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Background: Antidepressants are commonly used to treat symptoms of anxiety and depression in inammatory bowel disease (IBD). Recent studies
suggest a link between IBD activity and an individuals emotional state which raises the possibility that antidepressants may potentially modify the
disease course of IBD. This systematic review thus primarily aims to evaluate the efcacy of antidepressants on IBD activity, and secondarily, on anxiety
and depression.
Methods: MEDLINE, EMBASE, Cochrane (IBD Group), CINAHL, AMED, PsycINFO, and OpenGrey were searched from 1990 onward with no
restrictions on study design. A quality appraisal was conducted using several scales as appropriate for each study design. A narrative synthesis was also
conducted.
Results: Fifteen eligible studies included in the review (1 randomized controlled trial, 2 cohorts, 1 casecontrol, 1 cross-sectional survey, 1 qualitative, 2
audits, 1 case series, and 6 case reports) examined a range of antidepressants. Twelve studies suggested that antidepressants have a positive impact on
IBD course. Nine studies reported anxiety and depression as an outcome, of these 8 reported benecial effects of antidepressants. Most of the studies
were deemed to be at low risk of bias, apart from the case reports, which were at high risk of bias.
Conclusions: This research indicates that antidepressants may have a benecial effect on IBD course. However, it is currently not possible to determine
their efcacy for certain because of the lack of randomized trials. Further trials using objective measures of IBD activity, longer follow-up periods, and
larger sample sizes are needed.
(Inamm Bowel Dis 2017;23:534550)
Key Words: antidepressants, anxiety, depression, inammatory bowel disease, systematic review
534 | www.ibdjournal.org Inamm Bowel Dis Volume 23, Number 4, April 2017
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Inamm Bowel Dis Volume 23, Number 4, April 2017 Antidepressants in Inammatory Bowel Disease
The aim of this study is to (1) examine the evidence on the Primary Outcome
impact of antidepressants on disease activity, and (2) their impact
on comorbid symptoms of anxiety and depression in IBD.
1. Remission measured through changes in disease activity
indices as per respective cut-off values, as dened by study
MATERIALS AND METHODS authors (e.g., Crohns Disease Activity Index [CDAI], Sim-
ple Clinical Colitis Activity Index [SCCAI]), using calpro-
Search Strategy tectin, colonoscopy, or other similar measures (e.g., blood).
We searched MEDLINE, EMBASE, Cochrane (Cochrane
Inammatory Bowel Disease and Functional Bowel Disease Secondary Outcomes
Group), CINAHL, AMED, and PsycINFO. Search strategies
were compiled with the assistance of an academic librarian.
Articles published before 1990 were not included. No restrictions 1. Anxiety and depression symptoms, as measured through
were placed on language during the searches although for using any relevant diagnostic interview technique or
practical reasons, it was only possible to include English language screening scale.
articles. An example search strategy is presented in the Appendix,
Supplemental Digital Content 1, http://links.lww.com/IBD/B467. Data Extraction
Searches were conducted on third June 2016 by one author (B.J. Data pertaining to the sample, methods, and results were
D.M.). extracted from each of the included studies by 1 author (BJDM).
The reference lists of included articles were scanned and 1
journal (Gastroenterology) hand searched. Titles and abstracts of Quality Assessment
retrieved studies were screened for inclusion. The full text of Other than human participants this review applied no
potentially relevant articles was obtained, and the inclusion and restrictions on study design; therefore, the variety of study
exclusion criteria were applied. designs necessitated the use of several different quality assess-
ment tools. The Cochrane Risk of Bias tool was used for
Inclusion Criteria randomized trials;8 this was based on 8 questions which can be
Studies were included if they met the following criteria: addressed with either Low risk or High risk. The
1. Contained human participants, clinically diagnosed with NewcastleOttawa Scale (NOS) was used for observational
any form of IBD (i.e., Crohns disease [CD], ulcerative studies (casecontrol and cohorts),9 for which a study can score
colitis [UC], or intermediate colitis based on clinical, his- a possible of 8 points, a higher score signies a lower risk. The
tological, radiological, or endoscopic criteria). National Institute of Health (NIH) quality assessment tool was
2. Participants could be any age and any sex. used for audits, case reports, and case series.10 Another NIH
3. Participants were prescribed or took any of the following quality assessment tool was used to assess the quality of cross-
antidepressants: tricyclics, monoamine oxidase inhibitors, sectional surveys.11 Both of the NIH tools used gave a nal
serotonin reuptake inhibitors, serotonin and noradrenaline quality rating of Good, Fair, or Poor. Qualitative studies
reuptake inhibitors, or atypical antidepressants. Antidepres- were assessed using the Critical Appraisal Skills Programme
sants could be used both with and without other treatments, (CASP) tool.12 The CASP tool has 10 questions which can be
apart from other pharmacological psychiatric treatments answered Yes, Cant tell, or No; a Yes would imply
(such as anxiolytics). Standard care was assumed. a low risk of bias.
4. Any comparator.
Data Analysis
5. Any study design.
A narrative synthesis was used to describe and compare the
6. Contained an outcome measure of remission or anxiety/
studies. A meta-analysis was planned but not performed because
depression outcome (see Outcome Measures below).
of heterogeneity of study design and outcomes.
Exclusion Criteria
RESULTS
A total of 2193 studies were retrieved with 1840 screened
1. Participants were prescribed or took any other form of after duplicates were removed (Fig. 1). Fifteen studies were
medication used to treat depression or anxiety; such as included in the review: 1 placebo-controlled RCT, 1 prospective
herbal medicines and anxiolytics alone. and 1 retrospective cohort study, 1 retrospective casecontrol
study, 1 cross-sectional survey, 1 qualitative study, 1 report on
Outcome Measures a clinical case note audit, 1 audit, 1 case series, and 6 case reports.
For studies to be included in the review, they had to include The follow-up period of the studies varied from 6 weeks to 11
at least 1 of the following primary or secondary outcomes: years. The majority of the studies were from the United States
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Macer et al Inamm Bowel Dis Volume 23, Number 4, April 2017
Narrative Synthesis
FIGURE 1. PRISMA ow diagram. Of the 15 included studies, 14 (93%) addressed the primary
outcome measure of remission and 10 (67%) addressed the
secondary outcomes of anxiety/depression. See Table 5 for
(n 8) and Australia (n 3), with 1 study each from England, a description of each study and Table 6 for results.
Iran, New Zealand, and India.
RCT
Quality Assessment The RCT was conducted between 2013 and 2014 in Iran.13
Quality assessments of each individual study are shown in Forty-four participants were randomly allocated to either be pre-
Tables 14. The RCT13 was at low risk of bias with only high-risk scribed duloxetine (60 mg once a day) or a placebo for 12 weeks.
scores from the sections assessing attrition bias. Anxiety and depression were measured using the Hospital Anx-
Using the NOS for nonrandomized studies, Yanartas et al. iety and Depression Scale (HADS) and symptom severity using
(2016) was at low risk of bias, and Iskandar et al (2014) was at Lichtiger Colitis Activity Index (LCAI). Five patients were lost to
Daghaghzadeh et al13 Low risk Low risk Low risk Low risk Low risk High risk High risk Low risk
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Inamm Bowel Dis Volume 23, Number 4, April 2017 Antidepressants in Inammatory Bowel Disease
Total (/8)
Total
(/8)
6
leaving a total of 35 participants (UC: 22; CD: 13) in the analysis.
8
5
Symptom severity signicantly improved in the interven-
Nonresponse
tion group compared with the control group (P 0.02). Depres-
Rate (/1)
Follow-up of
Adequacy of
Cohorts (/1)
sion and anxiety also improved signicantly in the intervention
*
* group compared with the control group (depression P 0.041;
* anxiety P 0.049).
of Ascertainment for
Cohorts
Same Method
Controls (/1)
Enough for Outcomes
Was Follow-up Long
Cases and
The retrospective cohort study included 81 participants
to Occur? (/1)
taking tricyclic antidepressant (UC: 23; CD: 58)19 who were fol-
*
lowed over 11 years using outpatient records from a Gastroenter-
*
*
or Analysis (/2)
Comparability
of the Design
the Basis
of Cases
*
Denition of
Controls (/1)
Casecontrol Study
Represent-ativeness
ipants, 29 (UC: 14; CD: 15) who were sampled from an adult and
Denition
*
*
CaseControl
were assessed the year before and the year after initiation of
antidepressant therapy.
Study
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Macer et al
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TABLE 3. Quality Assessment of Cross-sectional Survey, Audits, Case Series, and Case ReportsNational Institute of Health Tool
Cross-sectional Objective Population Specied and Participation Rate Uniform Selection and Sample Size/Power Exposure(s) Measured Before the Sufcient
Survey Stated Dened? $50% Recruitment Estimate Outcome(s) Timeframe
Exposure Exposure Measures Dened, Exposure(s) Outcome Measures Dened, Outcome Confounding Quality
Cross-sectional Appropriately Valid, Reliable and Consistently Assessed Valid, Reliable and Consistently Assessors Attritrion Variables Measured Rating (Good/
Survey Measured Implemented .Once Implemented Blinded #20% and Adjusted for Fair/Poor)
Audits, Case- Question/ Population Intervention Outcome Measures Dened, Sufcient Statistical Results Quality
series & Case Objective Specied and Consecutive Subject Clearly Valid, Reliable, and Consistently Length of Methods Well Well Rating (Good/
Report Stated Dened Cases Comparability Described Implemented Follow-up Described Described Fair/Poor)
Mikocka- Yes Yes Yes Yes Yes Yes N/A Yes Yes Good
Walus et al2
Ramos Rivers No No N/A Yes No No Yes Yes No Poor
et al17
Walker et al18 Yes Yes Yes Yes Yes Yes No Yes Yes Good
Kane et al21 Yes No No No Yes No Yes N/A No Poor
Is Qualitative Was the Recruitment Strategy Was the Data Is There a Clear
Method Appropriate to the Aims of the Analysis Sufciently Statement of How Valuable is
Appropriate? Research? Rigorous? Findings? the Research?
admissions, and number of courses of steroids. Fewer relapses and semistructured, containing open-ended questions relating to IBD
courses of steroids in the year after starting an antidepressant were history, reasons for antidepressant therapy and details of the ther-
experienced in the intervention group than in the year before {1 apy, acceptance of the treatment, side effects, impact on IBD and
(04) (median [range]) versus 0 (04), P 0.002; 1 (03) versus quality of life, and attitudes toward taking part in future trials.
0 (04), P , 0.001, respectively}. The controls showed no changes The study showed that antidepressants helped disease course
between years 1 and 2 in relapses (1 [04] versus 1 [03], respec- (n 5), reduced pain and frequency of bowel movements (n 3),
tively) or courses of steroids (1 [02] versus 0 [03]). There was and reduced the frequency of symptoms or are up (n 3). Con-
a signicant difference between the 2 groups for number of re- versely, n 10 reported that antidepressants did not inuence dis-
lapses (P 0.03), but not for course of steroids (P 0.07). ease course, although the authors did concede that it was difcult to
distinguish between the effectiveness of different treatments. The
Cross-sectional Survey study also showed that the majority of the participants had a positive
The cross-sectional on-line survey, advertised between attitude toward antidepressants (n 9). Twelve of the participants
March 2012 and April 2013, included 98 participants (UC: 32; stated they would take part in further trials; 2 did not want to change
CD: 48; intermediate colitis: 3; missing type: 15) from a non- their antidepressant treatment because of their success with it.
clinical population recruited through the Australian IBD advocacy
and support group.15 Participants were required to be taking anti- Audits
depressants or had previously been on antidepressants since their The case-note audit was conducted at the center where the
IBD diagnosis. The aim of the study was to explore the use and participants from the qualitative study, mentioned above, were
type of antidepressants currently prescribed to IBD sufferers, their sampled. This retrospective analysis was from an IBD database at
effects on symptoms, and experiences of them. an Australian tertiary hospital, and assessed participants for type,
Participants had been taking antidepressants for an average frequency, and impact of antidepressant therapy on IBD course.2
of 4 (SD: 3.9) years, with a range of 4 weeks to 15 years. Of those The audit showed that from 287 participants (UC: 95; CD:
individuals taking antidepressants, 79% reported perceived im- 179; intermediate colitis: 13), 51 (18%) were currently taking
provements; however, 67% had observed no change in perceived antidepressants. Within the 51 taking antidepressants, 15 (30%)
disease activity. Disease activity was found to improve in 25% of individuals had inactive disease but presented with symptoms
participants. The study also showed perceived psychological well- such as pain or diarrhea, consistent with functional bowel
being had improved in 87% of participants. disorders, 11 (22%) were in full remission with no disease
activity, 2 (0.01%) had active disease, and the data for 23 (45%)
Qualitative Study participants were not recorded. Seventy-one patients had a history
The qualitative study interviewed 15 participants taking of antidepressant use, 45 (63%) were prescribed for anxiety and
antidepressants, sampled from The Royal Adelaide Hospital, depression, or both; 10 (14%) were for somatic complaints, and
a tertiary teaching hospital in South Australia.16 The interviews, no data were available for the remaining 16 (22.5%) patients.
conducted between January and March 2011, were While on antidepressants, 19 (28%) had inactive disease but had
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Macer et al
TABLE 5. Summary Table of the Included Studies
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Daghaghzadeh Placebo- 35 participants between 1865 Two groups. intervention UC 22; Disease duration, mean (SD): Depression and 12 wk
et al,13 Iran controlled years old (mean [SE] age: group (n 17) took CD 13 intervention6.49 (3.27) anxiety: mean (SD)
RCT 38 [8.08]), with no are up duloxetine 3060 mg once yrs; control8.17 (4.29) score across both
over previous 6 months. per day for 12 weeks. yrs (P 0.538). groups: 9.22 (3.45)
Selected from the GI clinic Control group (n 18) was and 8.17 (4.29),
of Alzahra Hospital placebo controlled, the respectively.
(Isfahan) between 2013 and subjects received placebo in Measured using
2014. the same form and packages HADS.
as duloxetine for the same
length of time. All
participants also received
mesalazine, 24 mg daily.
Experimental group n 17 Randomization: A third-party Symptom severity measured
(47% females); control physician using tables of using LCAI.
group n 18 (44% females) random numbers conducted
the randomization.
Blinding: A psychologist who
was not informed about
grouping of the subjects
assessed questionnaire
scores.
Yanartas et al,20 Prospective 67 participants (43 [64%] Participants had psychiatric UC 36; CDAI and MMS for the Major depression 6 mo
New Zealand cohort women) older than 17 years interviews using SCID-I. CD 31 assessment of disease (43.2%) and
old, mean age was 40.71 6 Participants also had SF-36 activity in patients with CD generalized anxiety
12.71 yrs, followed up in and ASEX tests for or UC, respectively. Along disorder (15%)
the IBD-specic assessing QoL and sexual with CRP, complete blood using HADS.
Iskandar et al,19 Retrospective 81 participants with IBD. mean Outpatient electronic medical UC 23; Baseline symptom severity Data were self-reported. 11 years
USA cohort (SD) age: 41.3 6 1.7; records were reviewed to CD 58 was assessed on a 4-point
69.1% females identify patients over an 11- Likert scale (0 no
year period between July symptoms, 3 severe,
2000 and June 2011. disabling symptoms). AD
treatment responses were
graded using an
established 4-point scale
(0 no improvement; 3
complete satisfaction).
TCA median dose Depression, n 23
(amitriptyline, nortriptyline, (28.4%). Anxiety,
desipramine) 25 mg, range n 5 (6.2%). Both,
10150 mg. TCA dose n 10 (12.3%).
increase by second follow-
up, 29/81 (35.8%).
Currently taking biologics
(22.4%), immuno-
modulators (31.0%) and 5-
ASA (12.1%).
Goodhand Retrospective 58 participants divided equally Patients with IBD using ADs to UC 14; Median age at diagnosis, NR 2 years
et al,14 USA casecontrol into 2 groups (n 29 IBD treat concomitant mood CD 15 (in years (range): AD group
and n 29 matched disorders. Citalopram 20 mg each group) 26 (1372); Controls
controls). Seventeen (2060 mg) and uoxetine 29 (1262). Median
females in each group. From 20 mg (2060 mg) were the disease duration, years
a tertiary adult and pediatric most commonly used ADs; (range): AD group5.2
IBD center located in other SSRIs were used and (140); Controls4.2
London. TCAs, NaSSa, and SNRIs. (131).
phenotype, baseline
medications, surgeries, and
relapse rate in year 1.
541
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Macer et al
TABLE 5. (Continued)
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Mikocka- Cross-sectional 98 participants (76 [78%] Questions in the survey were UC 32; Time with IBD symptoms, As diagnosed by N/A
Walus,15 survey female) from a national IBD related to type and dosage of CD 48; IC mean (SD): 13.7 (9.5) a clinician.
Australia advocacy and support group ADs; perceived outcome of 3; unknown years. Time since IBD
accessed the survey. Mean the treatment; perspectives type 15 diagnosis, mean (SD): 9.2
(SD) age: 37.7 (11.9). and experiences with the use (8.8).
of ADs as well as views on
the interactions between AD
treatment and their disease
course; respondents
acceptability of trials with
ADs.
Participants were currently Depression (n 25);
taking a mixture of or solely anxiety (n 10);
conventional and alternative both (12).
treatments.
Mikocka-Walus Qualitative 15 participants taking ADs (9 Semistructured interviews were UC 2; CD Time since diagnosis ranged Self-reported data. N/A
et al,16 interview [60%] females) selected conducted. 12; colitis of from 3 to 30.5 yrs, mean
Australia from a case-note audit. undetermined (SD) 16.8 (8.9). The
Mean (SD) age: 45.8 etiology 1 number of current
(17.11) years. symptoms reported per
patient ranged from 1 to
7, mean (SD) 3.5 (2.0).
Most common symptoms: pain Open-ended questions were Depression or
(86.7%), diarrhea (66.7%), asked about IBD history, depressed mood,
nausea (33.3%), fatigue reasons for taking Ads, and reported by 10
(26.7%), bloating (26.7%), details of this therapy (type, patients (66.7%), and
Mikocka-Walus Report on 287 (143 [50%] females). Patients details were collected UC 95; See Table 2 As diagnosed by N/A
et al,2 clinical case- Mean (SD) age: 47 (17). from an IBD database at an CD 179; clinicians.
Australia note audit Australian tertiary hospital. IC 13
Patients taking the following: Details on frequency, type, and Depression (45%);
5-ASA, azathioprine, outcome of AD treatment in combined depression
biologics, corticosteroids, terms of IBD course were and anxiety disorder
metronidazole, salazopyrin, collected. (23.5%)
pain killers, and
benzodiazepines.
Ramos Rivers Audit (Abstract) 855 IBD, mean age 47 6 15 Electronic medical records UC 352; History of GI surgery, N/A 4 yrs
et al,17 USA (422 [52%] females) (EMRs) were used to CD 503 46.7%
identify frequency and
classes of AD use. For the
most frequently used ADs,
differences in QoL (SIBDQ)
and IBD activity between
pts taking ADs and those
who did not during that
same 4-year period were
evaluated.
IBD activity measured using
HBI/UCDAI
Walker et al,18 Case series 8 IBD participants, 18 years Patients interviewed using Not specied GI symptom interview All participants 8 weeks
USA old or older. Selected from NIMH DIS, GI symptom diagnosed with
tertiary care medical faculty interview and the Briere major depression.
in Seattle. Child Maltreatment Conrmed by
Interview (history of Hamilton Depression
childhood abuse and Rating Scale
Macer et al
TABLE 5. (Continued)
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Kane et al,21 Case report 4 participants (2 women, Bupropion 100 mg for CD NR As diagnosed by 6 weeks
USA 2 unspecied) depression or smoking a clinician.
cessation for at least 6 Depression (n 2)
weeks.
Kast,22 USA Case report 33-year-old woman. Phenelzine 15 mg 3 times daily CD 18-year history of CD. Has Major depressive NR
for 1 month, then 30 mg undergone 3 bowel episodes and anxiety,
3 times daily after for 2 resections and had 10 as diagnosed by
years. watery bowel movements a clinician.
with severe abdominal
cramping daily.
Currently taking 75 mg
azathioprine, 60 mg
prednisone, and 3
acetaminophen/oxycodone
tablets daily.
Kast and Case report 44-year-old woman. Taking Bupropion 150 mg 3 times CD Woman10-year history of Femaleepisode of Female
Altschuler,23 uoxetine 40 mg every day daily for depression (female) IBD (CDAI202). major depression, at
USA for depression, and and smoking cessation superimposed on least 19
mesalamine 500 mg twice (male). a chronic mild months
a day. depressed state
(dysthymia). As
diagnosed by
a clinician.
45-yr-old man. Man20-year history of Male
IBD with multiple NR
surgeries, including 4
5-ASA, 5-aminosalicylic acid; ADs, antidepressants; ASEX, Arizona Sexual Experience Scale; CDAI, Crohns Disease Activity Index; CRP, C-reactive protein; DIS, Diagnostic Interview Schedule; GI, gastrointestinal; HADS,
Hospital Anxiety and Depression Scale; HAM-D, Hamilton Depression Rating Scale; HBI, Harvey-Bradshaw Index; IC, intermediate colitis; LCAI, Lichtiger Colitis Activity Index; NaSSa, noradrenergic and specic serotonergic
antidepressants; NR, not reported; QoL, quality of life; SCID-I, Structured Clinical Interview for DSM Disorders; SF-36, Short Form 36; SIBDQ, Short Inammatory Bowel Disease Questionnaire; SNRI, serotonin and noradrenaline
Follow-up
6 weeks
had inactive disease.
NR
The other study (reported as an abstract)17 we have classied
as an audit but may be better described as a series of annually
conducted cross-sectional surveys of patient IBD activity and anti-
Generalised anxiety
depressant use in an IBD clinic. The results showed that in 855 IBD
Anxiety
diagnosed by
diagnosed by
participants (UC: 352; CD: 503), the mean IBD activity decreased
disorder, as
a clinician.
a clinician.
Measurement and Assessment
Case series
The one case series included18 studied 8 IBD participants from
watery bowel movements
CD
Case Reports
(15 mg) at night.
(Abstract)
Case report
Case report
Kahn,26 USA
DISCUSSION
Joshi and
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Macer et al
TABLE 6. Summary of the Primary and Secondary Outcomes in the Included Studies
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Daghaghzadeh Placebo-controlled Severity of symptoms signicantly improved Depression signicantly improved compared Duloxetine recommended for disease
et al,13 Iran RCT compared with control (P 0.02). Intervention: with control (P 0.041). Intervention: mean activity, anxiety, and depression.
mean (SE) 6.23 (1.00) to 4.52 (0.54); control: mean (SE) 8.64 (0.89) to 7.47 (0.80); control: mean
(SE) 7.50 (0.80) to 6.83 (0.69). (SE) 9.77 (0.75) to 10.50 (1.18).
Anxiety signicantly improved compared with
control (P 0.049). Intervention: mean (SE)
7.94 (1.03) to 6.11 (0.99); control: mean (SE)
8.38 (1.04) to 8.50 (1.14).
Yanartas et al,20 Prospective cohort AD treatment was found to be associated with Depression (HAD-D) improved. Intervention: ADs recommended for disease
New Zealand an improvement in CDAI in patients with IBD. 10.62 (3.61) to 3.35 (4.01); control: 11.55 activity, anxiety, and depression.
Intervention: 197.41 (130.60) to 101.08 (2.85) to 10.15 (3.51).
(65.88) (P 0.011); control: 58.50 (74.94) to
83.50 (62.68) (P 0.710). No signicant
difference was observed between groups (P
0.570).
MMSIntervention: 2.71 (3.05) to 0.94 (1.91) (P Anxiety (HAD-A) improved. Intervention: 12.38
0.054); control: 2.78 (3.42) to 1.77 (1.98) (P (4.38) to 5.97 (4.45); control: 11.40 (4.60) to
0.464). No signicant difference was observed 11.05 (4.40).
between groups (P 0.926).
CRP decreased insignicantly in both groups.
Intervention: 6.58 6 13.89 to 4.61 6 4.03
(P 0.324); control: 4.30 6 3.79 to 4.35 6 3.47
(P 0.949). No signicant difference was
observed between groups (P 0.656).
Iskandar et al,19 Retrospective Likert baseline severity scores (CD: 2.07 6 0.03, Not measured Low-dose TCAs recommended for
USA cohort UC: 2.03 6 0.04, P 0.67). Patients with UC management of residual symptoms
responded signicantly better to TCA therapy, in IBD patients with minimal
1.86 6 0.13 for UC and 1.26 6 0.11 for CD inammation.
Goodhand et al,14 Retrospective Fewer relapses and courses of steroids in the year Not measured ADs recommended for disease
USA casecontrol after starting an AD than in the year before (1 [04] activity.
(median [range]) versus 0 [04], P 0.002; 1
[03] versus 0 [04], P ,0.001, respectively); the
controls showed no changes between years 1 and 2
in relapses (1 [04] versus 1 [03], respectively) or
courses of steroids (1 [02] versus 0 [03]).
Mikocka-Walus Cross-sectional Respondents reported taking an AD for an average of Psychological well-being had improved in 87% ADs recommended for anxiety and
(2014), Australia survey 4 (SD 3.9) years ranging from 4 wk to 15 yrs. (n 55) of participants. depression.
79% reported perceived improvements despite 67%
observing no change in disease activity. Disease
activity improved in 25% of participants.
Mikocka-Walus Qualitative ADs improved QoLprimarily psychological, as Three (20%) patients noted how they believed the ADs recommended for anxiety and
et al,16 Australia interview well as social and biological. reduction in feelings of stress mediated the depression.
positive inuence of the AD on IBD course.
5 (33%)helped disease course; 3 (20%)reduction
in pain and frequency of bowel movements; 10
(66%)did not inuence disease course, but
difcult to distinguish between treatments; 3 (20%)
reduction in frequency of symptoms or are ups
Mikocka-Walus Report on clinical 51 currently taking ADs. 71 received ADs in the past. Of the 51 patients currents taking ADs, 45% were ADs recommended for disease
et al,2 Australia case-note audit taking them for depression and 23% for activity.
a combined anxiety and depression disorder.
Disease activity on ADs (n 51): 15 (29%)
inactive disease but presented with symptoms
such as pain or diarrhea, consistent with functional
bowel disorders; 11 (22%)full remission with no
disease activity; 2 (0.04%)active disease; 23
(45%)no data were recorded
Macer et al
TABLE 6. (Continued)
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Kane et al,21 USA Case report Decrease in CDAI to ,150 within 6 weeks (without Not measured Bupropion recommended for disease
other changes to IBD medication). activity.
Kast,22 USA Case report First 7-days bowel movements described as soft, 34 Depression responded well. Phenelzine recommended for disease
per day with cramping. After increase to 30 mg, 1 activity and depression.
bowel movement per day with no cramping. Other
medication tapered off. After 2 years phenelzine
stopped, 6 weeks later admitted to hospital with
CD relapse.
Kast and Case report Female: 19-month remission, any attempts to stop Femalemajor depression remitted. The Bupropion recommended for disease
Altschuler,23 bupropion were associated with relapse. CDAI 0. baseline dysthymia remained. activity and depression.
USA Mesalamine was tapered off.
Male: CDAI 45. 34 episodes of diarrhea daily due
to ilealcecal value.
Scott et al,24 USA Case report Patients abdominal pain remained unchanged, Psychiatrist determined patients depression had Amitriptyline no effect on IBD.
assessed by visual analog scale, but no adverse not responded adequately. Although man
events were associated with transdermal stated his mood had improved at the end of 6-
amitriptyline. week therapy.
Joshi and Dixit,25 Case study After 2 weeks, decreased urgency of defecation and Improvement in anxiety features in 2 weeks. Mirtazapine recommended for disease
India (Abstract) reduced tenesmus were reported. After 6 weeks, After 6 weeks, patient had relief from anxiety activity and anxiety.
there was complete resolution of bloody diarrhea features.
and rectal pain.
Kahn,26 USA Case study Treatment ineffective. Became effective when Not measured Night dosing of mirtazapine and
(Abstract) psychiatrist changed sertraline to bedtime dosing. sertraline recommended for disease
activity.
ADs, antidepressants; CDAI, Crohns Disease Activity Index; CI, condence interval; CRP, C-reactive protein; HAD-A, Hospital Anxiety and Depression Scale-A; HAD-B, Hospital Anxiety and Depression Scale-B; MMS,
Modied Mayo Score; OR, odds ratio; QoL, quality of life; SSRI, selective serotonin reuptake inhibitor; TCAs, tricyclic antidepressants.
levels. Despite this encouraging nding, due to the limitations of Limitations of Included Studies
the observational study designs included, no rm conclusions can The majority of the included studies were observational,
be drawn about the efcacy or effectiveness of antidepressants in uncontrolled, and nonrandomized. Only 3 studies had follow-up
IBD. Nevertheless, judging by the success of antidepressant periods at 2 years or more, 5 studies had follow-up periods of 12
treatment in functional gut disorders and particularly the improve- weeks or less. IBD often takes longer than 12 months to go through
ments in bowel functions and abdominal pain,3,27 but also by cycles of relapse and remission. Population-based studies have
a signicant proportion of patients with IBD actively using anti- shown that after 5 years of being diagnosed as in remission, nearly
depressants (between 10% and 30%)2,28,29 antidepressants have 100% of patients have relapsed;38 therefore, follow-up periods that
a role to play in IBD management. Whether this is because they are shorter than this are not likely to capture long-term effectiveness.
inuence the inammatory processes or simply because they Many of the studies had small sample sizes and only
improve mood is hard to decipher at present, and their role in sampled participants from a single source; therefore, participants
IBD should be further investigated. are unlikely to be representative of the IBD population as a whole.
To the authors knowledge, only one other similar system- Furthermore, all studies did not account for differences by sex in
atic review has been conducted.5 The systematic review included their analyses, which is important because women may be at
12 relevant articles; however, the authors found a paucity of high- greater risk of anxiety and depression than men.39
quality data. None of the included articles were RCTs; 5 of them The nal limitation of the included studies is the study
were not primary research and the same group conducted 7 of the design. Only 1 RCT was included and 6 (40%) were case; 2
studies. The previous review, while acknowledging the poor studies were incompletely reported conference abstracts.
methodological quality of the included studies, concluded that
the results suggest that antidepressants have the potential to be Strengths and Limitations of This Review
used to help certain individuals cope with the emotional comor- There were a number of strengths to this review, the rst
bidities of IBD; such as anxiety and depression, improve quality being its comprehensive literature search which included an
of life, and possibly have a benecial effect on the IBD course. In extensive search string and a large number of databases, including
the 10 years since this review was conducted, the evidence seems gray literature. The review was also adapted to account for the
to have improved slightly. One RCT was included in this review differing study designs using a range of quality assessment tools.
but it had some limitations which may have biased the results. It Despite these strengths, there were a number of limitations
should be noted that another small trial has been published in to the review. Because of the limited resources, it was not possible
recent weeks,30 reporting no impact of uoxetine on disease activ- to have a second reviewer at either the screening or data extraction
ity over 12 months in CD but observing some potentially positive stages of the review. The review was also limited by only
impact of this antidepressant on the cytokine proles. including articles published in English. However, only 30 non-
There is much speculation around the potential mechanism English publications were excluded and based on the percentage
of action of antidepressants in altering the course of IBD. Three of of relevant English articles once titles and abstracts were screened
the included studies13,14,20 hypothesized that the improvements (2.9%), it would be unlikely that the non-English language
seen in patients could be because of the anti-inammatory prop- publications would have yielded further studies.
erties observed in antidepressants.31 There is evidence that anti-
depressants can lower circulating levels of tumor necrosis Future Research
factoralpha and this could potentially explain the positive ef- Further RCTs are required to improve understanding of the
fects of antidepressants on IBD course.32,33 Alternatively, and impact of antidepressants on IBD course. Trials should aim to recruit
most probably, improvements seen can be a direct result of the larger numbers of participants, and analyses should take account of
reduction in the symptoms of anxiety and depression as a result of potential sex differences. Future trials should also prioritize objective
antidepressants. The braingutmicrobiome research reviewed measures of disease activity (i.e., calprotectin, colonoscopy) over
elsewhere points toward this explanation.3436 However, further subjective (i.e., disease activity indices) when assessing IBD activity.
research is required to conclusively determine the exact mecha- The previous systematic review5 recommended that future
nism or mechanisms of action. research should differentiate between CD and UC; this recommen-
dation has not changed in light of this review ndings. Finally, longer
Current Guidelines follow-up periods (at least 5 years) are required to more accurately
A recent review of the international evidence-based guide- determine the efcacy of antidepressants therapy on disease course.
lines on managing IBD and its comorbid psychosocial issues37
concluded that psychological distress should be screened for and
treated appropriately, with psychotherapy/psychopharmacother- CONCLUSIONS
apy offered if required. The dominance of observational studies Antidepressants are commonly used by patients with IBD;
in this review precludes a judgment on the efcacy of antidepres- however, based on the ndings from this systematic review, it is
sants on IBD course, but results indicate the possibility of an not possible to determine for certain whether antidepressants have
effect which needs experimental verication. a benecial effect on the course of IBD. The state of research has
www.ibdjournal.org | 549
Copyright 2017 Crohns & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
Macer et al Inamm Bowel Dis Volume 23, Number 4, April 2017
improved over the last 10 years; however, nearly all the evidence adults with inammatory bowel disease (IBD). Gastroenterology. 2014;
comes from observational studies where cause and effect are 1:S-456.
18. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of
difcult to attribute. Further properly conducted RCTs with current psychiatric disorder to functional disability and distress in
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19. Iskandar HN, Cassell B, Kanuri N, et al. Tricyclic antidepressants for
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ACKNOWLEDGMENTS on depression, anxiety, quality of life, and sexual dysfunction in patients
We are very grateful to David Brown, Academic Liaison with inammatory bowel disease. Neuropsychiatr Dis Treat. 2016;12:
673683.
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