Download Common Psychological Disorders in Inflammatory Bowel Disease

Clinical Review
Common Psychological Disorders in
Inflammatory Bowel Disease and Implications
for Disease Management
Lesley A. Graff, PhD, and Sharon Dudley-Brown, PhD, FNP-BC
Abstract
• Objective: To review and describe the relationship
between mood disorders and inflammatory bowel disease (IDB), considering the evidence for prevalence
and comorbidity, as risk factors for disease course,
and for psychological interventions in IBD disease
management. • Methods: Review of the clinical literature, with a primary focus on human studies and English language
reports in the last decade to serve as an update to
prior reviews. • Results: Studies suggest that mood disorders are
more prevalent in IBD. Anxiety and depression that
pre-date IBD onset may be a risk factor for disease.
Mood disorders can adversely affect the course of
IBD, including more frequent relapses and greater risk
of surgery. Active or more severe disease and poorer
socioeconomic status are risk factors for the development of a mood disorder in IBD. Antidepressant medication and psychological therapy can improve anxiety
and depression in IBD, but the evidence for direct
improvement of IBD outcomes with these 2 therapy
approaches is still preliminary.
• Conclusion: The psychological health of the IBD patient is relevant in disease management given the relationship of mood disorders with disease outcomes.
GI practitioners are encouraged to screen for depression and anxiety and to initiate or refer for pharma-
cologic or psychological treatment when indicated.
There is potential for these interventions to positively
affect disease course directly in addition to mitigating
distress and improving quality of life.
C
rohn’s disease (CD) and ulcerative colitis (UC),
collectively described as inflammatory bowel
disease (IBD), are chronic, spontaneously relapsing and remitting inflammatory disorders of the gastro-
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intestinal tract. These diseases are as common as type
1 diabetes and twice as common as multiple sclerosis,
given prevalence rates conservatively estimated at 150 per
100,000 [1], and there is some indication that prevalence
rates may be rising [2]. Approximately 30% of those with
IBD are diagnosed before the age of 21 [3], making IBD
the most significant chronic disease of childhood and
adolescence, and a disease of lifelong struggle.
The current etiologic hypothesis of IBD suggests the
disease is triggered by an abnormal immune response to
microbial agents that reside in the gut [4,5]. These chronic
inflammatory disorders are painful, embarrassing, and
socially and physically limiting, and can persist throughout one’s lifetime [6]. Characterized by exacerbations and
remissions, symptoms typically include abdominal pain,
diarrhea, weight loss, and a variety of extraintestinal
symptoms. Disease management is accomplished through
a range of medications, including the use of steroids, immunomodulators, and the newer biologic agents; as well,
surgery is often required. Management goals include
achieving symptomatic remission, suppressing inflammation and achieving mucosal healing, controlling or minimizing complications, and maintaining remission. Overall,
the long-term course of IBD can include hospitalization,
surgery, and costly medications, as well as a reduced quality
of life (QOL) [7].
In addition to the clinical burden of the disease for
the patient, there is evidence of significant psychiatric
comorbidity that not only can add to the distress of the
patient experience but may also directly affect the course
From the Department of Clinical Health Psychology, Faculty
of Medicine, University of Manitoba, Winnipeg, Manitoba,
Canada (Dr. Graff), and the Schools of Medicine and Nursing, Johns Hopkins University, Baltimore, MD (Dr. DudleyBrown).
Vol. 20, No. 7 July 2013 JCOM 315
Mood Disorders and IBD
of the disease [8]. This paper will review the recent
clinical findings regarding mood disorders and IBD,
and consider implications and directions for intervention
when treating the IBD patient.
Prevalence of Mood Disorders in IBD
Anxiety and depression have been commonly reported
in patients with IBD. A recent clinical study comparing
IBD patients (n = 103) and healthy controls (n = 124)
reported significantly higher anxiety and depression
scores on a validated symptom self-report measure than
the healthy control sample [9]. In a population-based
study using case controls, Lerebours et al [10] compared
241 incident cases of IBD to 225 blood donor community controls. They found that those with IBD had
significantly higher levels of depression than the community controls, with similar findings for anxiety. A larger
case-control study compared rates of depression and
anxiety in patients with IBD relative to rates in 800,000
controls admitted to a hospital for minor medical reasons
[11]. Results indicated higher rates of both anxiety and
depression in the IBD patients that were especially evident early in the disease course. For those with CD, the
rates of anxiety or depression were 5 times higher than
for the controls, and for those with UC the rate of anxiety was 4 times higher and that of depression was twice
as high as controls. The Manitoba IBD cohort study is
the largest study, and one of only 2, to use a structured
clinical diagnostic interview to assess prevalence rates
when comparing mood disorders in those with IBD versus controls [12]. They reported higher lifetime rates of
depression in the IBD population-based sample (27% vs.
12%), and they noted lower rates of social anxiety in IBD
compared with the community controls (6% vs. 11%).
When rates of mood disorders in IBD have been compared with rates in other chronic diseases, CD patients
were found to have a higher prevalence of depressed
mood relative to those with erosive esophagitis, (25.4%
vs. 8.2%) [13]. Both UC and CD patients had similar levels of anxiety as those with chronic liver disease [14]. The
chronic liver disease patients had higher depression levels
than the IBD patients, which may relate to treatment
side effects with interferon for chronic liver disease and/
or may reflect the higher rates of substance abuse and associated depression often found in a chronic liver disease
population [14]. Generally, however, depression is more
likely to co-occur with chronic conditions characterized
by pain, such as IBD [15].
316 JCOM July 2013 Vol. 20, No. 7
There has been little attention to suicide risk with
depression in IBD, but one small study of CD patients (n = 69) specifically queried this and found 13%
acknowledged feeling suicidal due to their IBD [16].
These results were supported by a larger national study
that reported 17% of those with major depression and
IBD had considered suicide at some point in the previous
year [17].
All of these studies provide very strong support for a
higher prevalence of mood disorders in IBD compared
with the general community. Disease activity may play a
role, in light of the findings that depression and anxiety
levels were significantly higher for CD and UC patients
with active disease than matched healthy controls, but
were not significantly different for those in remission
[14], paralleling earlier findings in a population-based
study of psychological functioning in IBD [18].
Depression and Anxiety as Risk factors for
IBD Onset
Epidemiologic research has suggested that those with
depression are at a greater risk of subsequent development
of a variety of chronic diseases, including hypertension
(hazard ratio [HR] 1.6, 95% confidence interval [CI]
1.2–2.2), arthritis (HR 1.7, CI 1.3–2.2) and asthma
(HR 1.8, CI 1.3–2.5) [19], although the relatively lower
base rate of IBD may make it more difficult to discern
a downstream etiological relationship in epidemiologic
studies. A population-based Canadian study found that
depression antedated IBD diagnosis by at least 2 years
in 54% of those with a lifetime history, and that 79%
of people with IBD and a lifetime history of an anxiety
disorder had a first episode more than 2 years prior to
the IBD diagnosis [12]. This time frame might still be
considered concurrent to disease onset though, given the
lengthy period of 2 to 3 years that it can take to establish
a diagnosis. However, Kurina and colleagues [11] found
higher rates of depression 5 years prior to an IBD diagnosis, compared with the general population. Similarly,
the Nurses Health Study, which has tracked more than
150,000 women since 1992, reported that a higher level
of depressive symptoms at baseline was associated with a
greater risk of subsequently developing CD (OR 1.62),
although an increased risk for UC was not evident [20].
While the studies do not conclusively support an
etiological role for mood disorders in IBD onset, they
highlight the possibility that anxiety and depression may
in themselves be risk factors for IBD.
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Clinical Review
Mood Disorders and IBD Disease Course
Several studies have observed that anxiety and depressive
symptoms are likely to be more prominent in times of
increased disease activity and to improve when the disease activity is reduced [21]. Goodhand and colleagues
used a cross-sectional design to examine the relationships
between demographic, clinical and phenotypic factors,
and mood in patients with UC, CD, and healthy controls, focusing specifically on the association between
disease activity and mood [9]. They found that for both
UC and CD patients, anxiety and depression scores
were higher than for controls. In UC, anxiety was associated with perceived stress and a new diagnosis of
IBD, and depression was associated with stress, inpatient
status and active disease. In CD, anxiety was associated
with perceived stress, abdominal pain, lower socioeconomic status, and active disease (as measured by fecal
calprotectin and/or serum CRP), while depression was
associated with perceived stress and increasing age [9].
While associations cannot clarify causal direction, several
prospective studies have suggested that mood disorders
can negatively influence disease course in IBD. A small
2-year study tracking CD patients every 2 to 3 months
found that higher depression scores were associated with
subsequent elevated clinical disease scores (ie, Crohn’s
Disease Activity Index (CDAI) scores) in the following
time period [22]. In a study on the impact of depression
and anxiety on IBD relapse in CD and UC patients, Mittermaier and colleagues [23] found that depression levels
at baseline were significantly correlated with the total
number of relapses in the subsequent 18 months. Higher
anxiety at baseline was also related to more frequent
relapses. They also found that the time to first relapse
was significantly shorter for patients who were depressed
at baseline compared with those who were not (97 vs.
362 days).
Using a large electronic medical record (EMR) database of over 10,000 IBD patients, Ananthakrishnan et
al [24] identified that CD patients with a diagnosis of
depression or anxiety were 28% more likely to require
surgery than those without psychiatric comorbidity, after
adjusting for demographic and clinical disease factors.
They did not find the same outcome for UC patients,
although surgery rates tend to be lower for UC compared
with CD patients, which may be a confounder.
Depression may also interfere with effects of medication or through adherence more generally as other avenues to impact disease course. In a prospective study of
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CD patients, major depression was a risk factor for failure
to achieve remission with infliximab [25]. While it was
unclear whether adherence was the relevant mechanism
in the infliximab study, depression is associated with
lower behavioural adherence to treatment regimens in
chronic disease [26]. Poorer adherence to treatment in
IBD has been associated with a variety of demographic,
clinical and psychological factors, such as male gender,
young age, and mild disease, with adherence tending to
be lower in those suffering from anxiety or depression
[27]. A recent study on adherence in adolescents with
IBD found that higher anxiety and depression symptoms were associated with lower adherence, playing a
moderating role with specific barriers to adherence [28].
However, a large survey study of over 1000 members of a
national IBD association in France, found that selfreported nonadherence increased with anxiety and
moodiness, but was not associated with depression [29].
There has been some exploration of coping as a mediator of the impact of mood in IBD, although it has been
difficult to delineate these relationships. Dorrian and
colleagues examined the relative contribution of illness
perceptions and coping strategies to explain adjustment
to IBD, assessing adjustment in terms of psychological
distress, quality of life and functional independence [30].
In this study, coping did not independently predict these
aspects of adjustment once illness perceptions were controlled for. A recent study assessed the relationship among
IBD knowledge, coping, and medication adherence [31].
They found that individuals with IBD who had greater
disease knowledge and who were better informed about
their IBD were more likely to endorse adaptive coping
strategies, such as the use of more problem-focused coping and less emotion-focused coping, however they did
not assess disease outcomes.
While a self-management approach has been incorporated into the management of many chronic diseases, it is
unclear whether outcomes with these types of approaches
in IBD are influenced by comorbid mood disorders.
A review of self-management and educational interventions in IBD found 10 out of 18 studies had incorporated 1 or more measures of psychological well-being
[32]. Three studies showed a reduction in anxiety with
self-management interventions, 2 of which involved
CD patients, and 1 involving UC patients. The study
of UC patients implemented a “comprehensive lifestyle
modification program” that included stress management
training, disease education, and self-care. They found
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Mood Disorders and IBD
improvement in anxiety after 3 months, but no long-term
mood benefits 12 months after completion [33]. Overall,
however, none of these studies assessed mood in a mediating or moderating role, but rather mood was included
as a secondary outcome.
Risk factors for Development of Mood
Disorders in IBD
The risk of clinical depression or anxiety has been found
to be high in the year following an IBD diagnosis in
particular, with estimates of 4 to 5 times increased risk
compared with population base rates [11]. Loftus and his
colleagues [34] evaluated the risk of developing anxiety
or depression in children (ie, < 18 years old) with Crohn’s
disease using a 1:5 case-matched design, and found a
significantly elevated risk as well after the CD diagnosis
compared to nonIBD controls (HR 2.28 for anxiety;
HR 1.74 for depression). It is only recently, though, that
factors associated with developing one of these mood
disorders in IBD have been specifically explored.
An association with disease activity has consistently
been observed, such that those with active disease
were more likely to experience depression or anxiety
[9,13,14,35]. This association intuitively make sense as
the challenges of managing active symptoms and medications in a chronic disease with an unpredictable course
can be daunting for many patients.
The largest study to date to assess risk factors for
psychological comorbidity surveyed 1663 IBD patients
and examined clinical disease and socioeconomic factors
[35]. Multivariate analyses indicated that disease flares,
severe disease, self-reported poorer treatment adherence,
being unemployed, and socioeconomic deprivation were
each independently associated with anxiety for IBD
patients. Depression in IBD was associated with the
sociodemographic factors of age, unemployment, and social deprivation, as well as disease flares. A small Korean
study similarly reported lower socioeconomic status as a
risk factor for depression in IBD [36]. Other risk factors
for IBD patients that have been identified include family
history of depression (risk for anxiety [13]), and concurrent stress (risk for anxiety and depression [9]). However,
all of these studies used cross-sectional designs which do
not allow determination of causality. The associational
relationships could as readily be reflecting an effect of
mood disorders on disease and adherence for example, as
reflecting the opposite, namely that active disease is a risk
factor for the development of mood disorders.
318 JCOM July 2013 Vol. 20, No. 7
One prospective study examined onset of anxiety or depression following IBD hospitalization or surgery, and evaluated risk factors for the development of mood disorders
at that time [37]. Using the EMR database described
previously, for this study, Ananthakrishan and his group
first excluded all patients with a diagnosis of depression
or anxiety prior to or within 30 days of an IBD-related
surgery or hospitalization. They found a significantly
greater risk of depression following surgery for both UC
and CD, compared to IBD patients who had never had
surgery, with a median onset of depression 2.5 years
post-surgery. They reported similar findings for anxiety,
although the risk of anxiety post-surgery was smaller than
the risk for depression, compared to the IBD patients
who had never had surgery. There was also a significant
risk of depression or anxiety 5 years after an IBD-related
hospitalization, with a nearly twofold greater risk of
depression than for those with IBD who never needed
hospitalization.
Overall, these findings imply that active disease, and
in particular a more severe disease course as evidenced by
the need for surgery or hospitalization, may predispose to
psychological morbidity.
Why are Mood Disorders Co-occurring with
and Adversely Affecting IBD?
The studies reviewed in the previous sections suggest that
mood disorders may both affect and be affected by IBD.
A bidirectional influence in the brain-gut pathway has
been supported through prospective work with the functional gastrointestinal disorders. Koloski et al [38], in a
study assessing 1775 participants, concluded that psychological disorders both preceded and followed onset of
irritable bowel syndrome and functional dyspepsia. They
found that higher anxiety levels at baseline for those with
no evident functional GI disorder independently predicted the development of these functional GI disorders 12
years later. Similarly, those who had either IBS or functional dyspepsia but no elevated depression or anxiety at
baseline were much more likely to have clinically elevated
anxiety and depression when assessed 12 years later.
The complex interactions in the brain-gut axis have
been broadly studied, spanning interconnections among
the psycho-neuro-endocrine-immune systems implicated
in the pathogenesis and pathophysiology of IBD [39].
Multiple factors that might drive neuroimmune modulation in IBD have been identified and include psychological factors such as stress and depression, with
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Clinical Review
potential pathways via inflammation and/or autonomic
imbalance. Studies modeling colitis and depression in
mice found that depression increased susceptibility to
experimental colitis [40] and worsened colitis severity,
regardless of whether it was induced prior to inducing the colitis or following the colitis onset [41,42].
Depression in the mice was found to exacerbate the
colitis by interfering with the actions of the vagus nerve
that serve to counter inflammation [41]. These findings affirm that depression can negatively affect the
course of intestinal inflammation. There is also evidence
to support directional influence the other way, namely that inflammation may precipitate depression [43].
Elevated proinflammatory cytokines have been identified in depressed individuals even in the absence of any
comorbid inflammatory disease, and it is now recognized
that proinflammatory cytokines can access the brain
through humoral, neural and cellular pathways and alter
cerebral function [44].
The gut microbiome, which collectively refers to all
the microbes residing in the gut, may be another pathway
through which mood disorders and IBD interact, although
the work in this area is still in its infancy [45]. Research is
converging to suggest that intestinal microbes might be
involved centrally in modulating behavior and brain biochemistry, and that environmental influences such as stress
can affect the microbial balance in the gut [46]. Bercik and
colleagues [47] altered the gut bacterial composition in a
strain of timid mice through application of antibiotics and
observed significant behavior changes from shy to bold tendencies. They also colonized bacteria from opposite strains
of mice (ie, timid and bold) and observed parallel changes in
behavior, noting that the bolder mice became more hesitant
and anxious. In another study, this group induced inflammation through parasitic infection resulting in increased
anxious behavior, which subsequently abated when the mice
were treated with a beneficial gut microbe [48].
Collectively, the knowledge from these animal models
of the brain-gut axis provides insight into mechanisms and
common pathways. These findings may also highlight new
targets for intervention, and they support, at a conceptual
level, that treating one component of the mood-disease interrelationship may help to address the other component.
Psychological Health and Implications for
Treatment
Overall, the current evidence underscores that psychological health should be a clinical consideration in
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disease management for IBD. With an emerging model
suggesting a bidirectional relationship between mood
disorders and inflammatory bowel disease, assessment
and treatment of psychological concerns, in addition
to management of bowel symptoms and inflammation,
may decrease distress, improve quality of life for the
IBD patient, and potentially improve disease course
[49,50]. IBD specialty clinics in multiple countries have
adopted more of a biopsychosocial approach in their
management of IBD patients [51]. However, this approach is not yet common or standard practice, despite
consensus guidelines calling for more routine screening
and treatment of anxiety and depression [52]. A study
in the Netherlands found that less than 20% of IBD
patients with current significant anxiety or depressive
symptoms had recently received any intervention, either
psychological or psychiatric [53], suggesting undertreatment of comorbid mental health needs parallel to the
concerning under-treatment of depression in the general
population [54].
Anxiety and depression are very treatable conditions,
and have been responsive to both pharmacological and
psychological treatment approaches. The most widely
used antidepressant medications are the second generation serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) [55]. The
cognitive behavior therapies also have extensive empirical
support for treating mood disorders [56]. The efficacy
of these 2 approaches to treatment has been examined
in IBD, with some evaluation of impact on psychological
outcomes as well as IBD outcomes, albeit with varying
quality of study methodology.
Pharmacotherapy
While randomized controlled animal studies have found
that antidepressant therapy can attenuate induced colitis in mice [40,41], the handful of human studies that
have examined the use of antidepressants in IBD consist
mainly of case studies [57], with 1 open-label trial [58],
1 recent case-control study [59] and 1 small randomized controlled trial (RCT) [60]. A systematic review of
the case studies and the open-label trial concluded that
the targeted anxiety or depression generally responded
to treatment (primarily paroxetine or buproprion), and
most of the studies found a positive effect on IBD disease activity [57]. Goodhand and colleagues [59] used
retrospective case review to assess the disease course of
29 patients in the year before and after they were started
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Mood Disorders and IBD
on antidepressants for a comorbid mood disorder, comparing them to matched IBD controls who were not on
antidepressant medication. Eight different antidepressants were used across the cases, with the most common
being citalopram and fluoxetine. They found both an
improvement in mood symptoms and improvement in
IBD disease course, reporting significantly fewer IBD relapses and less use of steroids for those using antidepressant medication. The only RCT involved 50 UC patients
tracked prospectively for 8 weeks, half of whom were
treated with imipramine [60]. They reported improved
mood and decreased disease severity in the treated group,
however they did not randomize based on mood status,
resulting in baseline differences between groups.
This early stage data suggests antidepressant medications may positively affect IBD disease course in addition
to treating comorbid mood disorders. It is not clear from
the studies done to date whether any IBD improvement
is a result of treating the depression, or is more directly
impacting brain-gut processes relevant in IBD. Carefully
controlled studies are needed to examine whether this
treatment approach might improve IBD in the absence of
psychiatric comorbidity. Studies in non-IBD samples have
shown that antidepressant treatment has been associated
with decreases in inflammatory markers [61], providing
some support for the potential of these medications as
an adjunct for disease management in IBD. However it
is important to treat depression and anxiety regardless of
whether there is a direct positive effect on the IBD, as
these psychiatric disorders contribute to significant suffering and disability in their own right.
Psychotherapy
As with pharmacotherapy, there are 2 outcomes of interest when considering the utility of psychological therapies
in IBD—psychological functioning and impact on IBD
symptoms and course. A number of recent reviews, including a Cochrane review, have evaluated the efficacy
of psychological treatments in IBD [8,49,50,62–64],
with mixed conclusions. However, most included any
nonpharmacological interventions rather than considering only evidence-based psychotherapy interventions for
mood disorders and assessing their efficacy with comorbid mood disorders in IBD. For example, the Cochrane
review [62] concluded there was little support for the
efficacy of psychological therapy in IBD for either psychological or IBD outcomes, but they included studies
of patient education and supportive psychotherapies,
320 JCOM July 2013 Vol. 20, No. 7
which have not been established as efficacious for primary
depression or anxiety. In contrast, studies that have used
cognitive behavioral therapy (CBT) for depression or
stress management interventions based on CBT strategies, have more consistently reported significant improvements in the targeted anxiety or depression, and quality
of life for IBD patients [65–69].
CBT and stress management interventions have had
only modest effects on disease outcomes in IBD [64].
Of the studies noted previously with significant psychological functioning improvements, most also measured
outcomes for IBD and did not find any effect on disease
course [65,66,68,69]. However, improvements in IBD
symptoms post-treatment, including constipation fatigue,
pain, and abdominal distension, have been reported in a
few randomized controlled studies [70–72]. In addition,
a retrospective case-control study found that patients
who received psychological counseling had fewer relapses,
fewer outpatient visits, and decreased used of steroid medication and other relapse-related IBD medications in the
year following counseling relative to the year prior, with
no differences in outcomes for the control group [73].
The studies to date suggest that empirically supported psychological interventions, and in particular
CBT, can be applied to mood disorders in IBD with
positive effect, similar to what has been found for the
use of antidepressant medication in IBD. However,
the direct impact on IBD outcomes for patients with
or without a concurrent mood disorder has not been
clearly established. Recent controlled studies suggest
that psychological therapies hold promise as a useful adjunct to IBD management, but methodological issues such as inclusion of non–evidence-based
therapies, unselected IBD patients, or patients in remission with little elevated distress or disease activity need
to be addressed.
Other Novel Therapies
Hypnotherapy has been reported as an effective intervention for irritable bowel syndrome, but has only
recently been applied to inflammatory bowel disease.
A controlled experimental study of UC patients with
active disease demonstrated significant improvements
in both systemic and rectal mucosal inflammatory
responses following hypnosis compared to the control
group [74]. Two small uncontrolled clinical studies using
hypnotherapy found improvements in IBD symptoms.
One study provided gut-directed hypnotherapy to 15
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Clinical Review
Table. Managing psychological aspects of the IBD patient experience
Key points
Psychological health is relevant in managing IBD
There may be increased vulnerability for mood disorders around IBD diagnosis and around disease flare
To assess:
Add brief screening for psychological distress to clinical review of patient symptoms and functioning
Include 1-2 questions assessing levels of depression, anxiety, stress AND interference with daily functioning
• If negative, the questions have communicated that the patient’s psychological health is also important
• If positive, use more detailed query of mental health to determine clinical need
To address:
Consider initiating antidepressant medication or identify for follow-up with family physician
Consider referral for psychological intervention; CBT is generally more widely available and evidence-based than other psychotherapies.
medication-refractory IBD patients [75]. They found
that the majority of IBD patients experienced improved
symptoms (reclassified from severe to mild or moderate),
improved quality of life, and decreased use of corticosteroids, with results sustained for an average 5 year follow
up. The second study reported significant improvement
in disease-specific quality of life for 8 UC patients in
remission [76]. A further controlled study by the same
group, comparing hypnotherapy to an active attention
control for UC patients, reported that the treated group
was less likely to have a disease flare in the subsequent
12 months [77].
Bonaz and his group have explored the role of vagal
nerve inhibition in anti-inflammatory processes, given the
link between the hypothalamus-pituitary-adrenal axis and
stress in IBD. Their preliminary findings showed vagus
nerve stimulation improved colitis in rats, and they are
now piloting this novel approach in patients with CD [39].
Conclusions
There is increasing recognition that chronic disease management optimally involves attention to psychological
processes as well. This is becoming particularly evident
in IBD, as depression and anxiety are highly prevalent.
It may be that these mood disorders are consequences of
the challenges of coping with an illness that is defined by
an unpredictable course, fears of disease progression, and
painful and embarrassing symptoms. These disorders in
turn can worsen disease activity. The heterogeneity of the
inflammatory bowel diseases, in terms of disease type (ie,
CD, UC), disease activity, phenotype and genotype, add
complexity when discerning outcomes and interrelationships with psychiatric illness, as many studies do not diswww.jcomjournal.com
tinguish IBD subgroups across all of these dimensions.
Nevertheless, the weight of evidence for an adverse impact of these psychological factors on IBD supports the
call for more routine screening and care in the regular
course of health care provision (Table). The IBD patient
may be best served by a review of symptoms and functioning that includes queries regarding mental health,
as has been initiated with other chronic disease populations such as heart disease and diabetes [78,79]. The
time around IBD diagnosis and during periods of active
disease may be especially vulnerable periods for development of or exacerbation of these psychological disorders,
but routine review and intervention when indicated could
potentially mitigate the adverse effects to some degree.
While more rigorous studies of antidepressants and psychological therapies are needed to determine the impact
on physiological and symptom outcomes for IBD, their
effectiveness with mood disorders is well-established.
Perhaps it is time to integrate these approaches more fully
into the arsenal for IBD disease management.
Corresponding author: Lesley A. Graff, PhD, PZ350, 771
Bannatyne Ave., Winnipeg, MB Canada R3E 3N4, lgraff@
hsc.mb.ca.
Financial disclosures: None.
Author contributions: conception and design, LAG; analysis
and interpretation of data, LAG, SDB; drafting of article,
LAG, SDB; critical revision of the article, LAG, SDB; statistical expertise, LAG; collection and assembly of data, SDB.
References
1. Loftus CG, Loftus EV, Harmsen WS, et al. Update on the
incidence and prevalence of Crohn’s disease and ulcer-
Vol. 20, No. 7 July 2013 JCOM 321
Mood Disorders and IBD
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
ative colitis in Olmstead County Minnesota 1940-2000.
Inflamm Bowel Dis 2007;13:254–61.
Rocchi A, Benchimol E, Bernstein CN, et al. Inflammatory
bowel disease. A Canadian burden of illness review. Can J
Gastroenterol 2012;26:811–7.
Karwowski CA, Keljo D, Szigethy E. Strategies to improve
quality of life in adolescents with inflammatory bowel disease. Inflamm Bowel Dis 2009;15:1755–64.
Rioux KP, Madsen KL, Fedorak RN. The role of enteric microflora in inflammatory bowel disease: human and animal
studies with probiotics and prebiotics. Gastroenterol Clin
North Am 2005;34:465–82.
Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s
disease and ulcerative colitis. Nat Clin Pract Gastroenterol
Hepatol 2006;3:390–407.
Loftus EV, Schoenfeld P, Sandborn WJ. The epidemiology
and natural history of Crohn’s disease in population-based
patient cohorts from North America: a systematic review.
Aliment Pharmacol Ther 2002;16:51–60.
Bernstein CN. The natural history of inflammatory bowel
disease. In: Baumgart D, editor. Crohn’s disease and ulcerative colitis: from epidemiology and immunobiology to
a rational diagnostic and therapeutic approach. New York:
Springer; 2012:343–64.
Graff LA, Walker JR, Bernstein CN. Depression and anxiety
in inflammatory bowel disease: a review of comorbidity and
management. Inflamm Bowel Dis 2009;15:1105–18.
Goodhand JR, Wahed M, Mawdsley JE, et al. Mood disorders in inflammatory bowel disease: relation to diagnosis,
disease activity, perceived stress and other factors. Inflamm
Bowel Dis 2012;18:2301–9.
Lerebours E, Gower-Rousseau C, Merle V, et al. Stress life
events as a risk factor for inflammatory bowel disease onset:
a population-based case-control study. Am J Gastroenterol
2007;102:122–31.
Kurina LM, Goldacre MJ, Yeates D, et al. Depression and
anxiety in people with inflammatory bowel disease. J Epidemiol Community Health 2001;55:716–20.
Walker JR, Ediger JP, Graff LA, et al. The Manitoba IBD
Cohort study: a population-based study of the prevalence
of lifetime and 12-month anxiety and mood disorders. Am
J Gastroenterol 2008;103:1989–97.
Brandi MT, Ribeiro MS, Chebli LA, et al. Psychological distress in Brazilian Crohn’s disease patients: screening, prevalence and risk factors. Med Sci Monit 2009;15:PH101–8.
Hauser W, Janke K, Klump B, Hinz A. Anxiety and depression in patients with inflammatory bowel disease: comparisons with chronic liver disease patients and the general
population. Inflamm Bowel Dis 2011;17:621–32.
Bair MJ, Robinson RL, Katon W, Kroenke K. Depression
and pain comorbidity: A literature review. Arch Intern Med
2003;163:2433–45.
Mahadev S, Young J, Selby W, Solomon M. Self-reported
depressive symptoms and suicidal feelings in perianal
Crohn’s disease. Colorectal Dis 2011;14:331–5.
Fuller-Thomson E, Sulman J. Depression and inflammatory
bowel disease: findings from two nationally representative
322 JCOM July 2013 Vol. 20, No. 7
Canadian surveys. Inflamm Bowel Dis 2006;12:697–707.
18. Graff LA, Walker JR, Lix L, et al. The Manitoba IBD Cohort Study: the relationship of disease type and activity to
psychological functioning and quality of life. Clin Gastroenterol Hepatol 2006;4:1491–501.
19. Patten SB, Williams JV, Lavorato DH, et al. Major depression as a risk factor for chronic disease incidence: longitudinal analyses in a general population cohort. Gen Hosp
Psychiatry 2008;30:407–13.
20. Ananthakrishnan A, Khalili H, Pan A, et al. Association between depressive symptoms and incidence of Crohn’s disease and ulcerative colitis: results from the Nurses’ Health
Study. Clin Gastro Hepatol 2013:11:57–62.
21. Graff LA, Walker JR. Psychological factors. In: Bernstein
CN, editor. The inflammatory bowel disease yearbook.
London: Remedica; 2007: Vol 4, 99–150.
22. Mardini HE, Kip KE, Wilson JW. Crohn’s disease: a
two-year prospective study of the association between
psychological distress and disease activity. Dig Dis Sci
2004;49:2–497.
23. Mittermaier C, Dejaco C, Waldhoer T, et al. Impact of
depressive mood on relapse in patients with inflammatory
bowel disease: a prospective 18 month follow-up study.
Psychosom Med 2004;66:79–84.
24. Ananthakrishnan AN, Gainer VS, Perez RG, et al. Psychiatric comorbidity is associated with increased risk of
surgery in Crohn’s disease. Aliment Pharmacol Ther
2013;37:445–54.
25. Persoons P, Vermeire S, Demyttenaere K, et al. The impact
of major depressive disorder on the short and long-term
outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther 2005;22:101–10.
26. DiMatteo MR, Lepper HS, Croghan TW. Depression is a
risk factor for noncompliance with medical treatment: Meta
analysis of the effects of anxiety and depression on patient
adherence. Arch Intern Med 2000;160:2101–7.
27. Kane SV. Systematic review: adherence issues in the
treatment of ulcerative colitis. Aliment Pharmacol Ther
2006;23:577–85
28. Gray WN, Denson L, Baldassano R, Hommel K. Treatment
adherence in adolescents with inflammatory bowel disease:
the collective impact of barriers to adherence and anxiety/
depressive symptoms. J Ped Psychol 2012;37:282–91.
29. Nahon, S, Lahmek P, Saas C. Socioeconomic and psychological factors associated with nonadherence to treatment
in inflammatory bowel disease patients: results of the
ISSEO Survey. Inflamm Bowel Dis 2011;17:1270–6.
30. Dorrian A, Dempster M, Adair, P. Adjustment to inflammatory bowel disease: the relative influence of illness perceptions and coping. Inflamm Bowel Dis 2009;15:47–55.
31. Moradkhani A, Kerwin L, Dudley-Brown S, et al. Diseasespecific knowledge, coping, and adherence in patients with
inflammatory bowel disease. Dig Dis Sci 2011;56:2972–7.
32. Barlow C, Cooke D, Mulligan K, et al. A critical review of
self-management and educational interventions in inflammatory bowel disease. Gastroenterol Nurs 2010;33:11–8.
33. Langhorst J, Mueller T, Luedtke R, et al. Effects of a comwww.jcomjournal.com
Clinical Review
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
prehensive lifestyle modification program on quality-of-life
in patients with ulcerative colitis: a twelve-month followup. Scan J Gastro 2007;42:734–45.
Loftus E, Guerin A, Yu A, et al. Increased risk of developing anxiety and depression in young patients with Crohn’s
disease. Am J Gastroenterol 2011;106:1670–7.
Nahon S, Lahmek P, Durance C, et al. Risk factors of anxiety and depression in inflammatory bowel disease. Inflamm
Bowel Dis 2012;18:2086–91.
Cho O, Yoo Y, Yang S. Depression and risk factors
in patients with Crohn’s disease. J Korean Acad Nurs
2012;42:207–16.
Ananthakrishnan A, Gainer VS, Cai T, et al. Similar risk of
depression and anxiety following surgery or hospitalization
for Crohn’s disease and ulcerative colitis. Am J Gastroenterol 2013 [epub ahead of print].
Koloski NA, Jones M, Kalantar J, et al. The brain-gut
pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut
2012;61:1284–90.
Bonaz B, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology 2013;144:36–49.
Varghese AK, Verdu EF, Bercik P, et al. Antidepressants attenuate increased susceptibility to colitis in a murine model
of depression. Gastroenterology 2006;130:1743–3.
Ghia JE, Blennerhassett P, Collins SM. Impaired parasympathetic function increases susceptibility to inflammatory
bowel disease in a mouse model of depression. J Clin Invest
2008;118:2209–18.
Ghia JE, Blennerhassett P, Deng Y, et al. Re-activation of
inflammatory bowel disease in a mouse model of depression. Gastroenterology 2009;136:2280–88.
Lotrich FE, El-Gabalawy H, Guenther LC, Ware CF. The
role of inflammation in the pathophysiology of depression: different treatment and their effects. J Rheumatol
2011;Suppl 88:48–54.
Capuron L, Miller AH. Immune system to brain signalling: neuropsychopharmacological implications. Pharmacol
Ther 2011;130:226–38.
Shanahan F. The gut microbiota- a clinical perspective on lessons learned. Nat Rev Gastroenterol Hepatol
2012;9:609–14.
Forsythe P, Sudo N, Dinan T, et al. Mood and gut feelings.
Brain Behav Immun 2010;24:9–16.
Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic
factor and behavior in mice. Gastroenterology 2011;141:
599–609.
Bercik P, Verdu EF, Foster JA, et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters
central nervous system biochemistry in mice. Gastroenterology 2010;139:2102–12.
Goodhand JR, Rampton D, Wahed M. Management of
stress in inflammatory bowel disease: a therapeutic option?
Expert Rev Gastroenterol Hepatol 2009;3:661–79.
Triantafillidis JK, Merikas E, Gikas A. Psychological factors
and stress in inflammatory bowel disease. Expert Rev Gas-
www.jcomjournal.com
troenterol Hepatol 2013;7:225–38.
51. Mikocka-Walus A, Andrews JM, Bernstein CN, et al. Integrated models of care in managing inflammatory bowel
disease: a discussion. Inflamm Bowel Dis 2012;18:1582–7.
52. Caprilli R, Gassull MA, Escher JC, et al. European evidence based consensus on the diagnosis and management
of Crohn‘s disease: special situations. Gut 2006;55 [Suppl
1]:36–58.
53. Bennebroek Evertsz F, Thijssens NAM, Stokkerse PCF, et
al. Do inflammatory bowel disease patients with anxiety and
depressive symptoms receive the care they need? J Crohns
Colitis 2012;6:68–76.
54. Young AS, Klap R, Sherbourne CD, Wells KB. The quality
of care for depressive and anxiety disorders in the United
States. Arch Gen Psychiatry 2001;58:55–61.
55. Hansen RA, Gartlehner G, Lohr K, et al. Efficacy and safety
of second-generation antidepressants in the treatment of
major depressive disorder. Ann Int Med 2005;143:415–26.
56. Barlow DH, Allen LB, Choate ML. Toward a unified treatment for emotional disorders. Behav Ther 2004;35:205–30.
57. Mikocka-Walus A, Turnbull D, Moulding N, et al. Antidepressants and inflammatory bowel disease: a systematic
review. Clin Pract Epidemiol Ment Health 2006;2:24.
58. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability
and distress in patients with inflammatory bowel disease.
Gen Hosp Psychiatry 1996;18:220–9.
59. Goodhand JR, Greig FIS, Koodun Y, et al. Do antidepressants influence the disease course in inflammatory bowel
disease? A retrospective case-matched observational study.
Inflamm Bowel Dis 2012;18:1232–9.
60. Esmaeili A, Masjedi M, Ani A, et al. New insights of antidepressant therapy in the management of ulcerative colitis.
Gastroenterology 2008;134(4 Suppl 1):A–100.
61. Miller AH, Maletic V, Raison CL. Inflammation and its
discontents: the role of cytokines in the pathophysiology of
major depression. Biol Psychiatry 2009;65:732–41.
62. Timmer A, Preiss JC, Motschall E, et al. Psychological
interventions for treatment of inflammatory bowel disease.
Cochrane Database Syst Rev 2011;2:CD006913.
63. Sajadinejad MS, Asgari K, Molavi H, et al. Psychological
issues in inflammatory bowel disease: an overview. Gastroenterol Res Pract 2012;2012:106502.
64. McCombie AM, Mulder R, Gearry RB. Psychotherapy for
inflammatory bowel disease: a review and update. J Crohns
Colitis 2013 [epub ahead of print].
65. Boye B, Lundin K, Jantschek G, et al. INSPIRE study:
does stress management improve the course of inflammatory bowel disease and disease-specific quality of life
in distressed patients with ulcerative colitis or Crohn’s
disease? A randomized controlled trial. Inflamm Bowel Dis
2011;17:1863–73.
66. Mussell M, Bocker U, Nagel N, et al. Reducing psychological distress in patients with inflammatory bowel disease by
cognitive-behavioral treatment: exploratory study of effectiveness. Scand J Gastroenterol 2003;38:755–62.
67. Sibaja MAD, Moreno MIC, Hesse BM. Protocolized cog-
Vol. 20, No. 7 July 2013 JCOM 323
Mood Disorders and IBD
68.
69.
70.
71.
72.
73.
nitive-behavioural group therapy for inflammatory bowel
disease. Rev Esp Enferm Dig 2007;99:593–8.
Szigethy E, Whitton SW, Levy-Warren A, et al. Cognitivebehavioral therapy for depression in adolescents with inflammatory bowel disease: a pilot study. J Am Acad Child
Adolesc Psychiatry 2004;43:1469–77.
Szigethy E, Kenney E, Carpenter J, et al. Cognitive-behavioral therapy for adolescents with inflammatory bowel
disease and subsyndromal depression. J Am Acad Child
Adolesc Psychiatry 2007;46:1290–98.
Garcia-Vega E, Fernandez-Rodriguez C. A stress management programme for Crohn’s disease. Behav Res Ther
2004;42:367–83.
Mizrahi M, Reiher-Atir R, Levy S, et al. Effects of guided
imagery with relaxation training on anxiety and quality of
life among patients with inflammatory bowel disease. Psychol Health 2012;27:1463–79.
Shaw L, Ehrlich A. Relaxation training as a treatment for
chronic pain caused by ulcerative colitis. Pain 1987;29:287–93.
Wahed M, Corser M, Goodhand JR, Rampton DS. Does
74.
75.
76.
77.
78.
79.
psychological counselling alter the natural history of inflammatory bowel disease? Inflamm Bowel Dis 2010;16:664–49.
Mawdsley JE, Jenkins DG, Macey MG, et al. The effect of hypnosis on systemic and rectal mucosal measure
of inflammation in ulcerative colitis. Am J Gastroenterol
2008;103:1460–9.
Miller V, Whorwell P. Treatment of inflammatory bowel disease:
a role for hypnotherapy? Int J Clin Exp Hypn 2008;56:306–17.
Keefer L, Keshavarzian A. Feasibility and acceptability of
gut-directed hypnosis on inflammatory bowel disease: a brief
communication. Int J Clin Exp Hyp 2007;55:457–66.
Keefer L, Kiebles J, Martinovich Z et al. Behavioral interventions may prolong remission in patients with inflammatory bowel disease. Beh Res Ther 2011;49:145–50.
Lichtman JH, Bigger JT, Blumenthal JA et al. Depression
and coronary heart disease. Recommendations for screening, referral, and treatment. Circulation 2008;118:1768–75.
Katon W, Fan M-Y, Unutzer, J, et al. Depression and diabetes: A potentially lethal combination. J Gen Intern Med
2008;23:1571–5.
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