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doi:10.1136/gut.2008.163162
2009;58;367-378; originally published online 10 Nov 2008; Gut
A C Ford, N J Talley, P S Schoenfeld, E M M Quigley and P Moayyedi
review and meta-analysis
therapies in irritable bowel syndrome: systematic
Efficacy of antidepressants and psychological
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Efficacy of antidepressants and psychological
therapies in irritable bowel syndrome: systematic
review and meta-analysis
A C Ford,
1
N J Talley,
2
P S Schoenfeld,
3
E M M Quigley,
4
P Moayyedi
1
cCompeting interests:
Declared (the declaration can be
viewed on the Gut website at
http://www.gut.bmj.com/
supplemental)
1
Gastroenterology Division,
McMaster University, Health
Sciences Center, Hamilton,
Ontario, Canada;
2
Department
of Medicine, Mayo Clinic Florida,
Jacksonville, Florida, USA;
3
Division of Gastroenterology,
University of Michigan School of
Medicine, Ann Arbor, Michigan,
USA;
4
Department of Medicine,
Clinical Sciences Building, Cork
University Hospital, Cork, Ireland
Correspondence to:
Dr A Ford, Gastroenterology
Division, McMaster University
Medical Centre, 1200 Main
Street West, Hamilton, Ontario,
L8N 3Z5, Canada; alexf12399@
yahoo.com
Revised 7 October 2008
Accepted 14 October 2008
Published Online First
10 November 2008
ABSTRACT
Objective: Irritable bowel syndrome (IBS) is a chronic
functional gastrointestinal disorder. Evidence for treat-
ment of the condition with antidepressants and psycho-
logical therapies is conflicting.
Design: Systematic review and meta-analysis of rando-
mised controlled trials (RCTs). MEDLINE, EMBASE and the
Cochrane Controlled Trials Register were searched (up to
May 2008).
Setting: RCTs based in primary, secondary and tertiary
care.
Patients: Adults with IBS.
Interventions: Antidepressants versus placebo, and
psychological therapies versus control therapy or ‘‘usual
management’’.
Main outcome measures: Dichotomous symptom data
were pooled to obtain a relative risk (RR) of remaining
symptomatic after therapy, with a 95% confidence
interval (CI). The number needed to treat (NNT) was
calculated from the reciprocal of the risk difference.
Results: The search strategy identified 571 citations.
Thirty-two RCTs were eligible for inclusion: 19 compared
psychological therapies with control therapy or ‘‘usual
management’’, 12 compared antidepressants with pla-
cebo, and one compared both psychological therapy and
antidepressants with placebo. Study quality was generally
good for antidepressant but poor for psychological therapy
trials. The RR of IBS symptoms persisting with
antidepressants versus placebo was 0.66 (95% CI, 0.57
to 0.78), with similar treatment effects for both tricyclic
antidepressants and selective serotonin reuptake inhibi-
tors. The RR of symptoms persisting with psychological
therapies was 0.67 (95% CI, 0.57 to 0.79). The NNT was
4 for both interventions.
Conclusions: Antidepressants are effective in the
treatment of IBS. There is less high-quality evidence for
routine use of psychological therapies in IBS, but available
data suggest these may be of comparable efficacy.
Irritable bowel syndrome (IBS) is a functional
gastrointestinal (GI) disorder for which there is no
known structural or anatomical explanation. The
prevalence of IBS in the general population is
estimated to be between 5% and 20%,
1–4
and its
management accounts for up to 25% of a gastro-
enterologist’s workload in the outpatient clinic.
5
The condition tends to follow a chronic relapsing
and remitting course.
6–9
Effective therapies for IBS
are therefore required, in order to alleviate symp-
toms, and thereby reduce consultation behaviour
and consumption of other valuable medical
resources.
Patients with IBS are more likely to suffer from
coexistent mood disorder, anxiety and neuroticism
compared to healthy controls or individuals with
organic pathology,
10
and to report a low quality of
life.
11–13
A significant proportion of patients with
IBS who consult in tertiary care have an underlying
psychiatric illness,
14 15
and even non-consulters
have higher levels of depression when compared
to the general population.
16 17
The latest revision of the Rome criteria requires
the presence of recurrent abdominal pain or
discomfort, in association with a change in bowel
habit, for the diagnosis of IBS to be reached.
18
Patients with IBS often demonstrate increased
sensitivity in response to balloon distension of
the GI tract,
19
and this visceral hypersensitivity is
thought to contribute to the chronic pain experi-
enced by those with the condition. Antidepressant
drugs are often used in the treatment of chronic
pain, owing to their potential modulation of pain
perception, and have been shown to be effective in
this setting.
20
For these reasons, it would be reasonable to
assume a beneficial effect of antidepressant drugs,
such as tricyclic antidepressants (TCAs) and
selective serotonin reuptake inhibitors (SSRIs), or
psychological therapies, such as cognitive beha-
vioural therapy (CBT), on the symptoms of IBS.
However, evidence for this is conflicting, and
despite numerous systematic reviews examining
this issue there is no clear consensus.
21–28
This
uncertainty is reflected in British Society of
Gastroenterology (BSG) guidelines for the manage-
ment of the condition,
29
which state that evidence
for any benefit of TCAs is conflicting, and may be
limited to an improvement in pain, and therefore
recommend their use as second-line treatment for
this symptom. Similar recommendations are made
for the role of psychological therapies, whilst the
role of SSRIs in the management of IBS is not
specified. The American Gastroenterological
Association (AGA) technical review,
30
and the
American College of Gastroenterology (ACG)
position statement,
31
informed by a systematic
review, are similarly guarded.
The role of both antidepressants and psycholo-
gical therapies in the management of IBS is
therefore unclear at the present time. In an
attempt to address this uncertainty we have
conducted a systematic review and meta-analysis
of randomised controlled trials (RCTs) to estimate
the effect of antidepressant therapy and psycholo-
gical therapies on improvement or cure of IBS
symptoms.
Irritable bowel syndrome
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METHODS
Search strategy and study selection
A search of the medical literature was conducted using
MEDLINE (1950 to May 2008), EMBASE (1980 to May 2008),
and the Cochrane Controlled Trials Register (2007).
Randomised controlled trials examining the effect of antide-
pressants and psychological therapies in adult patients (over the
age of 16 years) with IBS were eligible for inclusion (box 1). The
first period of cross-over RCTs were also eligible for inclusion. In
the case of antidepressant trials the control arm was required to
receive placebo, whilst for studies of psychological therapies the
control arm could receive placebo, symptom monitoring
(including waiting list control), or a physician’s ‘‘usual manage-
ment’’. Duration of therapy had to be at least 7 days. The
diagnosis of IBS could be based on either a physician’s opinion
or symptom-based diagnostic criteria, supplemented by the
results of investigations to exclude organic disease, where
studies deemed this necessary. Subjects were required to be
followed up for at least 1 week, and studies had to report either
a global assessment of IBS symptom cure or improvement, or
abdominal pain cure or improvement, after completion of
treatment, preferably as reported by the patient, but if this was
not recorded then as documented by the investigator or via
questionnaire data. Where studies included patients with other
functional GI disorders, or did not report these types of
dichotomous data, but were otherwise eligible for inclusion in
the systematic review, we attempted to contact the original
investigators in order to obtain further information.
Studies on IBS were identified with the terms irritable bowel
syndrome and functional diseases, colon (both as a medical subject
heading (MeSH) and free-text terms), and IBS,spastic colon,
irritable colon, and functional adj5 bowel (as free-text terms).
These were combined using the set operator AND with studies
identified with the terms: psychotropic drugs,antidepressive
agents,antidepressive agents (tricyclic),desipramine,imipramine,
trimipramine,doxepin, dothiepin, nortriptyline,amitriptyline,selec-
tive serotonin reuptake inhibitors,paroxetine, sertraline, fluoxetine,
citalopram, venlafaxine, cognitive therapy, psychotherapy, behaviour
therapy, relaxation techniques, and hypnosis (both as MeSH terms
and free-text terms), and the following free-text terms:
behavioural therapy,relaxation therapy, and hypnotherapy.
There were no language restrictions and abstracts of the
papers identified by the initial search were evaluated by the lead
reviewer for appropriateness to the study question, and all
potentially relevant papers were obtained and evaluated in
detail. Foreign language papers were translated where necessary.
Abstract books of conference proceedings between 2001 and
2007 were hand-searched to identify potentially eligible studies
published only in abstract form. The bibliographies of all
identified relevant studies were used to perform a recursive
search of the literature. Articles were independently assessed by
two reviewers using pre-designed eligibility forms, according to
the prospectively defined eligibility criteria. Any disagreement
between investigators was resolved by consensus.
Outcome assessment
The primary outcomes assessed were the effect of antidepres-
sants compared to placebo, and the effect of psychological
therapies compared to control treatment or a physician’s ‘‘usual
management’’, on global IBS symptoms or abdominal pain after
cessation of treatment. Secondary outcomes included assessing
efficacy according to specific type of antidepressant or
psychological therapy, and adverse events occurring as a result
of antidepressant therapy.
Data extraction
All data were extracted independently by two reviewers on to a
Microsoft Excel spreadsheet (XP professional edition; Microsoft,
Redmond, Washington, USA) as dichotomous outcomes (global
IBS symptoms persistent or unimproved, or abdominal pain
persistent or unimproved) (box 2). In addition, the following
clinical data were extracted for each trial: setting (primary,
secondary or tertiary care-based), number of centres, country of
origin, dose of antidepressant or number of sessions of
psychological therapy administered, duration of therapy, total
number of adverse events reported, criteria used to define IBS,
primary outcome measure used to define symptom improve-
ment or cure following therapy, duration of follow-up,
proportion of female patients, and proportion of patients
according to predominant stool pattern. We also recorded the
handling of the control arm for trials of psychological therapies.
Data were extracted as intention-to-treat analyses, where all
drop-outs are assumed to be treatment failures, wherever trial
reporting allowed this.
Study quality
Assessment of study quality was performed independently by
two reviewers according to the Jadad scale (table 1),
32
which
records whether a study is described as randomised and double-
blind, the method of generation of the allocation schedule and
method of double-blinding, and whether there is a description
of drop-outs during the trial.
Data synthesis and statistical analysis
Data were pooled using a random effects model, to give a more
conservative estimate of the effect of individual therapies,
allowing for any heterogeneity between studies.
33
The impacts
of different interventions were expressed as a relative risk (RR)
of global IBS symptoms or abdominal pain persisting with
intervention compared to control with 95% confidence intervals
(CIs). The number needed to treat (NNT) and 95% CIs were
calculated from the reciprocal of the risk difference from the
meta-analysis.
The results of individual studies can be diverse, and this
inconsistency within a single meta-analysis can be quantified
with a statistical test of heterogeneity, to assess whether the
variation across trials is due to true heterogeneity or chance.
Box 1 Eligibility criteria
cRandomised controlled trials
cAdults (participants aged .16 years)
cDiagnosis of irritable bowel syndrome (IBS) based on either a
clinician’s opinion, or meeting specific diagnostic criteria (ie,
Manning, Kruis score, Rome I, II, or III), supplemented by
negative investigations where trials deemed this necessary
cCompared antidepressants with placebo, or psychological
therapies with either control therapy or a physician’s ‘‘usual
management’’
cMinimum duration of therapy, 7 days
cMinimum duration of follow-up, 7 days
cGlobal assessment of IBS symptoms or abdominal pain
following therapy (preferably patient-reported, but if this was
not available then as assessed by a physician or questionnaire
data)
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This quantity is termed I
2
, and its value ranges from 0% to
100%, with 0% representing no observed heterogeneity, and
larger values indicating increasing heterogeneity. A value below
25% is arbitrarily chosen to represent low levels of hetero-
geneity.
34
Where the degree of statistical heterogeneity was
greater than this between trial results in this meta-analysis,
possible explanations were investigated using sensitivity ana-
lyses according to trial setting, criteria used to define IBS,
whether method of randomisation or concealment of allocation
were reported, level of blinding, study quality according to the
Jadad scale and, for trials of psychological therapies, method of
handling of the control arm. These are exploratory only, and
may explain some of the observed variability, but the results
should be interpreted with caution.
Review Manager version 4.2.8 and StatsDirect version 2.4.4
were used to generate Forest plots of pooled relative risks and
risk differences for primary and secondary outcomes with 95%
CIs, as well as funnel plots. The latter were assessed for
evidence of asymmetry, and therefore possible publication bias,
using the Egger test.
35
RESULTS
The search strategy generated 571 citations of which 63
appeared to be relevant to the systematic review and were
retrieved for further assessment (fig 1). We successfully
contacted six of the primary investigators of the 63 studies to
clarify data, exclude patients with other functional GI disorders
from the analysis, or obtain original data sets to conduct
additional analyses ourselves in order to dichotomise data and
thereby maximise trial eligibility for the current meta-analysis.
Of these 63 RCTs, 31 were excluded for various reasons, leaving
32 eligible trials,
36–67
19 of which compared psychological
therapies to control therapy or a physician’s ‘‘usual manage-
ment’’,
38–50 62–67
12 compared antidepressants to placebo,
36 51–61
and one compared both psychological therapy and antidepres-
sants to placebo.
37
Agreement between reviewers for assessment
of trial eligibility was good (kappa statistic = 0.90).
Efficacy of antidepressants in the treatment of IBS
There were 13 studies comparing antidepressants to placebo for
the treatment of IBS,
36 37 51–61
including a total of 789 patients,
432 of whom received active therapy and 357 placebo. Seven of
the studies were conducted in secondary care,
36 52 56 58–61
and six
in tertiary care.
37 51 53–55 57
Eight studies used TCAs,
36 37 53 56 58–61
four studies SSRIs,
52 54 55 57
and one study both.
51
Ten of the
studies scored 4 or more on the Jadad scale.
37 51–58 60
The
proportion of female patients recruited by trials ranged from
44% to 100%. Six studies reported sub-type of IBS according to
predominant stool pattern.
52 54 55 57 58 60
One recruited only
constipation-predominant patients,
52
one included only diar-
rhoea-predominant,
60
and predominant stool pattern was mixed
in the other four.
54 55 57 58
Detailed characteristics of individual
studies are provided in table 2.
There were 182 of 432 (42.1%) patients assigned to
antidepressant therapy with persistent or unimproved IBS
symptoms following therapy, compared to 231 of 357 (64.7%)
Box 2 Methodology for data extraction
cOutcome of interest: improvement in global symptoms of
inflammatory bowel syndrome (IBS) preferable, if not reported
then improvement in abdominal pain
cReporting of outcomes: patient-reported preferable; if not
available, then investigator-reported
cTime of assessment: upon completion of treatment
cDenominator used: true intention-to-treat analysis; if not
available, then all evaluable patients
cCut-off used for dichotomisation: any improvement in global
symptoms of IBS or abdominal pain for Likert-type scales,
investigator-defined improvement for continuous scales; if no
investigator definition was available we used a >1 standard
deviation decrease in symptom score from baseline to
completion of treatment (we assessed whether the use of any
decrease in symptom score from baseline to completion of
therapy altered our analysis)
Table 1 Calculation of the Jadad score
Item Score
Was the study described as randomised? 1
Was the method used to generate the sequence of randomisation described
and appropriate (random numbers, computer-generated, etc)?
1
Was the study described as double-blind? 1
Was the method of double-blinding described and appropriate (identical
placebo, active placebo, dummy, etc)?
1
Was there a description of withdrawals and drop-outs? 1
Deduct one point if method used to generate sequence of randomisation
described, but inappropriate (allocated alternately, or according to date of
birth, or hospital number)
21
Deduct one point if study described as double-blind, but method of blinding
inappropriate
21
Figure 1 Flow diagram for the assessment of studies identified in the
systematic review.
Irritable bowel syndrome
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allocated to placebo. The relative risk of IBS symptoms
persisting or remaining unimproved after treatment with
antidepressant therapy versus placebo was 0.66 (95% CI, 0.57
to 0.78), with marginal statistically significant heterogeneity
detected between studies (I
2
= 26.4%, p = 0.17) (fig 2). The
number needed to treat with antidepressant therapy to prevent
IBS symptoms persisting in one patient was 4 (95% CI, 3 to 6).
The Egger test demonstrated evidence of funnel plot asymmetry
(p = 0.02), suggesting publication bias, with a lack of small
studies showing no effect of antidepressant therapy on the
symptoms of IBS (fig 3). However, this appeared to be driven by
the TCA arm of one small study,
51
and when this study arm was
excluded from the meta-analysis the asymmetry was no longer
statistically significant (Egger test, p = 0.07). Sensitivity ana-
lyses were conducted (table 3). Treatment effect appeared to be
increased in secondary care-based studies, studies that did not
state method of generation of the randomisation schedule or
method of concealment of allocation, and studies scoring less
than 4 on the Jadad scale. Heterogeneity between studies was
no longer significant when studies were subgrouped according
to whether or not the method of concealment of allocation was
reported. A statistically significant difference in treatment effect
was not detected in any of these subgroup analyses.
The effect of antidepressant therapy on abdominal pain was
reported by five studies,
52 53 55 58 60
with 63 of 127 (49.6%)
patients receiving antidepressants having persistent abdominal
pain following treatment, compared to 87 of 129 (67.4%)
subjects allocated to placebo, giving a relative risk of abdominal
pain persisting of 0.66 (95% CI, 0.41 to 1.06) with considerable
heterogeneity between studies (I
2
= 74.6%, p = 0.003).
Efficacy of TCAs in the treatment of IBS
Nine studies compared TCAs to placebo in a total of 575
patients.
36 37 51 53 56 58–61
Of the 319 patients receiving active
therapy, 132 (41.4%) had persistent symptoms after treatment,
compared to 153 of 256 (59.8%) receiving placebo. The relative
risk of IBS symptoms persisting with TCAs compared to
placebo was 0.68 (95% CI, 0.56 to 0.83), with marginal
Table 2 Characteristics of randomised controlled trials of antidepressants versus placebo in irritable bowel syndrome (IBS)
Study (first
author, year and
reference no.) Country Setting
Diagnostic criteria
used for IBS
Criteria used to define
symptom improvement
following therapy Sample size
Antidepressant
used
Duration of
therapy
Jadad
score
Heefner 1978
53
USA Tertiary care Clinical diagnosis and
investigations
Patient-reported
improvement in abdominal
pain
44 Desipramine
150 mg od
2 months 4
Myren 1982
59
Norway Secondary care Clinical diagnosis and
investigations
Patient-reported
improvement in global
symptoms
61 Trimipramine
50 mg od
4 weeks 2
Nigam 1984
36
India Secondary care Clinical diagnosis and
investigations
Patient-reported
improvement in global
symptoms
42 Amitriptyline
12.5 mg od
12 weeks 3
Boerner 1988
56
Germany Secondary care Clinical diagnosis and
investigations
Patient-reported
improvement in global
symptoms
83 Doxepin 50 mg od 8 weeks 4
Bergmann 1991
61
Germany Secondary care Clinical diagnosis and
investigations
Patient-reported
improvement in global
symptoms
35 Trimipramine
50 mg od
3 months 2
Vij 1991
58
India Secondary care Clinical diagnosis and
investigations
Patient-reported
improvement in global
symptoms
50 Doxepin 75 mg od 6 weeks 5
Drossman 2003*
37
USA Tertiary care Rome I >Score of 28 on treatment
satisfaction questionnaire
172 Desipramine 50 mg
od for 1 week, then
100 mg od for
1 week, then
150 mg od
thereafter
12 weeks 5
Kuiken 2003
54
Holland Tertiary care Rome I and
investigations
Patient-reported
improvement in global
symptoms
40 Fluoxetine 20 mg
od
6 weeks 5
Tabas 2004
55
USA Tertiary care Rome I Patient-reported
improvement in well-being
90 Paroxetine 10 mg,
increasing to
20 mg then 40 mg
if no improvement
12 weeks 5
Vahedi 2005
52
Iran Secondary care Rome II and
investigations
Patient-reported
improvement in abdominal
pain
44 Fluoxetine 20 mg
od
12 weeks 5
Tack 2006*
57
Belgium Tertiary care Rome II and
investigations
Patient-reported 50%
decrease in days with
symptoms
23 Citalopram 20 mg
for 3 weeks
increasing to
40 mg od for next
3 weeks
6 weeks 4
Talley 2008
51
Australia Tertiary care Rome II and
investigations
Patient-reported adequate
relief of symptoms
51 Imipramine 50 mg
od or citalopram
40 mg od
12 weeks 5
Vahedi 2008
60
Iran Secondary care Rome II and
investigations
Patient-reported
improvement in global
symptoms
54 Amitriptyline
10 mg od
2 months 5
*Further information obtained from the original investigators.
od, once daily.
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Figure 2 Forest plot of randomised controlled trials of antidepressants versus placebo in irritable bowel syndrome. CI, confidence interval; n, number
of patients with persistent or unimproved symptoms; N, total number of patients treated; RR, relative risk.
Table 3 Sensitivity analyses to examine factors contributing to heterogeneity in randomised controlled trials of antidepressants versus placebo in
irritable bowel syndrome (IBS)
Factor Number of trials Number of patients
Relative risk of IBS symptoms
persisting (95% CI) p Value for the difference I
2
(p value)
Setting
Secondary care 7 369 0.57 (0.44 to 0.75) 0.08 39.2% (0.13)
Tertiary care 6 420 0.76 (0.64 to 0.91) 0% (0.56)
Criteria used to define IBS
Rome I or II 7 474 0.65 (0.50 to 0.84) 0.86 41.7% (0.10)
Clinical diagnosis 6 315 0.67 (0.54 to 0.83) 11.7% (0.34)
Method of randomisation
Stated 7 501 0.68 (0.54 to 0.85) 0.66 35.8% (0.14)
Not stated 6 288 0.63 (0.49 to 0.82) 20.4% (0.28)
Concealment of allocation
Stated 3 313 0.78 (0.63 to 0.96) 0.12 5.1% (0.37)
Not stated 10 476 0.62 (0.50 to 0.75) 24.1% (0.22)
Blinding
Double 12 754 0.70 (0.61 to 0.80) 0.03 6.9% (0.38)
Not stated 1 35 0.30 (0.13 to 0.59) N/A
Score on Jadad scale
>4 10 651 0.70 (0.59 to 0.83) 0.29 19% (0.26)
,4 3 138 0.51 (0.29 to 0.90) 56.6% (0.10)
CI, confidence interval.
Irritable bowel syndrome
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statistically significant heterogeneity detected between studies
(I
2
= 26.9%, p = 0.21) (fig 2), and evidence of funnel plot
asymmetry (Egger test, p = 0.03). Again, this was driven by
one study,
51
and when this was removed from the analysis there
was no longer statistically significant publication bias (Egger
test, p = 0.09). The number needed to treat with TCAs to
prevent IBS symptoms persisting in one patient was 4 (95% CI,
3 to 8).
Efficacy of SSRIs in the treatment of IBS
Five studies compared SSRIs with placebo in a total of 230
patients.
51 52 54 55 57
There were 50 of 113 (44.2%) patients
allocated to SSRIs with persistent symptoms following therapy,
compared to 83 of 117 (70.9%) placebo patients. The relative
risk of IBS symptoms persisting with SSRIs compared to
placebo was 0.62 (95% CI, 0.45 to 0.87), with statistically
significant heterogeneity between studies (I
2
= 38.1%, p = 0.17)
(fig 2), but no evidence of funnel plot asymmetry (Egger test,
p = 0.60). The number needed to treat with SSRIs to prevent
IBS symptoms persisting in one patient was 3.5 (95% CI, 2 to
14).
Adverse events with antidepressant therapy
Eleven of the studies reported adverse events data,
36 37 51–54 56–60
but only six provided the total number of patients experiencing
adverse events with antidepressants compared to placebo in a
total of 301 patients.
53 54 56–59
There were 27 of 149 (18.1%)
patients assigned to antidepressants reporting adverse events
compared to 14 of 152 (9.2%) allocated to placebo. The relative
risk of experiencing adverse events with antidepressants
compared to placebo was 1.63 (95% CI, 0.94 to 2.80), with no
heterogeneity detected between studies (I
2
= 0%, p = 0.67).
There were no serious adverse events, the commonest reported
by patients allocated to antidepressant therapy were drowsiness
and dizziness.
Efficacy of psychological therapies in the treatment of IBS
We identified 20 studies comparing various psychological
therapies to control therapy or a physician’s ‘‘usual manage-
ment’’ for the treatment of IBS in a total of 1278 patients.
37–50 62–67
One study was conducted in primary care,
49
and the remainder
in tertiary care. Six studies used CBT,
37 40 43 45 47 49
four studies
used relaxation training or therapy,
38 41 46 48
three studies used
multi-component psychological therapy,
39 42 65
two studies used
hypnotherapy,
62 66
two studies used dynamic psychother-
apy,
50 64
one study used self-administered CBT,
67
one study
used stress management,
44
and one study used both CBT and
relaxation therapy.
63
The control arm received symptom
monitoring in 11 studies,
38–434547486267
usual care in seven
studies,
44 46 49 50 63–65
supportive therapy in one study,
66
and
placebo in one study.
37
Thirteen of the studies scored only 1 or
2 on the Jadad scale,
38–45 47 48 50 62 65
and none scored 4 or more.
The proportion of female patients recruited by trials ranged
from 57% to 100%. Ten studies reported sub-type of IBS
according to predominant stool pattern.
38 39 41–43 47 64–67
No study
recruited constipation or diarrhoea-predominant patients
exclusively. Detailed characteristics of individual studies are
provided in table 4.
IBS symptoms persisted in 356 of 700 (50.9%) patients
receiving psychological therapies compared to 419 of 578
(72.5%) receiving physician’s ‘‘usual management’’ or control
therapy. The relative risk of IBS symptoms persisting with
psychological therapies compared to physician’s ‘‘usual manage-
ment’’ or control therapy was 0.67 (95% CI, 0.57 to 0.79) (fig 4),
with considerable heterogeneity detected between studies
(I
2
= 72.9%, p,0.0001), and evidence of funnel plot asymmetry
(Egger test, p,0.0001), with a lack of small studies showing no
effect of psychological therapies on the symptoms of IBS (fig 5).
The number needed to treat with psychological therapies to
prevent IBS symptoms persisting in one patient was 4 (95% CI,
3 to 5).
As nine of the studies of psychological therapies were
conducted by the same group of investigators we performed a
post hoc sensitivity analysis according to study centre. There
were 270 patients with IBS in the nine studies published by
Blanchard and colleagues,
38–40 42 43 47 48 62 67
and 11 studies pub-
lished by other groups of authors reporting on 1008
patients.
37 41 44–46 49 50 63–66
The efficacy of psychological therapies
in studies published by Blanchard and colleagues appeared to be
greater (RR = 0.59; 95% CI, 0.42 to 0.82; I
2
= 71.9%, p = 0.0002)
than studies conducted in other centres (RR = 0.71; 95% CI,
0.58 to 0.87, I
2
= 76.4%, p,0.0001), although a statistically
significant difference was not detected (p =0.35). We performed
a further subgroup analysis according to handling of the control
arm. The RR of symptoms persisting was lower in studies using
symptom monitoring (0.54; 95% CI, 0.39 to 0.76) than in those
where usual management, supportive therapy, or placebo were
the control intervention (RR = 0.75; 95% CI, 0.62 to 0.91),
though again this difference was not statistically significant
(p = 0.09).
Efficacy of CBT in IBS
Seven studies compared CBT to control therapy or physician’s
‘‘usual management’’ in 491 patients.
37 40 43 45 47 49 63
IBS symp-
toms persisted in 118 of 279 (42.3%) of those assigned to CBT
compared to 130 of 212 (61.3%) of those allocated to control
therapy or physician’s ‘‘usual management’’, with a relative risk
of symptoms persisting of 0.60 (95% CI, 0.42 to 0.87), and a
number needed to treat of 3 (95% CI, 2 to 7). There was
statistically significant heterogeneity between studies
(I
2
= 70.7%, p = 0.002), and evidence of funnel plot asymmetry
(Egger test, p = 0.01), with a lack of small studies showing no
effect of CBT on the symptoms of IBS. When the three studies
conducted in the same centre were excluded from the
analysis,
40 43 47
the beneficial effect of CBT on symptoms of
IBS disappeared (RR of symptoms persisting =0.79; 95% CI,
0.56 to 1.13).
Figure 3 Funnel plot of randomised controlled trials of antidepressants
versus placebo in irritable bowel syndrome.
Irritable bowel syndrome
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Table 4 Characteristics of randomised controlled trials of psychological therapies versus control therapy or a physician’s ‘‘usual management’’ in irritable bowel syndrome (IBS)
Study (first author, year
and reference no.) Country Setting
Diagnostic criteria used for
IBS
Criteria used to define symptom
improvement following therapy Sample size
Psychological therapy
used
Duration of therapy (no.
of sessions) Jadad score
Neff 1987
42
USA Tertiary care Clinical diagnosis >50% reduction in baseline symptom
score
19 Multi-component
psychological therapy
8 weeks (12) 2
Lynch 1989
41
Canada Tertiary care Clinical diagnosis >50% reduction in diary rating of
symptoms
21 Relaxation therapy 2 months (8) 2
Guthrie 1991
50
England Tertiary care Clinical diagnosis and
investigations
Patient-reported improvement in global
symptoms
102 Dynamic psychotherapy 3 months (7) 2
Shaw 1991
44
Wales Tertiary care Clinical diagnosis and
investigations
Patient-reported overall benefit from
treatment
35 Stress management
programme
6 months (6) 1
Blanchard 1992
39
USA Tertiary care Clinical diagnosis and
investigations
>50% reduction in baseline symptom
score
20 and
77*
Multi-component
psychological therapy
8 weeks (12) 2
Blanchard 1993
38
USA Tertiary care Clinical diagnosis and
investigations
>50% reduction in baseline symptom
score
23 Progressive muscle
relaxation
8 weeks (10) 2
Greene 1994
40
USA Tertiary care Clinical diagnosis and
investigations
>50% reduction in baseline symptom
score
20 Cognitive behavioural
therapy
8 weeks (10) 1
Payne 1995
43
USA Tertiary care Rome I and investigations >50% reduction in baseline symptom
score
22 Cognitive behavioural
therapy
8 weeks (10) 2
Galovski 1998
62
USA Tertiary care Clinical diagnosis >50% reduction in baseline symptom
score
12 Hypnotherapy 6 weeks (12) 2
Vollmer 1998
47
USA Tertiary care Rome I and investigations >50% reduction in baseline symptom
score
34 Cognitive behavioural
therapy
10 weeks (10) 2
Keefer 2001
48
USA Tertiary care Clinical diagnosis >50% reduction in baseline symptom
score
15 Relaxation response
meditation
6 weeks (6) 2
Boyce 2003{
63
Australia Tertiary care Rome I and investigations >1 standard deviation decrease in
baseline symptom score{
105 Cognitive behavioural
therapy and relaxation
therapy
8 weeks (8) 3
Creed 2003{
64
England Tertiary care Rome I Patient-reported improvement in global
symptoms
171 Dynamic psychotherapy 3 months (8) 3
Drossman 2003{
37
USA Tertiary care Rome I >Score of 28 on treatment satisfaction
questionnaire
169 Cognitive behavioural
therapy
12 weeks (12) 3
Tkachuk 2003
45
Canada Tertiary care Rome I and investigations Patient-reported improvement in global
symptoms
28 Cognitive behavioural
therapy
9 weeks (10) 2
Heitkemper 2004{
65
USA Tertiary care Rome I >50% reduction in symptom score 95 Multi-component
psychological therapy
8 weeks (8) 2
Simren 2004
66
Sweden Tertiary care Rome II and investigations Patient-reported improvement in global
symptoms
28 Hypnotherapy 12 weeks (12) 3
Kennedy 2005{
49
England Primary care Clinical diagnosis Improvement in symptom severity
banding by one band (graded severe to
none on a four-point Likert-scale)
149 Cognitive behavioural
therapy
6 weeks (6) 3
Sanders 2007{
67
USA Tertiary care Rome II and investigations >50% reduction in baseline symptom
score
28 Self-administered cognitive
behavioural therapy
10 weeks (5) 3
van der Veek 2007
46
Holland Tertiary care Rome II Reliable change index >1.96 (pre-therapy
score minus post-therapy score divided
by standard error of the difference)
105 Relaxation training 3 months (4) 3
*Two separate studies reported in one paper.
{Criteria defined as part of the current systematic review in the absence of an author-specified definition.
{Further information obtained from original investigators.
Irritable bowel syndrome
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Efficacy of relaxation training or therapy in IBS
Five studies compared relaxation training or therapy to control
therapy or physician’s ‘‘usual management’’ in 234
patients.
38 41 46 48 63
IBS symptoms persisted in 94 of 122
(77.0%) of those assigned to relaxation training or therapy
compared to 100 of 112 (89.3%) of those allocated to control
therapy or physician’s ‘‘usual management’’, with a relative risk
of symptoms persisting of 0.82 (95% CI, 0.63 to 1.08), and
statistically significant heterogeneity between studies
(I
2
= 68.2%, p = 0.01).
Efficacy of hypnotherapy in IBS
Two studies compared hypnotherapy to control therapy or
physician’s ‘‘usual management’’ in 40 patients.
62 66
IBS symp-
toms persisted in 7 of 20 (35%) of those assigned to
hypnotherapy compared to 15 of 20 (75%) of those allocated
to control therapy or physician’s ‘‘usual management’’, with a
relative risk of symptoms persisting of 0.48 (95% CI, 0.26 to
0.87), and a number needed to treat of 2 (95% CI, 1.5 to 7).
Efficacy of multi-component psychological therapy in IBS
Three studies compared multi-component psychological ther-
apy to control therapy or physician’s ‘‘usual management’’ in
211 patients.
39 42 65
IBS symptoms persisted in 55 of 106 (51.9%)
of those assigned to multi-component psychological therapy
compared to 80 of 105 (76.2%) of those allocated to control
therapy or physician’s ‘‘usual management’’, with a relative risk
of symptoms persisting of 0.69 (95% CI, 0.56 to 0.86), and a
number needed to treat of 4 (95% CI, 3 to 8).
Efficacy of dynamic psychotherapy in IBS
Two studies compared dynamic psychotherapy to control
therapy or physician’s ‘‘usual management’’ in 273 patients.
50 64
IBS symptoms persisted in 61 of 138 (44.2%) of those assigned
to dynamic psychotherapy compared to 95 of 135 (70.4%) of
those allocated to control therapy or physician’s ‘‘usual
management’’, with a relative risk of symptoms persisting of
0.60 (95% CI, 0.39 to 0.93), and a number needed to treat of 3.5
(95% CI, 2 to 25).
Efficacy of self-administered CBT and stress management in IBS
There was only one study using each of these treatment
modalities.
44 67
Self-administered CBT had little effect on
symptoms over control therapy or physician’s ‘‘usual manage-
ment’’, whilst stress management appeared to reduce the risk of
IBS symptoms persisting following therapy.
DISCUSSION
This systematic review and meta-analysis has demonstrated a
significant benefit of antidepressants over placebo, and psycho-
logical therapies over control therapy or a physician’s ‘‘usual
management’’, for the treatment of IBS. The number needed to
treat in both cases, to prevent one IBS patient’s symptoms
persisting, was 4. Tricyclic antidepressants and SSRIs were
equally effective, with no significant differences detected in
either the relative risk of symptoms persisting or the number
needed to treat between the two drug classes. Adverse events
were more common in patients assigned to antidepressants than
those allocated to placebo, but a statistically significant
difference was not detected. The overall treatment effect was
very similar for psychological therapies, but there was most
evidence for CBT. Multi-component psychological therapy,
dynamic psychotherapy, and hypnotherapy were also effective
in IBS, though in smaller numbers of patients. Relaxation
therapy did not have a statistically significant effect on IBS
symptoms, though there were few eligible published studies,
and this could therefore be due to a type II error. There was also
insufficient evidence for stress management and self-adminis-
tered CBT.
We are aware of six previous systematic reviews that have
examined the efficacy of antidepressants in IBS.
21–26
Unfortunately, all of these have methodological limitations.
Four of these considered only English-language articles,
21 22 24 25
three did not extract and combine data to give an overall
treatment effect,
21 23 25
three extracted data incorrectly from
eligible studies,
22 24 26
two included cross-over studies in the
analysis,
22 24
one only identified three of ten truly eligible studies
published at the time of their review,
26
one included trials of
antidepressants in functional GI disorders and did not report
IBS patients separately,
22
and one only considered treatments
available in the USA.
23
It is therefore not surprising that these
reviews have reached different conclusions about the role of
antidepressants in IBS. In addition, there have been several
RCTs published in the interim.
Two of these reviews also examined the role of psychological
therapies in the treatment of IBS,
23 25
and both stated that
although the quality of the available evidence was poor these
approaches may lead to an improvement in individual IBS
symptoms. However, there was no data synthesis undertaken
to provide an estimate of this effect. A review by Lackner et al
published in 2004 identified 17 studies,
27
but only ten of these
provided extractable dichotomous data for analysis. The
authors estimated a number needed to treat with psychological
therapies to improve one case of IBS of 2. However, the total
number of included patients was 185, and nine of the ten
studies emanated from a single centre. A recent Cochrane
Collaboration systematic review of the efficacy of hypnother-
apy identified only four RCTs,
28
though again data were not
combined owing to concerns about differences in outcome
measures and study design. A descriptive analysis was under-
taken, and reported that hypnotherapy was superior to control
therapy in terms of its effect on both abdominal pain and global
IBS symptoms. Only one of these studies was eligible for the
current systematic review and meta-analysis.
62
The remaining
three trials were ineligible as two did not provide extractable
data and one used psychotherapy as the control intervention.
The current systematic review and meta-analysis is superior
to these previous reviews for several reasons. First, we have used
rigorous methodology including a report of our search strategy
and inclusion criteria, exclusion of non-randomised studies,
independent data extraction by two reviewers, and use of an
intention-to-treat analysis, to ensure that the treatment effect
has not been overestimated. Second, we included non-English
RCTs in the analysis, and contacted investigators of potentially
eligible studies to either obtain dichotomous data or to exclude
patients with other functional GI disorders from the analysis.
This inclusive approach has ensured that we have identified
more relevant published articles than previous systematic
reviews in this area, including trials eligible for inclusion at
the time of other reviews but not successfully identified by the
authors. This has provided us with access to data for almost 800
IBS patients treated with antidepressants versus placebo, and
almost 1300 patients randomised to psychological therapies
versus control therapy or a physician’s ‘‘usual management.
Third, we have pooled data to give an overall treatment effect,
and a number needed to treat. Whilst this approach could be
criticised by some, owing to differences in the methodology of
Irritable bowel syndrome
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Figure 4 Forest plot of randomised controlled trials of psychological therapies versus control therapy or a physician’s ‘‘usual management’’ in irritable
bowel syndrome. CI, confidence interval; n, number of patients with persistent or unimproved symptoms; N, total number of patients treated;
RR, relative risk.
Irritable bowel syndrome
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individual included studies, we performed sensitivity analyses to
explore reasons for heterogeneity between studies, and to assess
effect of study location, design and setting on overall treatment
effect, which remained significant in all the subgroups we
examined. Finally, we have extracted and pooled adverse events
data. This has not been carried out by previous investigators,
and provides further useful data for both the physician and the
patient.
There are limitations of this systematic review and meta-
analysis, which arise owing to characteristics of the published
literature available for synthesis. Although eligible RCTs of
antidepressant therapy were of good to moderate quality, there
was evidence of heterogeneity between these studies and
publication bias. However, the difference in favour of anti-
depressants remained statistically significant when only higher
quality studies, according to the Jadad scale,
32
were considered
in the analysis. Heterogeneity was of borderline significance,
and was reduced when the effect of reporting the method of
concealment of allocation was examined, and publication bias
was no longer statistically significant when one small outlying
study was excluded from the analysis. Subgroup analyses
demonstrated that treatment effect was less in trials based in
tertiary-care settings, and RCTs that reported method of
generation of the randomisation schedule and concealment of
allocation. It is not surprising that antidepressant therapy was
less effective in subjects recruited in tertiary care, as these are
likely to be the patients whose symptoms are the most difficult
to treat. Our observation that studies that did not report the
method of generation of the randomisation schedule or
concealment of allocation tended to report an exaggerated
treatment effect is in line with reports from the systematic
review literature.
68
These issues may mean that the true
treatment effect has been overestimated, but there is still
evidence from our subgroup analyses that the use of anti-
depressants in IBS is beneficial. Furthermore, the RCT
conducted by Creed et al also randomised a large number of
IBS patients to antidepressant therapy with an SSRI,
64
and
compared their outcomes with those allocated to a physician’s
usual management. As this study did not have a placebo arm it
was not eligible for inclusion in the current meta-analysis,
but again there was a statistically significant improvement in
IBS symptoms in those receiving SSRI compared to usual
management.
Psychological therapies for IBS also seem to be effective, but
there are more serious issues regarding the validity of the
findings. There was significant heterogeneity when all studies
were combined, which raises concerns over the appropriateness
of such an approach, although as all these treatment modalities
address possible underlying psychological aspects of the condi-
tion we felt that this was useful and justified. When subgroup
analyses were conducted according to the type of psychological
intervention used this heterogeneity persisted, suggesting that it
was not entirely due to differences in the intervention applied.
There was also evidence of a large degree of publication bias,
and this remained when only RCTs of CBT, the intervention
with the most available published evidence, were considered. A
further concern was that nine of the eligible studies originated
from the same centre, and when a subgroup analysis was
conducted examining this issue there appeared to be a greater
treatment effect in these nine studies than in the 11 studies
emanating from other centres, though a statistically significant
difference was not detected.
Another concern common to eligible RCTs of antidepressants
and psychological therapies is a lack of adherence to recom-
mendations from the Rome committee for the design of
treatment trials for functional GI disorders.
69
Many of the
studies did not use the Rome criteria to define the presence of
IBS, did not provide evidence of a power calculation, did not use
a validated outcome measure to define treatment success and, in
the case of RCTs of psychological therapies, investigators were
blinded to treatment allocation in only three studies,
37 63 64
as in
this situation double-blinding would be difficult to achieve.
However, a significant proportion of the trials were designed
and conducted before these recommendations were made, and
many of the eligible studies do meet other methodological
criteria specified by these recommendations, such as a minimum
duration of therapy of 8–12 weeks, a parallel study design,
patient follow-up after therapy to assess symptoms, and use of
patient-reported improvement in symptoms. The fact that the
majority of trials only followed up patients for between 8 and
12 weeks means that the effect of both these therapies on IBS
symptoms in the longer term remains unknown. Finally, only
one of these eligible RCTs was conducted in primary care,
49
and
seven in secondary care,
36 52 56 58–61
meaning that the results may
not be generalisable to patients encountered in these settings.
It would appear from these data that both TCAs and SSRIs
are effective for the treatment of IBS. Only four patients need to
be treated to improve or cure one patient’s symptoms. This is an
important finding, as previous systematic reviews have given
conflicting evidence of their efficacy, and therefore current
national guidelines for the management of the condition from
the BSG, AGA and ACG make either conflicting or vague
recommendations for the role of antidepressant therapy in the
treatment of IBS.
29–31
SSRIs have a theoretical advantage in
being potentially better tolerated than TCAs. Imipramine has
been shown to prolong orocaecal and whole gut transit times,
whereas paroxetine decreases orocaecal transit time,
70
so it may
be that TCAs will work better in diarrhoea-predominant IBS
and SSRIs in constipation-predominant, although the studies
included did not evaluate this issue. The mechanism of action of
these drugs remains speculative, though it is plausible that they
have a general effect in increasing pain thresholds in IBS
sufferers, as they are beneficial in neuropathic pain.
71
It is also
possible that any improvement in symptoms following therapy
in these trials arose from the successful treatment of co-existent
depression. Data from the trials included in this review do not
support this hypothesis however. Three studies reported that
Figure 5 Funnel plot of randomised controlled trials of psychological
therapies versus control therapy or a physician’s ‘‘usual management’’ in
irritable bowel syndrome.
Irritable bowel syndrome
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there was no significant relationship between depression scores
and improvement in IBS symptoms,
55 57 58
and one RCT
reported that treatment effect with desipramine was better in
those without evidence of co-existent depression.
37
These
findings are consistent with a systematic review of 61 trials
evaluating antidepressants in neuropathic pain,
71
where there
was no correlation between symptom improvement and
depression score.
Psychological therapies for the treatment of IBS appear to
have a similar treatment effect, though often in groups of
patients in specialist centres who have failed pharmacological
treatment. As studies are small, and of poorer methodological
quality, no definitive proposal can be made concerning their
role, although when the nine studies of psychological therapies
conducted in the same centre were excluded in a sensitivity
analysis the remaining trials were larger, on average, than those
of antidepressant treatments. There appears to be the most
evidence for CBT, in terms of number of RCTs, but when the
three small trials emanating from a single centre were excluded
from the analysis there was no longer any beneficial effect of
CBT on IBS symptoms. Psychological therapies may have a role
for patients who do not respond to conventional medical
treatment, but further data from large, well-designed, high
quality RCTs are required before any firm recommendations for
their place in the management of IBS can be made.
In summary, this systematic review has demonstrated that
both antidepressants and psychological therapies, particularly
CBT, are efficacious in the treatment of IBS in the short-term,
with only four patients needing to be treated to improve or cure
one patient’s symptoms. Current guidelines for the manage-
ment of the condition should be updated to include this
important and novel information.
Acknowledgements: This study was performed to inform the American College of
Gastroenterology monograph on irritable bowel syndrome. We would like to thank Drs
A Foxx-Orenstein, W Chey, L Brandt, L Schiller, B Spiegel and E Achkar for their
contributions to the discussion concerning the role of antidepressants and
psychological therapies in the treatment of irritable bowel syndrome. We are grateful
to the following investigators for answering our data queries and, where applicable,
providing us with their original data sets for analysis: Drs P Boyce, K Cain, F Creed, D
Drossman, M Heitkemper, R Jones, K Sanders, P Seed, J Tack and B Tomenson. We
would also like to thank Dr P Bercik for assisting us with the translation of foreign
language articles.
Funding: This study was funded by the American College of Gastroenterology.
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