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Depression and anxiety are common in patients with inflammatory bowel disease (IBD).[1-3] Perceived stress, major life events and severity of depressive symptoms increase risk of Crohn's disease (CD) and ulcerative colitis (UC).[4-6] While active disease itself is associated with both depression and anxiety, evidence supports a potential independent effect of stress on influencing risk of relapse.[5-12] As well, the effect of perceived stress appears to be mainly exerted through the mood components, suggesting that psychiatric co-morbidity may influence natural history of CD and UC. In mouse models of dextran sodium sulphate (DSS)-induced colitis, induction of depression through intraventricular injection of reserpine resulted in reactivation of quiescent colitis, which could be prevented by administering desmethylimipramine, an antidepressant.
Psychiatric co-morbidity has been mostly examined in the context of its effect on health-related quality of life in CD and UC.[15, 16] However, the few studies that have previously examined the effect of psychiatric co-morbidity on disease activity, in particular, on the subsequent course of CD and UC, have several limitations including reliance on symptom-based disease activity indices that often correlate poorly with objective disease activity and short duration of follow-up.[2, 6, 7, 17-20] In addition, while a wealth of literature exists regarding the healthcare costs associated with anxiety and depression in a primary-care population or in other chronic diseases including asthma, congestive heart failure and chronic obstructive pulmonary disease, limited data exist for IBD patients.[11, 21-28]
The aims of our study were as follows: (i) to examine the frequency of depression and anxiety (prior to surgery or hospitalisation) in a large multi-institution electronic medical record (EMR)-based cohort of CD and UC patients, (ii) to define the independent effect of psychiatric co-morbidity on risk of subsequent surgery or hospitalisation in CD and UC, and (iii) to identify the effect of depression and anxiety on healthcare utilisation in our cohort. We hypothesise that psychiatric co-morbidity is an independent risk factor for more aggressive disease behaviour in CD and UC.
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Depression and anxiety occur in a significant proportion of patients with CD and UC.[1-3] Prior studies have mostly examined the effect of such psychiatric co-morbidity on symptom-based activity indices and health-related quality of life,[15, 16] both of which may be confounded by the co-existence of functional symptoms.[32-34] Using disease-specific hard endpoints, we demonstrate that co-existing psychiatric co-morbidity was independently associated with a modestly increased risk of surgery in CD with a stronger effect for anxiety. In addition, such psychiatric co-morbidity was also associated with several measures of increased healthcare utilisation.
The prevalence of psychiatric co-morbidity in our cohort was greater than that identified among younger CD patients, and was only slightly lower than that identified through structured questionnaires in two Canadian studies.[1, 2, 35] However, studies utilising detailed psychiatric interview have found the prevalence to be as high as 60% reflecting variations in methods used to ascertain these diagnoses, populations studied (tertiary referral centre vs. population-based cohorts), severity of disease in the underlying population and time frame of study.
There is considerable interest in the role of stress and psychiatric co-morbidity in triggering relapses in CD and UC.[5-8, 10, 11, 36, 37] In mice models of colitis, induction of depression is associated with reactivation of quiescent inflammation. Epidemiologically, this hypothesis has been examined using cross-sectional and prospective studies. However, there exists significant heterogeneity in ascertainment of exposure and outcomes. In a prospective study of 101 CD patients with a 1-year follow-up, Bitton et al. demonstrated that patients with lower stress and lower scores on avoidance coping were less likely to relapse than those with higher perceived stress. As subsequently demonstrated by Camara et al., the association between perceived stress and exacerbation of CD may be influenced more by mood (depression and anxiety) than nonmood components, making it important to examine whether depression and anxiety are independent risk factors for more severe disease.
In this study, we demonstrate that a diagnosis of depression or anxiety prior to surgery was independently associated with a modestly increased risk for subsequent surgery in CD after adjusting for potential confounders in a propensity-score adjusted model. By excluding patients who had their first diagnosis code for depression or anxiety following their surgery, we minimised the possibility of ‘reverse causality’ whereby having surgery or hospitalisation increases risk of depression or anxiety. In addition, adjusting for medication use prior to surgery as a marker of disease severity, we found that our estimates of the association between psychiatric co-morbidity and surgery remained unchanged, further supporting the independent effect of such factors. Finally, consistent with this direction of effect, we also found an association with increased use of corticosteroids, immunosuppressive or anti-TNF biological therapy in CD patients with co-existing depression or anxiety and corticosteroid use in UC patients.
There have been only a few prior studies that have examined the effect of depression on disease course prospectively. Mardini et al. demonstrated that depressive symptoms at baseline were associated with increased disease activity in CD over a 2-year follow-up. Similarly, Mittermaier et al., in a mixed cohort of UC and CD patients identified a correlation between depression scores at baseline and number of relapses over an 18-month follow-up. Thus, our findings are consistent with this prior literature. In contrast, in a cohort comprising 59 IBD patients (32 CD) followed over 1 year, baseline depression or anxiety was not associated with number of relapses, although arguably the power to detect a significant association in such a small sample is limited. One challenge in interpreting prior studies has been the reliance on symptom-based measures of disease activity, which may correlate poorly with objective markers of inflammation and could be influenced by the co-existence of functional symptoms.[32-34] Indeed, disorders such as irritable bowel syndrome (IBS) may be common in patients with CD and UC, and could influence interpretation of symptom-based disease activity scores, particularly in the setting of depression. Thus, facilitated by our longer duration of follow-up, our findings extend the results of the prior studies that were restricted to symptomatic flares to include disease-specific hard endpoints such as the need for IBD-related surgery.
We also observed some potential heterogeneity in effects with a stronger effect among women and older patients, although neither interaction met statistical significance. The gender difference could relate to genetic susceptibility to depression among women including oestrogen receptor polymorphisms, impact of fluctuating hormone levels and differences in coping. Older patients tend to have greater co-morbidity, an increased risk of depression and lower reserve with respect to changes in their health status and its impact on functioning. The reason behind the difference in effect between CD and UC remains unclear. Despite a majority of the risk loci being shared between CD and UC, considerable differences exist in the effect of environmental factors on the two diseases. Although most notably observed are the divergent effects of smoking and appendectomy on disease risk, prior work including ours examining the effect of depressive symptoms on disease risk has demonstrated a stronger effect on CD. Whether this is because of different dominant pathways of influence in CD (innate immunity, autophagy) compared with UC (epithelial barrier function) merits further exploration, as depressive and psychosocial stress may not have a uniform impact on all components of the immune system.
The second key aspect of our study is the examination of healthcare utilisation among the cohort of IBD patients with psychiatric co-morbidity. Adjusting for potential confounders and duration of follow-up, we identified that depression or anxiety is associated with significantly greater rates of all-cause hospitalisation and out-patient visits including to gastroenterologists. Also concerning is our finding of the independent effect of psychiatric co-morbidity on undergoing abdominal imaging studies, primarily CT scans. We were not able to ascertain whether the imaging studies obtained were appropriate, but several recent studies have highlighted the high frequency of radiographic studies in CD patients.[41-43] Thus, it is important for treating physicians to recognise that underlying psychiatric co-morbidity could be a potential risk factor for multiple radiologic studies, to practise judicious use of imaging studies and use alternate imaging modalities such as magnetic resonance imaging (MRI) studies wherever indicated and possible in such patients. Although the excess healthcare utilisation associated with depression or anxiety has not been specifically examined in the context of IBD, our findings are consistent with studies in the primary-care population and other chronic diseases where depression and anxiety are associated with increased healthcare utilisation.[23, 24, 28] Specifically, the higher odds ratios we identified for all-cause hospitalisation (compared with primary IBD-related hospitalisations) and overall out-patient visits (compared with visits to gastroenterologists) highlight that in addition to its effect on IBD itself, the impact of depression or anxiety on overall healthcare utilisation may be greater for non-IBD-related measures as has been demonstrated previously for asthma.
In addition to its effect on healthcare utilisation, we also found that psychiatric co-morbidity was associated with an increase in use of corticosteroids in both CD and UC, and immunomodulator use in UC. There are a few potential reasons for this association. First, it is possible that, as noted by prior studies, co-existing anxiety or depression may be associated with increased symptoms, which may lead to initiation of systemic steroids. Secondly, use of systemic steroids itself is associated with significant neuropsychiatric side effects – euphoria and mania in the acute setting, and depression with long-term use.[45-47] As the timing of initiation or cessation of such episodic therapy is often incompletely captured in the EMR, we were not able to establish causal association between medication use and psychiatric co-morbidity, but this association is consistent with that identified with other disease-specific measures such as office visits and need for surgery.
Our study has several implications. To our knowledge, ours is the first study examining the effect of co-existing depression or anxiety on IBD-related surgery over a prolonged follow-up. By excluding those who had first reported a diagnosis of psychiatric co-morbidity following surgery or hospitalisation, and using propensity score adjustment, we minimised the possibility of reverse causality or residual confounding by disease severity, and increased the robustness of our findings. Although the strength of association remains fairly modest when adjusted for other potential confounders, depression or anxiety forms a potentially modifiable risk factor for subsequent disease relapses or surgical morbidity. In addition, both depression and anxiety are also associated with impairment in disease-specific as well as overall health-related quality of life and psychosocial functioning. Thus, our results, in conjunction with prior studies in the literature, suggest a potential need for routine screening for psychiatric co-morbidity in IBD patients. In addition, there is continued need for research on interventions addressing depression and anxiety in IBD patients as the literature so far has been limited and conflicting.[22, 48, 49] Such interventions may improve mood and health-related quality of life as well as natural history of disease and IBD-related healthcare costs. There is also need for continued basic research on the identification of the mechanisms how stress and psychological factors influence IBD course, and whether there are genetic, environmental or psycho-behavioural risk factors that increase susceptibility to the effect of stress.
There are a few limitations of our study. We relied on the use of administrative codes to identify the presence and date of diagnosis of depression and anxiety in our IBD cohort. Thus, there is the possibility of misclassification. However, this would likely bias the results towards the null, and would result in the true effect being larger than in our study. We also validated the accuracy of these codes in our data. However, we acknowledge that there may exist differences between studies that rely on established diagnoses compared with those using a structured psychiatric interview for cross-sectional assessment. We also accounted for the fact that the diagnosis code of depression or anxiety may be secondary to increased frequency of healthcare utilisation by adjusting for the density of such utilisation in our analysis and found no difference in our odds ratios. We acknowledge the possibility of residual confounding by disease severity or unmeasured confounders as exists in all observational studies. To minimise the effect of this, we used propensity score adjustment. However, propensity scores incorporate only known confounders and fail to completely account for unknown confounders including psycho-socioeconomic variables. Given the retrospective design of the study, we also did not have detailed information regarding the severity of psychological co-morbidity or the impact of treatment for anxiety or depression on healthcare utilisation and need for surgery in IBD. In particular, the use of antidepressants or antianxiety medications is inadequately captured within our electronic medical record system; thus, the impact of such interventions on disease course merit exploration in future studies. We also did not have prospectively collected disease activity indices, endoscopic or other biomarkers of ongoing inflammation. Finally, because ours are referral institutions, we may not have identified exposures or outcomes that were predominantly documented outside our healthcare system. However, the consistency of our results adjusting for healthcare utilisation density (as a measure of comprehensiveness of care within our health system) increases our confidence in our findings. We were also not able to examine the effect of psychiatric co-morbidity on medication non-adherence.
In conclusion, using a large multi-institution cohort of IBD patients, we demonstrate that the presence of depression or anxiety is associated with a modestly increased risk of surgery in patients with CD. We did not identify a similar association in UC patients. In addition, psychiatric co-morbidity was associated with significantly greater disease- and nondisease-related healthcare utilisation in both CD and UC, suggesting a need for routine screening for depression and anxiety in IBD patients. Further establishment of the effectiveness of interventions to address this component of IBD care is important to improve patient outcomes.