Burden of comorbid anxiety and depression in patients with inflammatory bowel disease: a systematic literature review

ABSTRACT

Introduction

Patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, often have comorbid anxiety and depression that affects their quality of life (QoL) and management of their IBD.

Areas covered

A systematic literature review (SLR) was conducted to identify articles and conference abstracts on comorbid anxiety and depression in IBD patients using MEDLINE® and Embase® (January 2003 − June 2018). The impact of these psychological comorbidities on QoL and economic burden was examined. Non-pharmacologic interventions and disease-specific unmet clinical needs associated with these comorbidities were also evaluated.

Expert opinion

There is evidence that individual and group-based cognitive behavioral therapy can reduce rates of anxiety and depression in adults and adolescents with IBD. Patients with IBD and anxiety or depression had an increased risk of hospitalization, emergency department visits, readmission, and used outpatient services more often than people without these conditions. Several disease-specific unmet clinical needs for IBD patients were identified. These included lack of reimbursement for mental-health care, inconsistent screening for psychological comorbidities and patients not consulting mental-health professionals when needed. IBD patients may benefit from integrated medical and psychological treatment, and should be considered for behavioral treatment.

Plain Language Summary

Background

People with IBD may have mental-health conditions, such as anxiety and depression. These conditions can affect people’s quality of life and how they manage their IBD.

What did this review look at?

We found 79 publications on anxiety or depression in people with IBD, published between January 2003 and June 2018. In people with IBD and anxiety or depression, researchers looked at: the impact on health-related quality of life and healthcare utilization, including access to and reimbursement for mental-health services how effective interventions that do not involve the use of medicines were (known as non-pharmacologic therapy).

What were the main findings from this review?

People with IBD and anxiety or depression were more likely to be admitted to hospital and visit emergency departments than people without these conditions. Access to mental-health care varied and some people with IBD were not screened for depression.

Individual and group-based talking therapy (known as cognitive behavioral therapy) reduced rates of anxiety and depression in some people with IBD.

What were the main conclusions from this review?

We found evidence that people with IBD and anxiety or depression may benefit from certain non-pharmacologic interventions. However, many people with IBD and anxiety or depression did not have access to mental-health services. Healthcare professionals should address gaps in patient care to improve outcomes in people with IBD and anxiety or depression.

See Additional file 1 for an infographic plain language summary.

KEYWORDS:

• Anxiety
• cognitive behavioral therapy
• Crohn’s disease
• depression
• inflammatory bowel disease
• psychological comorbidity
• quality of life
• systematic literature review
• ulcerative colitis

1. Introduction

Inflammatory bowel diseases (IBD) are chronic, immune-mediated diseases of the gastrointestinal tract, which include Crohn’s disease (CD) and ulcerative colitis (UC). IBD is estimated to affect over 3 million people in the United States [1] (US) and 2.5–3 million in Europe [2]. In addition, there is a rising incidence of IBD in Asian countries [3]. The peak onset of IBD is in people aged between 15 and 40 years, and the condition is characterized by periods of remission, with few or no symptoms, and flare-ups when disease symptoms are severe [4,5].

IBD has an impact on more than just the gastrointestinal tract, as patients often have psychological comorbidities, such as anxiety and depression [6–9]. These comorbidities are independent predictors of the severity of IBD symptoms, not only negatively impacting a patient’s quality of life (QoL), but also increasing healthcare utilization and caregiver burden [5,10–13]. Patient questionnaires are readily available that can be used to help diagnose anxiety and depression [14]. Once confirmed, there are available options to help patients with IBD manage these comorbidities, and there is a growing support for behavioral interventions such as cognitive behavioral therapy (CBT) [14].

Understanding the epidemiology of psychological comorbidities in patients with IBD is important for both providers of treatment for IBD and payers, as it has a direct impact on healthcare utilization. For example, patients with IBD and a mental-health diagnosis have around a 2-fold increase in healthcare costs compared with patients without such a comorbidity [15], increasing the economic burden of IBD [16]. Psychological factors in patients with IBD, including anxiety and depression, are also associated with fatigue, which is an important clinical problem [17,18]. In addition, there can be a psychological impact on caregivers and family members when living with patients with IBD, which in turn can affect both the patient’s and caregiver’s QoL [11]. Understanding the barriers to accessing mental-health services and other unmet emotional needs for patients with IBD is important. Managing psychological comorbidities such as anxiety and depression may improve outcomes in patients with IBD by improving self-management and treatment adherence, and by reducing the need for unplanned, expensive care [19]. It is therefore important to identify effective interventions for the treatment of these comorbidities, and disease-specific unmet clinical needs [20].

In patients with IBD, QoL has been evaluated in previous systematic literature reviews (SLRs) relative to healthy populations or other patient populations, and within-disease states (active or inactive IBD) [21,22]. SLRs have also reported risk factors for developing psychological comorbidities and the impact of depression on disease course in IBD patients [23,24]. This SLR explores the social and economic burden of IBD when patients have psychological comorbidities such as anxiety or depression. We review non-pharmacologic options for the treatment of anxiety and depression in patients with IBD. We also identify barriers to accessing mental-health care, with the goal of advancing care for IBD patients with comorbid anxiety and/or depression.

2. Methods

2.1. Research questions

The primary research questions were:

i) What is the evidence of the social and economic burden of anxiety and depression in patients with IBD, including disease-specific unmet clinical needs

ii) What is the evidence for the use of non-pharmacologic interventions, such as CBT for anxiety and depression in patients with IBD?

2.2. Search strategy

MEDLINE® and Embase® were searched (via ProQuest®) for potentially eligible full-text articles and conference abstracts published between 1 January 2003 and 14 June 2018 on psychological comorbidities (i.e. anxiety or depression) in patients with IBD. Major heading terms in each database were combined with keyword searches of the title and abstract, with duplicate publications removed automatically.

2.3. Selection criteria

Relevant publications were identified using prespecified PICOS criteria (Table 1). Publications were considered eligible for inclusion in the review if they described studies of patients with IBD (including CD and UC) and anxiety or depression. In addition, publications had to include a study abstract and be published in the English language for inclusion in the SLR.

Table 1. MEDLINE® and Embase® search strategy

Disease	Search terms
Psychosocial comorbidity	(MESH.EXACT(‘Anxiety’) OR MESH.EXACT(‘Depression’) OR EMB.EXACT(‘anxiety’) OR EMB.EXACT(‘depression’) AND (ti,ab(anxiety or depression or psychosocial)))
Inflammatory bowel disease	(EMB.EXACT(‘inflammatory bowel disease’)) OR (EMB.EXACT(‘ulcerative colitis’)) OR (EMB.EXACT(‘Crohn disease’)) OR (MESH.EXACT(‘Inflammatory Bowel Diseases’)) OR (MESH.EXACT(‘Colitis, Ulcerative’)) OR (MESH.EXACT(‘Crohn Disease’)) OR (TI,AB(‘crohns disease’ OR ‘crohn disease’ OR ‘crohn’s disease’ OR ‘crohns disorder’ OR ‘crohn disorder’ OR ‘crohn’s disorder’ OR ‘ulcerative colitis’ OR IBD OR ‘inflammatory bowel disease’))

2.4. Literature screening

One reviewer screened the title and abstract of all eligible articles based on the PICOS criteria (Table 2). The full text of any articles that met the inclusion criteria was then evaluated for final inclusion in the SLR. A second, independent reviewer screened 10% of included/excluded articles to ensure quality control. We examined 4 recently published SLRs pertaining to the outcomes of interest (anxiety or depression in patients with IBD) for any articles that were not identified in the literature search to identify any missing original research [6,23–25].

Table 2. Inclusion and exclusion criteria for the systematic literature review (PICOS criteria)

PICOS criteria	Inclusion criteria	Exclusion criteria
Population	IBD (includes ulcerative colitis and Crohn’s disease) Psychological comorbidities (includes anxiety or depression) Adult or adolescent populations	Not IBD No psychological comorbidities Not adults or adolescents
Interventions	Not applicable	Not applicable
Comparators	Not applicable	Not applicable
Outcomes	Clinical outcomes (e.g. symptoms, severity) Non-pharmacologic interventions Resiliency to psychological comorbidities Epidemiology (e.g. prevalence, incidence) Social/quality of life (e.g. patient-rated outcomes, caregiver-rated outcomes) Economic (e.g. heathcare utilization; total, direct, and indirect costs; absenteeism or presenteeism in work/school) Disease-specific unmet needs	Outcomes not associated with disease burden, non-pharmacologic interventions, or unmet needs
Study design	Not applicable	Not applicable
Publication type	Studies including a study abstract Systematic reviews^a	No study abstract Press releases or editorials Non-systematic reviews
Location	All	No restriction
Language	English	Not English
Time period	1 January 2003 to 14 June 2018	Published before 2003

^aFour recently published SLRs pertaining to the outcomes of interest (anxiety or depression in patients with IBD) were examined for any articles that were not identified in the literature search to identify any missing original research.

IBD, inflammatory bowel disease; PICOS, patient/problem, intervention, comparison group, outcome, study; SLR, systematic literature review.

2.5. Data extraction

After all relevant publications had been identified and received, the relevant data were extracted from the articles by a single reviewer. The second reviewer performed an independent review of the extracted data from 10% of the articles to ensure quality control. Variables including study and patient characteristics, burden characteristics (clinical, social, and economic), disease-specific unmet clinical needs and study conclusions were extracted. Demographic age was extracted and used to stratify results by age, if available.

2.6. Statistical analysis

The SLR used descriptive statistics for all outcomes analyzed (Table 2). For binary outcome data, the numerator and denominator (sample size) were extracted. For continuous scales and scores, the mean/median score was extracted as well as the standard error, standard deviation (SD) or confidence interval (CI). Baseline, endpoint, and change-from-baseline values were extracted, as well as mean differences (and their respective standard errors, SDs or CIs) between cohorts, if reported.

2.7. Study outcomes assessed

Data on the epidemiology, social burden (QoL for patients and caregivers, disability and productivity, and coping strategies), economic burden including healthcare utilization employment implications, and disease-specific unmet clinical needs, and non-pharmacologic interventions were extracted (Table 2). This manuscript intentionally omitted studies that focused on symptom severity [26–29], and/or only reported rates of incident anxiety and depression in patients with IBD [30]. While no publications were found looking at resiliency, 10 publications [31–40] described the coping strategies and scales used by IBD patients with anxiety or depression. These publications are also not summarized in this manuscript.

3. Results

3.1. Summary of the literature search

The PRISMA guidelines were adhered to for reporting the results of this SLR [41]. The initial literature search identified 1548 publications in MEDLINE® or Embase® (Figure 1). In addition, 3 publications (2 full-text articles and 1 conference abstract) were included from the review of SLR references. In total, the titles/abstracts of 1551 publications were screened. Predefined PICOS criteria were applied in a 2-step screening process. A total of 1381 articles were excluded in the title/abstract review and 91 were excluded in the full-text review, leaving 79 publications (Figure 1). Of the 79 included studies, 36 were from published articles and 43 were conference abstracts. These publications comprised of 35 cross-sectional studies, 29 cohort studies, 8 case-control studies, 4 randomized controlled trials, 2 case reports, and 1 survey.

Figure 1. Summary of article and abstract screening (PRISMA diagram)

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SLR, systematic literature review.

3.2. Outcome measures

3.2.1. Prevalence of anxiety and depression in patients with IBD

The prevalence of depression in patients with IBD ranged from 2.2% [16] to 62.3% [42] across 35 studies. Of these, 26 studies were in adult populations, 1 was in an adolescent population, and 8 did not specify the age of the population. The prevalence by country (for 27 studies) is summarized in Figure 2A/Supplemental Table 1 [5,7–9,16,20,43–63], while the remaining 8 studies (all conference abstracts) [42,64–70] did not specify the country. A few studies found the prevalence rates ranged between 39.5% and 44.4% for psychosocial comorbidities (including anxiety and depression) in patients with IBD [71–73].

Figure 2. Prevalence (%) by country of psychological comorbidities in patients with IBD: [A] depression and [B] anxiety

Sources: [A] Australia [43]; Brazil [45]; Canada [7,46]; China [49]; France [50]; Iran [51]; Italy [52]; Netherlands [20]; New Zealand [54]; Singapore [55]; South Korea [53]; Spain [56]; UK [57,58]; USA [16,60]. Sources: [B] Australia [43,44]; Brazil [45]; Canada [46,47]; China [49]; France [50]; Iran [51]; Italy [52]; Netherlands [20]; New Zealand [54]; Singapore [55]; South Korea [53]; Spain [56]; UK [58]; USA [16,62]. IBD, inflammatory bowel disease; UK, United Kingdom; USA, United States of America.

he reported prevalence of anxiety ranged from 7.6% (5 years after IBD diagnosis) [46] to 41.8% [44] across 25 studies. Of these, 20 studies were in adult populations and 5 did not specify the age of the population. The prevalence of anxiety by country is summarized in Figure 2B/Supplemental Table 2 [7,9,16,20,43–56,58,62,63], while the remaining 4 studies (all conference abstracts) [65,66,70,74] did not specify the country.

3.2.2. Social burden

Overall, 17 studies across 14 countries looked at the social burden of anxiety and depression in patients with IBD, and these are discussed in further detail below [5,7,11,44,45,48,49,51,54–56,64,74–78]. The domains of social burden included QoL, disability, productivity and employment, and caregiver burden.

3.2.2.1. Quality of life

The most frequently used tools to measure QoL were the Inflammatory Bowel Disease Questionnaire (IBDQ) [7,48,49,56,77] and the Short IBDQ (SIBDQ) [5,11,44,64,74,76,78]. Two versions of the IBDQ questionnaire were used: 1 comprised 32 questions, across 4 domains, with scores ranging from 32 (worse QoL) to 224 (better QoL). The second version comprised 36 questions, across 5 domains, with scores ranging from 36 (worse QoL) to 252 (better QoL). The SIBDQ comprises 10 questions to measure physical, social, and emotional status domains with scores ranging from 10 (poor health-related QoL) to 70 (good health-related QoL) [79].

The study by Victor et al. (2014) reported that patients with IBD and depression had a mean SIBDQ score of 35 (SD 11), but there was no control group for comparison [64]. A cross-sectional study of IBD patients (n = 258), recruited from 2 outpatient clinics and 5 office-based gastroenterologists in Australia, reported that patients with anxiety had significantly lower SIBDQ scores compared with those without anxiety, 44.0 versus 57.4, respectively (p < 0.001) [44]. Three other studies reported significantly lower SIBDQ scores in IBD patients with psychological comorbidities compared with those without; however, total SIBDQ scores were not stated [74,76,78]. Anxiety correlated with a lower SIBDQ (correlation coefficient, −0.62; p < 0.0001) in a cross-sectional study of consecutive IBD patients (CD, n = 147; UC, n = 73) [74]. These authors also looked at QoL in a larger group of IBD patients (CD, n = 205; UC, n = 152) and reported that the proportion of patients with low SIBDQ scores was significantly higher for patients with anxiety than for those without anxiety (78.3% vs 21%; p < 0.0001) [78]. A cross-sectional survey of patients with IBD (n = 295) also reported mean SIBDQ scores were significantly lower in depressed patients compared with non-depressed patients (3.7 ± 1.4 vs 5.2 ± 1.5; p < 0.001) [76]. Patients with IBD attending regularly scheduled clinic appointments (CD, n = 55; UC, n = 50) were evaluated to look at the impact of psychological comorbidity on overall QoL in patients with active disease and those in remission (Figure 3A) [5]. Overall, IBD patients with depression had lower SIBDQ scores compared with patients without depression (p = 3.95 × 10⁻⁵ for CD; p = 0.00141 for UC) [5].

Figure 3. Impact of psychological comorbidity on overall QoL in patients with IBD: [A] SIBDQ scores and [B] IBDQ scores

Note: [A] All the comparisons between depressed and non-depressed patients were statistically significant, except in patients with active CD (p-values not stated in the publication) [5]. Note: [B] IBDQ scores are reported for patients with IBD and major depressive disorder or any anxiety disorder in the Walker 2008 study. Mean IBDQ scores for Walker 2008 [7] and Luo 2017 [49]; median IBDQ scores for Mittermaier 2004 [77]. CD, Crohn’s disease; IBD, inflammatory bowel diseases; IBDQ, Inflammatory Bowel Disease Questionnaire; QoL, quality of life; SIBDQ, Short Inflammatory Bowel Disease Questionnaire; UC, ulcerative colitis.

In 3 further studies, IBDQ total scores were significantly lower in IBD patients with psychological comorbidities compared with those patients without anxiety or depression (Figure 3B) [7,49,77]. A cross-sectional survey of patients in Canada, Australia, and the UK with UC who had colectomy surgery in the preceding 10 years (n = 424) reported that depression was significantly associated with poorer totaI IBDQ scores (p < 0.0001) [48]. In a separate cross-sectional study (n = 875), patients with IBD and depression had a worse health-related QoL than those patients without depression (p < 0.05) [56]. In a cross-sectional cohort study of patients attending an IBD center in China (n = 219), anxiety symptoms (p < 0.001) and higher medical costs (p = 0.001) were strong and independent predictors of reduced health-related QoL, independent of disease activity [49].

3.2.2.2. Disability, productivity, and employment

In the studies included in this SLR, 2 tools were used to measure disability and productivity. The Work Productivity and Activity Index (WPAI) comprises 30 questions over 4 domains, with a higher percentage score indicating greater impairment. Anxiety correlated directly with a lower WPAI score (p = 0.0001) in a cross-sectional study of consecutive IBD patients (CD, n = 147; UC, n = 73) [74]. The IBD-Disability Index (IBD-DI) has 28 questions spanning 5 domains, with scores ranging from −80 (maximum degree of disability) to 22 (no disability). In a Dutch, nationwide, web-based survey, IBD patients (CD, n = 1373; UC, n = 909) with work disability had higher rates of depression (16.7% and 20.0%) compared with employed patients (6.5% and 7.4%), for patients with CD and UC, respectively [75]. Statistically lower IBD-DI scores were reported in a cross-sectional study (CD, n = 95; UC, n = 105) for patients with psychological comorbidities compared with those without comorbidities (IBD-DI, −9 ± 14 with anxiety vs 6 ± 13 without anxiety, p < 0.001; IBD-DI, −12 ± 16 with depression vs 5 ± 13 without depression, p < 0.001, respectively) [55].

The cross-sectional study by Brandi (2009) reported that 43.3% of CD patients with anxiety symptoms were unemployed, compared with 39.7% of CD patients without anxiety symptoms [45]. For CD patients with depressed mood, unemployment rates were 46.4% compared with 39.9% in CD patients without depressed mood [45]. In a retrospective study of consecutive patients with IBD attending a clinician’s office or hospital for IBD treatment, 41.7% of IBD patients with anxiety reporting losing working hours due to their disease compared with only 11.4% of those without anxiety [78].

3.2.2.3. Caregiver burden

In the study by Jedel (2015), the mean Zarit Burden Inventory (ZBI) score was used to assess caregiver burden (0 indicates low burden, up to 88 for high burden) [11]. Spouses of IBD patients with symptoms of depression reported a greater burden (ZBI 21.3; SD 12.3) than spouses of patients without depression (ZBI 14.9; SD 10.5) but this difference was not statistically significant (p = 0.12) [11].

3.2.3. Economic burden

Overall, 18 studies investigated the economic burden of anxiety or depression in patients with IBD, in terms of hospital admissions, emergency department visits, and use of mental-health services [8,12,16,20,44,48,57,64,80–89]. No studies were identified that investigated the cost of non-pharmacologic interventions in patients with IBD and anxiety or depression.

3.2.3.1. Healthcare resource utilization

3.2.3.1.1. Hospital admissions and emergency department visits

A retrospective analysis of the US National Inpatient Sample database in 2011 (IBD hospitalizations 67,560; non-IBD hospitalizations 1,591,206) found significantly higher rates of mood disorders and anxiety in patients hospitalized for IBD compared with non-IBD hospitalizations: anxiety (9.6% vs 6.1%; p < 0.001) and mood disorders (20.3% vs 14.1%; p < 0.001) [81]. In a multi-institution cohort study in the US (CD, n = 5405; UC, n = 5429), IBD patients with psychological comorbidities were more likely to be hospitalized for all-cause admissions than patients without these comorbidities (CD 83% vs 54%; adjusted odds ratio [OR], 1.48; 95% CI, 1.19 – 1.83; UC 74% vs 49%; adjusted OR, 1.28; 95% CI, 1.07 – 1.52) in patients diagnosed between 1988 and 2010 [82]. Psychological comorbidities also increased the likelihood of being admitted for IBD-related hospitalizations compared with patients without these comorbidities (CD 54% vs 33%; adjusted OR, 1.05; 95% CI, 0.88 – 1.26; UC 28% vs 22%; adjusted OR, 0.77; 95% CI, 0.63 – 0.93) [82]. Depression at baseline was a risk factor for increased emergency department (ED) visits (relative risk [RR], 1.38; 95% CI, 1.14 – 1.65; p = 0.001) in a prospective cohort study of IBD patients (CD, n = 297; UC, n = 413), but anxiety was not a significant risk factor (RR, 1.11; 95% CI, 0.87 – 1.41; p = 0.395) [83].

A retrospective cohort study (n = 52,498 hospitalizations) reported that IBD patients with CD and anxiety (OR, 1.31; 95% CI, 1.21 – 1.43) or depression (OR, 1.27; 95% CI, 1.07 – 1.50) had an increased risk of readmission within 90 days after their first admission compared with those patients who were not readmitted [12]. Among patients with UC, both anxiety (OR, 1.28; 95% CI, 1.14 – 1.45) and depression (OR, 1.35; 95% CI, 1.07 – 1.70) were associated with a significant increase in odds of readmission compared with patients who were not readmitted [12]. A retrospective analysis of medical records of IBD patients in the US (n = 356) admitted to the hospital for an unplanned IBD-related reason reported that depression increased the risk of readmission within 90 days compared with those without depression (hazard ratio, 1.99; 95% CI, 1.33 – 3.00; p = 0.0009) [80].

A prospective, cohort study evaluating the integration of psychological support into routine care for IBD patients (n = 500; 67% completed psychological screening) demonstrated that anxiety was positively correlated with ED visits (p = 0.024), outpatient appointments (p = 0.030), and appointment cancellations (p = 0.005) [84]. Depression at baseline (RR, 1.38; 95% CI, 1.24 – 1.76) and anxiety (RR, 1.31; 95% CI, 1.21 – 1.40) were associated with an increased risk of ED visits in a prospective cohort study of IBD patients (n = 381) [87]. A prospective cohort study in Spain also reported an increased risk of ED visits for patients with IBD (CD, n = 297; UC, n = 413) and depression at baseline (RR, 1.38; 95% CI, 1.14 – 1.65; p = 0.001) compared with IBD patients without depression [83]. However, there was no difference in the risk of ED visits for patients with anxiety at baseline compared with patients without anxiety (RR, 1.11; 95% CI, 0.87 – 1.41; p = 0.395) [83].

3.2.3.1.2. Use of mental-health services

Patients with IBD (CD, n = 138; UC, n = 93) attending an outpatient clinic in the Netherlands completed the Trimbos/iMTA Questionnaire for Costs Associated with Psychiatric illness (to assess mental-health care use) and the Hospital Anxiety and Depression Scale (HADS) [20]. In the subgroup of patients with high levels of depression or anxiety (indicative of anxiety and/or depressive disorder; n = 95), 17.9% reported that they had received psychological or psychiatric help in the prior 4 weeks [20]. A retrospective study of patients with IBD (CD, n = 185; UC, n = 92) reported that a subgroup of patients (n = 24) had moderate or severe anxiety (as measured using the GAD-7 questionnaire), of whom only 13% reported that they had seen a psychiatrist during the preceding year [85]. The Canadian Community Health Survey 1.1 (CCHS), conducted from 2000 to 2001, and the National Population Health Survey (NPHS), conducted from 1996 to 1997, are 2 large, nationally representative surveys using similar designs and questionnaires [8]. A cross-sectional study of these surveys, which focused on IBD patients with depression, reported that 13.2% (CCHS, n = 501) and 13.8% (NPHS, n = 211) of patients had attended self-help groups in the preceding 12 months [8]. In the CCHS cohort, 52.4% (with depression) vs 11.1% (without depression) had consulted a mental-health professional (p < 0.001) [8]. Patients with IBD and depression were also more likely to consult their family doctor (26.9%) than a psychiatrist (12.8%) or psychologist (12.4%) [8]. A retrospective medical record review of outpatient visits for IBD patients (2014 to 2015; n = 124 patients; 244 visits) found that only 17% of visits for patients with symptoms of anxiety or depression had documentation of potential need for psychological intervention [89].

The Canadian study by Fuller-Thomson and Sulman (2006) reported that up to half of patients with IBD and depression were not consulting a mental-health professional [8]. Additionally, in the preceding 12 months, 41.1% of IBD patients with depression in the CCHS cohort reported that they did not receive healthcare when they felt it was needed, compared with 22.4% of IBD patients without depression [8]. For the NPHS cohort, 21.4% of patients with IBD and depression (vs 11.3% of those without) reported that they did not receive healthcare when they felt it was needed [8]. A review of medical records of consecutive IBD patients attending an urban university gastroenterology practice in the US (n = 207) found that screening for depression was inconsistent; documented in 32.4% of patients while neither documented nor addressed in 67.6% of patients with IBD [88]. A pilot study of pediatric patients attending a multidisciplinary IBD clinic in the US (n = 40) found that 35% of claims for psychology care were not reimbursed [86].

3.2.4. Non-pharmacologic interventions

Ten publications reported the results of non-pharmacologic interventions for treating psychological comorbidities in patients with IBD [86,90–98]. Of these, 5 studies were in adult populations [93,94,96–98], 3 were in adolescent populations [90–92], and 2 studies did not specify the age of the population [86,95]. Behavioral approaches for the treatment of psychological comorbidities comprised CBT [90–93], group-based CBT [94,95], and a number of other approaches (group-based disease education [96], a patient-engagement program [97], a psychological support study [86], and a 1-day behavioral treatment workshop [98]).

3.2.4.1. Cognitive behavioral therapy

Four studies conducted in the Netherlands [93] and the US [90–92] reported the effects of CBT on the rates of anxiety or depression in patients with IBD (Figure 4) [90–93]. An open-label trial of adolescents with IBD and depression (CD, n = 7; UC, n = 4) reported improvement in mean Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) – Present and Lifetime Version scores from a baseline score of 5.64 (SD 1.21) to 1.09 (SD 1.14) at 3.3 months (p < 0.001) [91]. The long-term extension study reported that improvements in K-SADS were maintained in terms of the mean (SD) number of depressive symptoms per adolescent over 6 months (1.36 [1.50]) and 1 year (1.45 [2.16]) (p < 0.001) [92]. An open-label pilot study testing the benefits of CBT for adolescents with IBD and anxiety (n = 9) reported that, after CBT (average treatment for 12.5 weeks), 50% of patients no longer met the criteria for their principal anxiety disorder, as measured by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [90]. In a randomized controlled trial of adults with IBD (n = 118), CBT reduced the rates of anxiety and depression from 35.7% and 25.0% at baseline, to 10.4% and 4.2% after therapy (at 3.5-months’ follow-up), respectively, based on the number of patients with HADS scores ≥11 [93]. A statistically significant improvement was observed in the IBDQ total score, systemic and emotional domains (p < 0.01), but not in the social domain (p = 0.13) in patients who completed CBT compared with the control group [93]. A statistically significant improvement was also observed in mental aspects of patients’ QoL (p < 0.01) using the Short Form Health Survey: SF-36, but not in physical aspects (p = 0.80) [93].

Figure 4. CBT in the treatment of anxiety and depression in [A] adolescents and [B] adults with IBD

Note: [A] Szigethy 2006 [92] was a long-term extension of Szigethy 2004 [91]; improvement was sustained in the extension part of the study. Note: [B] Based on percentage of patients with HADS score ≥11, indicating probable anxiety or depression. ^a Reigada 2013 [90]; ^b Szigethy 2004 [91]; ^c Szigethy 2006 [92]; ^d Bennebroek Evertsz 2017 [93]. CBT, cognitive behavioral therapy; HADS, Hospital Anxiety and Depression Scale; IBD, inflammatory bowel disease.

3.2.4.2. Group-based cognitive behavioral therapy

In a controlled study of adult patients with IBD from the Spanish CD and UC Association (n = 57), average BDI scores significantly decreased (p ≤ 0.05) from 13.9 at baseline to 6.88 after group therapy (one 2-hour session per week for 10 weeks) [94]. Preliminary results from a pilot study reported that group workshops (one 1-hour session per week for 8 weeks, with 2 group facilitators) significantly reduced depression scores in patients with IBD with depression (n = 5), when compared with a control group of IBD patients without depression (n = 4; p < 0.05) [95].

3.2.4.3. Non-cognitive behavioral therapy based approaches

No benefit was observed for a group-based disease education program (one session lasting 2–3 hours per week for 8 weeks) in adults with IBD with anxiety (n = 26), with a mean baseline HADS anxiety score of 9.3, and a score of 9.0 at the 6-month follow-up assessment [96]. In a pilot study of adult patients with IBD (n = 41), a patient-engagement program (focused on psychological tools) was effective in reducing the levels of anxiety and depression in patients with IBD [97]. This program included social work, psychiatric evaluation, a mind-body stress management and lifestyle program, nutrition counseling, and health education. Generalized Anxiety Disorder (GAD) assessment scores decreased from 9.2 at baseline to 6.6 after 1 year in IBD patients with anxiety [97]. A separate pilot study reported on the provision of psychological support services for pediatric IBD patients (n = 40); however, the results focused on reimbursement, and no outcomes were reported for treatment effectiveness [86]. A pilot study of a 1-day behavioral treatment intervention (behavioral change training, acceptance, and mindfulness training and IBD education) in adult patients with IBD and psychological comorbidities (n = 20) reported that there was a non-statistically significant improvement in anxiety and depressive symptoms in approximately half of the patients [98].

4. Conclusion

The aim of this SLR was to assess the evidence on the social and economic burden, behavioral treatment options, and disease-specific unmet needs associated with comorbid anxiety or depression in patients with IBD. Although the prevalence of anxiety or depression reported in patients with IBD varied widely, the prevalence rates were similar to those reported in a previous SLR [6]. Other studies have reported that the prevalence of anxiety and depression is lower in children and adolescents than in adults with IBD [99].

Various measures, most commonly the SIBDQ and IBDQ, were used to measure QoL. Several studies, mainly involving around 100–350 patients, reported that QoL scores were significantly lower in IBD patients with psychological comorbidities compared with IBD patients without these comorbidities [5,7,44,49,76,77]. Patients with IBD and anxiety or depression reported lower productivity [74] and higher work disability [55] than IBD patients without these psychological comorbidities in 2 medium-sized studies (220 and 200 patients, respectively). There was limited evidence reported on the psychosocial impact of IBD on caregivers. One small cross-sectional study indicated that a patient’s psychological functioning correlated with the psychological state of their spouse/significant other, and that coping with IBD may be better understood as a shared experience [11].

There were several studies that reported an increased risk of hospitalization [82], ED visits [83,84,87], readmission after first admission [12,80], and use of outpatient services in IBD patients with psychological comorbidities. Few studies reported on employment rates; however, those that did found that IBD patients with psychological comorbidities had lower rates of employment than IBD patients without anxiety or depression [44,45,78].

Several disease-specific unmet needs for patients with IBD were identified. These included inconsistent screening for depression [88] and a lack of reimbursement for mental-health care [86]. In addition, evidence from a large cohort study found that IBD patients with psychological comorbidities reported that they were not consulting a mental-health professional or that they did not receive mental-health care when they felt it was needed [8]. These studies were carried out in Canada and the United States, so these barriers may not apply to patients in Europe.

There is only limited short-term evidence available for the beneficial effects of behavioral treatments, such as CBT, on depression and QoL in patients with IBD [100,101]. This SLR found evidence that CBT, both individual and group-based, reduced rates of anxiety and depression in both adult and adolescent patients with IBD [90–95]. However, the studies in adolescents involved only small numbers of patients with no control groups [90–92] and the randomized controlled trial in adults was underpowered for its primary outcome measure [93]. There was limited evidence reported for the effectiveness of other non-pharmacologic interventions, such as patient-engagement programs and group-based disease education. However, 2 of these studies were pilot studies [86,97], and the study by Larsson et al. (2003) was limited by the high number of patient dropouts [96].

In this SLR we broadened the search criteria to examine the disease burden across different health systems and populations to report the breakdown of the prevalence rates of anxiety and depression in IBD patients by country. Many of the prevalence estimates were from studies in small populations (≤200 patients) and from a limited number of countries, and as such, these estimates may be limited in their generalizability. We found few studies that provided information on adolescent IBD populations, highlighting that further research is needed to assess the burden of anxiety or depression in this group of patients. The majority of the evidence identified on psychological comorbidities in patients with IBD was obtained from non-controlled studies. As such, there is likely inconsistency and heterogeneity among the included studies; therefore, the evidence is unlikely to be sufficiently rigorous to draw indirect comparisons on the impact of treatments. Results of the included studies may be biased through selective reporting of cases and/or selecting a non-randomized study cohort. There is also a lack of standardization in the measures and scales used to assess psychological symptom severity in patients with IBD.

It is also important to note that new studies have been published since this systematic review was completed. For example, a randomized controlled trial of young adults and adolescents (n = 70) found no evidence that disease-specific CBT along with standard medical care improved psychological symptoms or health-related QoL [102,103]. The authors concluded that this could be due to most patients having no or only mild IBD symptoms at baseline and noted that it is still unclear which patients will benefit most from CBT and how the intervention should be delivered. In a study of 121 young people with IBD, having negative illness perceptions at baseline predicted those at higher risk of developing a psychological comorbidity [104]. Negative illness perceptions and having depression were also linked with a lower health-related QoL in study of 10–20-year-old patients with IBD [105]. Therefore, psychological interventions targeting negative illness perceptions and depression could improve health-related QoL in young patients with IBD.

A systematic review and meta-analysis of randomized controlled trials evaluating non-pharmacological interventions concluded that such interventions significantly reduced anxiety, depression, and disease specific QoL in adults with IBD compared to control groups, but the effect sizes were small [106]. In a cross-sectional study, high resilience was independently associated with lower disease activity and better QoL in patients with IBD and with fewer IBD surgeries in patients with CD [107]. A trial of integrated psychological screening and intervention reported that engagement in psychological intervention was six times greater for patients who were treated in-service compared to those who had an external referral for the intervention. Overall QoL and levels of anxiety and depression improved when patients were followed-up after 1 year, indicating that psychological care can work well when integrated into routine care [108].

Despite these limitations, which are inherent in SLRs, the evidence gathered in this SLR may provide an important resource to understand more about the global burden of psychological comorbidities in patients with IBD. By including all the evidence, such as data from conference abstracts and studies that may be considered of lower research quality, this SLR may be valuable to a larger audience of policymakers in a wider range of countries. As there are variations in health systems across the world, by broadening the inclusion criteria in this SLR, we have provided evidence that may be used to more fully examine the disease burden of anxiety and depression in IBD patients across different health systems.

5. Expert opinion

There is a need for mental-health integration in IBD care settings, and the psychological impact of IBD must be considered when treating patients with IBD. If psychological comorbidities such as anxiety or depression are not identified and addressed, then the burden on patients and the healthcare system is compounded. The current approach to psychosocial care suggests that clinicians are intervening too late during patient care [109]. Risk factors and/or precursors to the development of anxiety and depression in patients with IBD are not yet fully understood. Research into these risk factors may help interventions to be developed that could be delivered earlier on during patient care. The psychosocial impact of IBD on caregivers also warrants further investigation. Although there is short-term evidence for the effectiveness of behavioral interventions, such as individual and group-based CBT, in reducing rates of anxiety and depression in patients with IBD, longer-term studies are needed.

Patient access to quality, IBD-focused health psychologists early on in care is limited. It is important to identify mechanisms to overcome the current barriers that prevent patients with IBD from accessing mental-health care for psychological comorbidities. Psychological interventions that target anxiety and depression in patients with IBD could in turn reduce the increased costs associated with healthcare utilization in these patients. Managing psychological comorbidities such as anxiety and depression may improve outcomes in patients with IBD by improving self-management and treatment adherence, and by reducing the need for unplanned, expensive care. There have been a number of studies using Web-based and mobile health apps to deliver CBT programs for anxiety and depression, including some studies in patients with IBD. This approach has the potential for widespread delivery of these interventions to IBD patients and may be of particular use in younger patients due to the widespread use of smartphones and tablets in this cohort. As such, this approach for delivering CBT merits further study, using mobile apps that are tailored for IBD patients. More research is needed to identify approaches that integrate medical and psychological treatment for patients with IBD into clinical practice, such as the use of positive psychology interventions as an earlier way to prioritize emotional health in IBD [110].

Currently, there are gaps in patient care and barriers to the use of non-pharmacologic interventions. Addressing these patient care gaps could help healthcare professionals to intervene and improve outcomes in IBD patients with comorbid anxiety or depression. In order to address these gaps, a number of barriers must be overcome, including the lack of knowledge, attitudes, and skills of gastroenterology providers in addressing mental-health disorders; limitations in time during busy clinical appointments; available resources for appropriate screening and treatment referrals; and additional studies documenting the beneficial outcomes and cost-effectiveness of these interventions [106]. In addition, there is a lack of mental-health guidelines and quality indicators for measuring outcomes across different sites and countries. We propose a multi-tiered approach to addressing these barriers in the near future. This includes ongoing education of our colleagues and patients about the importance of mental health and IBD; development and validation of screening and treatment tools for the IBD clinic; and identification of additional digital, remote, and regional resources to address the mental-health problems of our patients. These efforts should be recognized, studied, and funded appropriately so that research demonstrating their clinical and cost effectiveness will feed back into such efforts for ongoing support and success.

Article highlights

• Patients with IBD often have psychological comorbidities such as anxiety and depression, which can have a negative impact on their quality of life.

• These comorbidities can increase health utilization through an increased risk of hospitalization, readmission to hospital and use of outpatient services.

• There are a number of unmet needs including inconsistent screening for depression, and patients not consulting mental-health professionals when needed.

• Individual and group-based cognitive behavioral therapy may help reduce rates of anxiety and depression in adults and adolescents with IBD.

• Research is needed to identify barriers that prevent patients with IBD from accessing mental-health care as psychological interventions may reduce the increased costs associated with healthcare utilization.

Declaration of interest

M Dubinsky has received research funding from AbbVie, Janssen, Prometheus and Pfizer; has served as a consultant for AbbVie, Arena, Boehringer Ingelheim, Celgene, Eli Lilly, Genentech, Janssen, Pfizer, Prometheus, Salix, Shire, Takeda and UCB; is a co-director of the Susan and Leonard Feinstein IBD Clinical Center, and is a co-founder of Mi-Test Health and Cornerstones Health, co-founder and shareholder of Trellus Health and Cornerstones Health.

I Dotan has served on Advisory Boards/Speakers Bureau for Janssen, AbbVie, Takeda, Pfizer, Genentech/Roche, Neopharm, Celltrion, Rafa Laboratories, Ferring Pharmaceuticals Inc., Falk Pharma, MSD and Medtronic/Given Imaging; has received research funding from AbbVie, Pfizer and Altman Research; speaker or consultancy fees from Janssen, AbbVie, Takeda, Pfizer, Genentech/Roche, Arena, Neopharm, Gilead, Celltrion, Rafa Laboratories, Ferring, Falk Pharma, MSD, Protalix, Medtronic/Given Imaging, Medison, Sublimity Therapeutics and DSM.

D T Rubin has received research funding from Takeda; has served as a consultant for AbbVie, AbGenomics, Allergan, Inc., Arena Pharmaceuticals, Biomica, Bristol-Myers Squibb, Dizal Pharmaceuticals, Ferring Pharmaceuticals Inc., Genentech/Roche, Janssen Pharmaceuticals, Lilly, Mahana Therapeutics, Medtronic, Merck & Co., Inc, Napo Pharmaceuticals, Pfizer, Prometheus Laboratories, Shire, Takeda, TARGET PharmaSolutions Inc, and is a co-founder of Cornerstones Health, Inc.

M Bernauer and D Patel are employees of Pharmerit and were paid consultants to Pfizer in connection with the development of this manuscript.

R Cheung was an employee of Pfizer at the time of this research and owns stock or options in Pfizer.

I Modesto and M Latymer are employees of and own stock or options in Pfizer.

L Keefer has received research funding from AbbVie, served as a consultant to Pfizer and AbbVie, and is co-founder and shareholder of Trellus Health.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Authors’ contributions

M Bernauer, D Patel, and R Cheung were involved in the design and conduct of this SLR. All authors had access to the results of the SLR, provided critical feedback during the development of this manuscript, and approved the final version for submission.

Acknowledgments

Medical writing support was provided by Jacqui Oliver, PhD, of Engage Scientific Solutions and was funded by Pfizer.

Supplemental Material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work (systematic literature review and medical writing support) was funded by Pfizer.