 year before enrollment is shown in Table 3. Baseline laboratory data, CDAI, CAI, depressive mood, or state and trait anxiety did not correlate, whereas IBDQ showed a strong correlation (p <.001) with the number of relapses within the previous year.


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  		TABLE 3. Correlation of Disease-Related and Psychometric Variables at Baseline With the Total Number of Relapses Within 1 Year Before Enrollment
 
The correlation of the disease related and psychometric variables at baseline with the frequency of relapses within the following 18 months is presented in Table 4. Relapse rates revealed a correlation with baseline depressive mood, disease-specific quality of life, and state and trait anxiety. No correlation was found with baseline laboratory data, CDAI, or CAI.


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  		TABLE 4. Correlation of the Disease-Related and Psychometric Variables at Baseline With the Total Number of Relapses Within 18 Months of Follow-Up
 
Recurrence rates after 18 months did not differ between patients with acute-onset of IBD and patients with longer duration of disease (p =.2).

Depressed and Nondepressed Patients
At baseline, depression (BDI >=13 points) was found in 17 (28%) of 60 patients. Depressed and nondepressed patients did not differ in terms of laboratory data; gender; age; disease duration; severity of disease; smoking habits; and use of corticosteroids, nonsteroidal anti-inflammatory drugs, or oral contraceptives. In depressed patients with CD, the CDAI count at baseline was higher than in nondepressed subjects (112 vs. 72, p <.01) but within a range indicating inactive disease. Depressed patients reported more bowel movements (p <.05) and showed a tendency for decreased well-being (p =.07) but did not differ in pain rating (p =.3). In UC, there was no difference between the two groups regarding CAI counts. Depression was found equally distributed between patients experiencing their first flare of IBD and those with longer-lasting disease (p =.15). At baseline, depressed patients showed significantly more state and trait anxiety, lower health-related quality of life, more disease-related concerns and worries, and more recently perceived stress than nondepressed patients (Table 2).

Figure 1 displays the course of depressive mood expressed in BDI scores for depressed and nondepressed subjects during follow-up. The survival functions of the time to relapse are shown in Figure 2. Patients with depression at baseline showed a higher probability for relapses within 18 months than patients without depression (Cox F test, p <.05). The median time until first relapse was 97 days for patients with depression compared with 362 days for nondepressed subjects (p <.05).



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  		Fig. 1. BDI scores remained stable during the 18 months of follow-up. Patients with IBD were divided into depressed (BDI >=13) and nondepressed subjects (BDI <13) at baseline.

 


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  		Fig. 2. Patients with depression (BDI >=13) were at risk for an earlier relapse than nondepressed subjects (BDI <13); *p <.05. Arrows indicate median time to first relapse.

 
Severity of Depression
Beck Depression Inventory scores assessing depressive mood at baseline correlated significantly both with the development of flares (Kendall {tau}, -0.1877; p <.05) and with the total number of flares during follow-up (Kendall {tau}, 0.2023; p <.05). BDI scores also correlated with the time until first relapse (Kendall {tau}, -0.2314; p <.05): the higher the score at baseline, the earlier a flare was experienced.

The results of the regression model showed a significant correlation between BDI scores at baseline and the total number of relapses after 12 (p <.01) and 18 months (p <.01) of follow-up. The same correlation (p <.01) was found between the number of flares within the previous year before enrollment and the relapse rates after 12 and 18 months of follow-up. Medication and smoking status at baseline had no influence on relapse rates. Adding baseline CDAI scores to the regression model revealed no impact of baseline disease activity on CD recurrence rates after 12 (p =.96) and 18 (p =.35) months.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
This is the first prospective, long-term follow-up study on patients with IBD in remission after a flare assessing the influence of depressive mood on the course of the disease. Our data indicate that depressive mood associated with anxiety and lower HRQOL may be a risk factor for early clinical recurrence and more active disease.

Depression and anxiety are significantly more common in people with IBD than in the general population (33–35). Addolorato et al. (34) observed that more than 80% of IBD patients with active disease suffered from state anxiety, and approximately 60% had concomitant depression. The rate is similar to that found in other patient groups with chronic physical illness (36). Patients have a high risk for developing these mental disorders during the first year after diagnosis of IBD (35).

Three prospective studies dealing with the possible influence of depressive mood on disease activity in IBD have been reported (2,8,37). Andrews et al. (2) included IBD patients either with a flare or in remission and showed that the presence of psychiatric illness adversely affected physical recovery. However, the time of follow-up was not indicated in this article, and no continuous monitoring of the patients was performed. Levenstein et al. (8) included patients with UC in complete clinical remission for at least 2 months and could not find an association between depressive mood and exacerbation during follow-up. North et al. (37) enrolled patients with IBD regardless of their disease activity and had semiannual intervals between clinic visits. This study reported modest associations between intestinal symptoms and the mood scales used.

Because depressive mood at baseline may be a result of disease activity before enrollment in this study, we retrospectively assessed the number of relapses experienced by these patients within the previous year. There was no correlation between depressive mood and the number of preceding disease flares, whereas impaired disease-related quality of life was detected in patients with more relapses.

Patients with depression did not differ in the parameters reflecting disease activity (eg, ESR, leukocytes, and C-reactive protein) and in medication at baseline from nondepressed subjects. Although CDAI counts at baseline were significantly different between depressed and nondepressed patients, scores were below 150 points, indicating inactive CD in both groups. Although it appears conceivable that this difference could be attributed to the subjective subitems of this score rated higher by patients with depression, we could not completely confirm this assumption. However, no data can be found that demonstrate a relation between relapse rates and CDAI scores below 150 points (indicating inactive CD), which was also shown in our regression model. The relatively stable course of depressive mood, expressed as BDI scores during follow-up, may reflect an untreated depression or dysthymia occurring independently from IBD, or may be a result of recent recurrence of the chronic disease (maladaptive coping style).

One may also argue that the chronic diseases CD and UC may lead to physical deconditioning resulting in symptoms similar to the signs of depression (eg, fatigue, changes in sleep patterns, low appetite, loss of weight and libido). Anemia, for instance, is a frequent complication in IBD that may also account for these symptoms (38,39). However, the evaluation of these somatic symptoms is included in many questionnaires on depressive mood. We decided to use the BDI to detect depression in our patients because Lustman et al. (27) demonstrated that not only the cognitive but also the somatic items of this score may effectively discriminate depressed from nondepressed subjects with a chronic disease.

Depression is associated with alterations of both cellular and humoral immunity (40–42). In the pathogenesis of IBD, immune alterations play a pivotal role (43). Nevertheless, a strong connection between immune parameters and individual characteristics of depression has not yet been established (44). Thus, more research is warranted in this patient population to elucidate the pathophysiologic mechanisms of the relation among disease activity, immune function, and depression.

This study contributes to the growing evidence that psychological factors play an independent important role in the course of IBD and are not merely secondary to the chronic disease. Identifying depression in patients with IBD may support clinicians to target better patients at high risk for relapse requiring closer monitoring and prevention strategies. It also emphasizes the need for sufficient training of clinicians in performing psychodiagnostic interviews and integrated psychosomatic assistance for hospital centers specialized in treating IBD. Furthermore, intervention studies are needed to evaluate the effect of psychotherapy on the course of IBD in the depressed patient population.

Our study may be limited by the fact that we did not differentiate between CD and UC because of the sample size. Moreover, although the study had enough power to detect differences between depressed and nondepressed subjects, a larger number of patients may have revealed more modest, but perhaps clinically meaningful, differences between groups. It would also have been interesting to assess short-term effects of depression, anxiety, and perceived stress on disease activity; however, this was beyond the scope of this study. Ideally, severity and duration of previous disease exacerbations in addition to the number of previous flares should have been considered in relation to psychological status at baseline and the subsequent course of disease, although this would have been possible only by continuous, weekly evaluation of CDAI scores before enrollment. The strength of this study is the prospective, continuous 18-month follow-up of patients with IBD enrolled after a clearly defined event (relapse) to assess disease recurrence with regard to biopsychosocial parameters.

In conclusion, we were able to show that psychological factors such as depressive mood associated with anxiety and an impaired HRQOL after a relapse may influence the further course of disease activity. Because physicians can neither heal nor predict the course of IBD, maintenance of remission is a major goal of treatment. Our study elucidates that depressive mood represents a further risk factor for clinical recurrence of disease that should deserve more consideration in the clinical treatment of patients with IBD.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
REFERENCES
 
We are grateful to Douglas Drossman for his helpful comments on a draft of this paper and to our patients for their generous collaboration. This study was supported by Grant Hochschuljubiläumsstiftung Nr. H-158/98.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
ACKNOWLEDGMENTS
 REFERENCES
 
*Drs. Mittermaier and Dejaco contributed equally to the article. Back

Received for publication July 14, 2003.

Revision received August 10, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 

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