Effect of Antidepressants and Psychological Therapies, Including Hypnotherapy, in Irritable Bowel Syndrome: Systematic Review and Meta-Analysis

nature publishing group1350

The American Journal of GASTROENTEROLOGY VOLUME 109 | SEPTEMBER 2014 www.amjgastro.com

see related editorial on page x

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CLINICAL AND SYSTEMATIC REVIEWS

INTRODUCTION Irritable bowel syndrome (IBS) is one of the commonest functional gastrointestinal disorders worldwide, with a prev-alence of between 5 and 20 % , depending on the criteria used to define its presence ( 1 ). Although the condition is more common in women and in younger individuals, evidence for

the effect of socioeconomic status on prevalence is conflict-ing ( 2 ). Patients with IBS take more sickness-related absences from work than those without bowel symptoms ( 3 ). A recent burden-of-illness study in the United States estimated that IBS cost almost $ 1 billion in direct costs and another $ 50 million in indirect costs ( 4 ). In addition, patients with IBS

Effect of Antidepressants and Psychological Therapies, Including Hypnotherapy, in Irritable Bowel Syndrome: Systematic Review and Meta-Analysis Alexander C. Ford , MBChB, MD 1 , 2 , Eamonn M.M. Quigley , MD, FRCP, FACP, FACG, FRCPI 3 , Brian E. Lacy , MD, PhD 4 , Anthony J. Lembo 5 , Yuri A. Saito 6 , Lawrence R. Schiller , MD, MSHS, RFF, FACG, AGAF 7 , Edy E. Soff er 8 , Brennan M.R. Spiegel , MD, MSHS, RFF, FACG, AGAF 9 and Paul Moayyedi , MBChB, PhD, MPH, FACG 10

OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence relating to the treatment of this condition with antidepressants and psychological therapies continues to accumulate.

METHODS: We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Trials recruiting adults with IBS, which compared antidepressants with placebo, or psychological therapies with control therapy or “ usual management, ” were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95 % confi dence interval (CI).

RESULTS: The search strategy identifi ed 3,788 citations. Forty-eight RCTs were eligible for inclusion: thirty-one compared psychological therapies with control therapy or “ usual management, ” sixteen compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis. The RR of IBS symptom not improving with antidepressants vs. placebo was 0.67 (95 % CI = 0.58 – 0.77), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms not im-proving with psychological therapies was 0.68 (95 % CI = 0.61 – 0.76). Cognitive behavioral therapy, hypnotherapy, multicomponent psychological therapy, and dynamic psychotherapy were all benefi cial.

CONCLUSIONS: Antidepressants and some psychological therapies are effective treatments for IBS. Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained remarkably stable.

Am J Gastroenterol 2014; 109:1350–1365; doi: 10.1038/ajg.2014.148; published online 17 June 2014

1 Leeds Gastroenterology Institute, St James ’ s University Hospital , Leeds , UK ; 2 Leeds Institute of Biomedical and Clinical Sciences, University of Leeds , Leeds , UK ; 3 Division of Gastroenterology and Hepatology, Department of Medicine, Houston Methodist Hospital , Houston , Texas , USA ; 4 Dartmouth-Hitchcock Medical Center, Gastroenterology , Lebanon, New Hampshire, USA ; 5 The Beth Israel Deaconess Medical Center , Boston , Massachusetts , USA ; 6 Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , Minnesota , USA ; 7 Digestive Health Associates of Texas, Baylor University Medical Center , Dallas , Texas , USA ; 8 Division of Gastroenterology at Cedars-Sinai, University of Southern California , Los Angeles , Califoria , USA ; 9 Department of Gastroenterology, VA Greater Los Angeles Healthcare System , Los Angeles , California , USA ; 10 Division of Gastroenterology, McMaster University, Health Sciences Center , Hamilton , Ontario , Canada . Correspondence: Alexander C. Ford, MBChB, MD , Leeds Gastroenterology Institute, St James ’ s University Hospital , Beckett Street , Room 125, 4th Floor, Bexley Wing, Leeds LS9 7TF UK . E-mail: [email protected] Received 25 February 2014; accepted 29 April 2014

CME

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Antidepressants and Psychological Therapies in IBS

consume > 50 % more health-care resources than matched controls without IBS ( 5 ).

Eff ective treatment of IBS is therefore extremely important for the individual, health-care systems, and society as a whole. However, the cause of IBS remains obscure, meaning that there is no single unifying explanation for the symptoms toward which therapy can be targeted. Patients with IBS demonstrate visceral hypersensitivity to painful stimuli ( 6,7 ), abnormal cen-tral processing of pain ( 8 ), and higher levels of psychological comorbidity compared with healthy controls without IBS ( 9,10 ). As a result, antidepressants, which have pain-modifying proper-ties ( 11,12 ), and psychological therapies have been proposed as potential treatments for IBS.

Despite the fact that the use of antidepressants in IBS is wide-spread ( 13 ), until recently the evidence for their effi cacy was dis-puted, partly owing to the fact that previous systematic reviews and meta-analyses that had examined this issue had limitations ( 14 ). In addition, despite the fact that the use of psychological therapies is recommended for the management of IBS by previ-ous guidelines ( 15,16 ), access to these interventions is limited in some countries, and there may also be a reluctance on the part of physicians to consider referral ( 17 ). In our previous systematic review and meta-analysis ( 18 ), conducted to inform the American College of Gastroenterology ’ s monograph on the management of IBS ( 15 ), we summarized all available evidence for both antide-pressants and psychological therapies up to 2009. However, in the intervening 5 years, there has been a considerable amount of evi-dence published. We have therefore re-examined this issue.

METHODS Search strategy and study selection We updated our previous systematic review and meta-analy-sis ( 18 ). A search of the medical literature was conducted using MEDLINE (1946 to December 2013), EMBASE, and EMBASE Classic (1947 to December 2013), and the Cochrane central register of controlled trials. Randomized controlled trials (RCT) examining the eff ect of antidepressants and psychological thera-pies in adult patients (over the age of 16 years) with IBS were eligible for inclusion ( Box 1 ). Th e fi rst period of crossover RCTs, before crossover to the second treatment, were also eligible for inclusion. In the case of antidepressant trials, the control arms were required to receive placebo, whereas for studies of psycho-logical therapies the control arm could receive placebo, symptom monitoring (including waiting list control), or a physician ’ s “ usual management. ”

Duration of therapy had to be at least 7 days. Th e diagnosis of IBS could be based on either a physician ’ s opinion or symptom-based diagnostic criteria, supplemented by the results of investiga-tions to exclude organic disease, where the investigators 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, aft er completion of therapy, 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 IBS among patients with other functional gastroin-testinal 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.

Th e literature search was performed as part of a broader exer-cise to inform an update of the American College of Gastroen-terology ’ s monograph on the management of IBS. Specifi cally, studies on IBS were identifi ed with the terms irritable bowel syndrome and functional diseases, colon (both as medical sub-ject heading and free text terms), and IBS , spastic colon , irri-table colon , or functional adj5 bowel (as free text terms). Th ese were combined using the set operator AND with studies identi-fi ed with the following terms: psychotropic drugs , antidepressive agents , antidepressive agents (tricyclic) , desipramine , imipramine , trimipramine , doxepin, dothiepin, nortriptyline , amitriptyline , selective serotonin reuptake inhibitors , paroxetine, sertraline, fl uoxetine, citalopram, venlafaxine, cognitive therapy, psychother-apy, behavior therapy, relaxation techniques, or hypnosis (both as medical subject heading terms and free text terms). Th e fol-lowing free text terms were used: behavioral therapy , relaxation therapy , or hypnotherapy .

Th ere were no language restrictions, and abstracts of the papers identifi ed by the initial search were evaluated by the lead reviewer for appropriateness to the study question, and all potentially rel-evant papers were obtained and evaluated in detail. Foreign lan-guage papers were translated where necessary. Abstract books of conference proceedings between 2001 and 2013 were hand-searched to identify potentially eligible studies published only in abstract form. Th e bibliographies of all identifi ed relevant studies were used to perform a recursive search of the literature. Articles were independently assessed by two reviewers using predesigned eligibility forms, according to the prospectively defi ned eligibility criteria. Any disagreement between investigators was resolved by consensus.

Box 1. Eligibility criteria

Randomized controlled trials. Adults (participants aged > 16 years). Diagnosis of IBS based on either a clinician ’ s opinion or meeting specifi c diagnostic criteria * , supplemented by negative investigations where trials deemed this necessary. Comparison of antidepressants with placebo, or psychological therapies with a control therapy, including a physician ’ s “ usual management, ” symptom monitoring, supportive therapy, or placebo . Minimum duration of therapy 7 days. Minimum duration of follow-up 7 days. Dichotomous assessment of response to therapy in terms of effect on global IBS symptoms or abdominal pain following therapy. † * Manning, Kruis score, Rome I, II, or III. † Preferably patient-reported, but if this was not available then as assessed by a physician or questionnaire data.


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Data synthesis and statistical analysis Data were pooled using a random-effects model ( 20 ), to give a more conservative estimate of the effect of antidepressants and psychological therapies, allowing for any heterogeneity between studies. The impacts of different interventions were expressed as a relative risk (RR) of global IBS symptoms or abdominal pain not improving with intervention compared with control with 95 % confidence intervals (CIs). Adverse events data were also summarized with RRs. The number needed to treat (NNT) and the number needed to harm, with 95 % CIs, were calculated from the reciprocal of the risk differ-ence of the meta-analysis.

Heterogeneity, which is variation between individual study results arising as a result of either diff erences in study partici-pants or methodology, was assessed using both the I 2 statistic with a cutoff of ≥ 50 % , and the χ 2 test with a P -value < 0.10, used to defi ne a signifi cant degree of heterogeneity ( 21 ). Where the degree of statistical heterogeneity was greater than this between-trial results in this meta-analysis, possible explanations were investigated using subgroup analyses according to the type of antidepressant or psychological therapy used, trial setting, cri-teria used to defi ne IBS, whether method of randomization or concealment of allocation were reported, level of blinding, risk of bias of included trials, and, for trials of psychological therapies, method of handling of the control arm. We compared individual RRs between these analyses using the Cochran Q statistic. Th ese were exploratory analyses only, and they may explain some of the observed variability, but the results should be interpreted with caution.

Review Manager version 5.1.4 (RevMan for Windows 2008, the Nordic Cochrane Centre, Copenhagen, Denmark) and Stats-Direct version 2.7.7 (StatsDirect, Cheshire, England) were used to generate Forest plots of pooled RRs and risk diff erences for primary and secondary outcomes with 95 % CIs, as well as fun-nel plots. Th e latter were assessed for evidence of asymmetry, and therefore possible publication bias or other small study eff ects, using the Egger test ( 22 ), if there were suffi cient (10 or more) eli-gible studies included in the meta-analysis, in line with recent recommendations ( 23 ).

RESULTS Th e search strategy identifi ed a total of 3,788 citations, of which 92 published articles appeared to be relevant and were retrieved for further assessment ( Figure 1 ). Of these 92 articles, 46 were excluded for various reasons, leaving 46 eligible articles, 29 of which compared psychological therapies with control therapy in the form of symptom monitoring, physician ’ s “ usual manage-ment, ” or supportive therapy, 16 compared antidepressants with placebo, and one compared both psychological therapies and antidepressants with placebo. Agreement between reviewers for assessment of trial eligibility was excellent (kappa statistic = 0.93). Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis.

Outcome assessment Th e primary outcomes assessed were the eff ects of antidepressants compared with placebo, and the eff ects of psychological therapies compared with control therapy or a physician ’ s “ usual manage-ment, ” on global IBS symptoms or abdominal pain aft er cessation of therapy. Secondary outcomes included assessing effi cacy accord-ing to a specifi c type of antidepressant or psychological therapy, and adverse events occurring as a result of therapy.

Data extraction All data were extracted independently by two reviewers on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft , Redmond, WA) as dichotomous outcomes (global IBS symp-toms unimproved, or abdominal pain unimproved; Box 2 ). In addition, the following clinical data were extracted for each trial: setting (primary, secondary, or tertiary care-based), number of centers, 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 defi ne IBS, primary outcome measure used to defi ne symp-tom improvement 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, with all drop-outs assumed to be treatment failures, wherever trial reporting allowed this.

Assessment of risk of bias Th is was performed independently by two investigators, with disagreements resolved by discussion. Risk of bias was assessed as described in the Cochrane handbook ( 19 ), by recording the method used to generate the randomization schedule and conceal allocation, whether blinding was implemented, what proportion of patients completed follow-up, whether an intention-to-treat analysis was extractable, and whether there was evidence of selective reporting of outcomes.

Box 2. Data extraction methodology

Outcome of interest: Improvement in global IBS symptoms preferable; if this was not reported then improvement in abdominal pain. Reporting of outcomes: Patient-reported was preferable; if this was not available then investigator-reported. Time of assessment: Upon completion of therapy. Denominator used: True intention-to-treat analysis; if this was not available then all evaluable patients. Cutoff used for dichotomization: Any improvement in global IBS symptoms or abdominal pain for Likert-type scales, investigator-defi ned improvement for continuous scales; if no investigator defi nition was available then we used ≥ 1 s.d. decrease in symptom score from baseline to completion of therapy (we assessed if the use of any decrease in symp-tom score from baseline to completion of therapy altered our analysis).


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Effi cacy of antidepressants in the treatment of IBS In total, there were 17 RCTs comparing antidepressants with placebo in the treatment of IBS ( 24 – 40 ), which evaluated 1,084 patients, 592 of whom received active therapy and 492 received placebo. Ten trials used tricyclic antidepressants (TCAs) ( 24 – 26,28,29,34 – 38 ), six used selective serotonin reuptake inhibi-tor (SSRIs) ( 27,30,31,33,39,40 ), and one studied both ( 32 ). Only three of the RCTs were at a low risk of bias ( 36,38,39 ). Th e propor-tion of female patients recruited by trials ranged from 42 to 100 % . Th e majority of trials did not diff erentiate between the type of IBS patients recruited, with only seven studies providing data on this ( 27,30,31,33 – 35,39 ), one of which recruited only IBS-C patients ( 33 ) and another recruited only IBS-D patients ( 34 ). Detailed characteristics of individual RCTs are provided in Table 1 .

Overall, 260 (43.9 % ) of 592 patients assigned to antidepressant therapy reported unimproved IBS symptoms following therapy, compared with 330 (65.0 % ) of 508 patients allocated to placebo. Th e RR of IBS symptoms not improving aft er treatment with anti-depressant therapy vs. placebo was 0.67 (95 % CI = 0.58 – 0.77), with marginally signifi cant heterogeneity detected between studies

( I 2 = 37 % , P = 0.06; Figure 2 ). Th ere was statistically signifi cant asymmetry in the funnel plot (Egger test, P = 0.05), suggesting publication bias or other small study eff ects; however, this was driven by the TCA arm of one small study ( 32 ) and disappeared with its exclusion from the analysis (Egger test, P = 0.13). Th e NNT with antidepressants was 4 (95 % CI = 3 – 6).

Subgroup analyses were conducted ( Table 2 ). Treatment eff ect appeared to be increased in secondary care-based studies, studies that did not state the method of generation of the randomization schedule or method of concealment of allocation, and studies at a high or unclear risk of bias. A statistically signifi cant diff erence in treatment eff ect was detected for study setting and level of blind-ing only.

Th e eff ect of antidepressant therapy on abdominal pain was reported by seven RCTs ( 26,27,30,33 – 35,38 ), with 87 (47.8 % ) of 182 patients receiving antidepressants having no improvement in abdominal pain following treatment, compared with 123 (72.8 % ) of 169 subjects allocated to placebo, and the RR of abdominal pain not improving was 0.62 (95 % CI = 0.43 – 0.88), with considerable heterogeneity between studies ( I 2 = 72.4 % , P = 0.001).

Effi cacy of TCAs in the treatment of IBS . Eleven RCTs compared TCAs with placebo, including a total of 744 patients ( 24 – 26,28,29,32,34 – 38 ). Of 416 patients receiving active therapy, 180 (43.3 % ) had no improvement in symptoms aft er treatment, compared with 209 (63.7 % ) of 328 receiving placebo. Th e RR of IBS symptoms not improving with TCAs compared with placebo was 0.66 (95 % CI = 0.56 – 0.79), with no statistically signifi cant hetero-geneity detected between studies ( I 2 = 35 % , P = 0.12; Figure 2 ), and evidence of funnel plot asymmetry (Egger test, P = 0.02). Again, this was driven by one study ( 32 ), and when this was removed from the analysis there was no longer statistically signifi cant publication bias (Egger test, P = 0.06). Th e NNT with TCAs was 4 (95 % CI = 3 – 6).

Effi cacy of SSRIs in the treatment of IBS . Seven trials compared SSRIs with placebo in a total of 356 patients ( 27,30 – 33,39,40 ). In all, 80 (45.5 % ) of 176 patients allocated to SSRIs had no improve-ment in symptoms following therapy, compared with 121 (67.2 % ) of 180 placebo patients . Th e RR of IBS symptoms not improving with SSRIs compared with placebo was 0.68 (95 % CI = 0.51 – 0.91), but with statistically signifi cant heterogeneity between studies ( I 2 = 49 % , P = 0.07; Figure 2 ). Th e NNT with SSRIs was 4 (95 % CI = 2.5 – 20).

Adverse events with antidepressant therapy Only seven trials reported on overall adverse events with antide-pressants vs. placebo ( 25 – 28,31,35,37 ). In total, 65 (31.3 % ) of 208 patients assigned to antidepressants experienced adverse events, compared with 33 (16.5 % ) of 200 patients allocated to placebo. When data were pooled, the incidence of adverse events was signifi cantly higher among those taking antidepressants (RR of experiencing any adverse event = 1.63; 95 % CI = 1.18 – 2.25). Th e number needed to harm was 9 (95 % CI = 5 – 111). Th ere were no serious adverse events. Drowsiness and dry mouth were more

Excluded (n=46) because:

•

•

••

•

•

•

•

•

No dichotomous data reported=10

Dual publication=9

Not the control intervention ofinterest=5

Cross-over study with noextractable data=4

No placebo or comparator arm=4

Not randomized=3

Review article=2

Study protocol only=1

Studies identified in literaturesearch (n=3,788)

Studies retrieved for evaluation(n=92)

Excluded (title and abstract revealednot appropriate) (n=3,696)

Outcome of interest not reported=8

Eligible studies (n=46):Psychologicaltherapies=29Antidepressants=16Psychologicaltherapies andantidepressants=1

•

••

Figure 1 . Flow diagram of assessment of studies identifi ed in the updated systematic review and meta-analysis.


1354R

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Tabl

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tics

of r

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ple

size

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of

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Patie

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min

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44 (N

ot

repo

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D

esip

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2

Mon

ths

Met

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of ra

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and

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61 (5

5)

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42 (N

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83 (N

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35 (8

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Pa

tient

-rep

orte

d 50

%

decr

ease

in d

ays

with

sy

mpt

oms

23 (7

8)

Cita

lopr

am 2

0 m

g o.

d. fo

r 3 w

eeks

in

crea

sing

to 4

0 m

g o.

d. fo

r nex

t 3 w

eeks

6 W

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of

allo

catio

n st

ated

. Dou

ble-

blin

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Talle

y ( 3

2 )

Aust

ralia

Te

rtiar

y ca

re

Rom

e II

and

inve

stig

atio

ns

Patie

nt-r

epor

ted

adeq

uate

re

lief o

f sym

ptom

s 51

(61)

Im

ipra

min

e 50

mg

o.d.

or c

italo

pram

40

mg

o.d.

12 W

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of

allo

catio

n st

ated

. Dou

ble-

blin

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Tabl

e 1

cont

inue

d on

follo

win

g pa

ge


1355

REV

IEW


common in patients randomized to TCAs than those receiving placebo.

Effi cacy of psychological therapies in the treatment of IBS Th ere were a total of 30 articles, reporting on 32 separate RCTs, comparing various psychological therapies with control therapy in the form of symptom monitoring, physician ’ s “ usual manage-ment, ” supportive therapy, or placebo for the treatment of IBS in a total of 2,189 patients ( 36,41 – 69 ). Six RCTs used cognitive behav-ioral therapy (CBT) ( 36,46,50,53,57,59 ); fi ve trials used relaxation training or therapy ( 42,49,51,58,69 ); fi ve RCTs, reported in four separate articles, used hypnotherapy ( 45,56,65,67 ); four trials, reported in three separate articles, used multicomponent psycho-logical therapy ( 41,48,52 ); two RCTs used self-administered or minimal-contact CBT ( 54,68 ); two trials used Internet-delivered CBT ( 62,66 ); two RCTs used dynamic psychotherapy ( 44,47 ); one trial used mindfulness meditation training ( 61 ); one RCT used stress management ( 55 ); one trial used stress management or CBT ( 60 ); one RCT used CBT or self-administered CBT ( 64 ); one trial used multicomponent psychological therapy delivered in-person or mainly via the telephone ( 63 ); and one RCT used CBT or relax-ation therapy ( 43 ).

Th e control arm received symptom monitoring in 16 RCTs, reported in 15 articles ( 41,42,45,46,49,51 – 54,57,59,60,62,64,66 ); usual care in 13 trials, reported in 12 articles ( 43,44,47,48,50,55,58,63,65,67 – 69 ); supportive therapy in 2 RCTs ( 56,61 ); and placebo in 1 trial ( 36 ). None of the trials were at a low risk of bias, owing to the inability to blind participants to the nature of the intervention received. Th e proportion of female patients recruited by trials ranged from 52 to 100 % . Detailed character-istics of individual trials are provided in Table 3 . Adverse events data were poorly reported by included RCTs, precluding any meaningful analysis.

Overall, IBS symptoms did not improve in 639 (51.9 % ) of 1,232 patients receiving psychological therapies, compared with 839 (76.1 % ) of 1,102 receiving control in the form of symptom moni-toring, physician ’ s “ usual management, ” supportive therapy, or pla-cebo. Th e RR of IBS symptoms not improving with psychological therapies was 0.68 (95 % CI = 0.61 – 0.76; Figure 3 ), with consider-able heterogeneity detected between studies ( I 2 = 71 % , P < 0.001), and evidence of funnel plot asymmetry, or other small study eff ects (Egger test, P < 0.001), with a lack of small studies showing no eff ect of psychological therapies on the symptoms of IBS ( Figure 4 ). Th e NNT with psychological therapies was 4 (95 % CI = 3 – 5).

Subgroup analyses were conducted ( Table 4 ). Treatment eff ect appeared to be increased in tertiary care-based studies, RCTs that used clinical criteria to defi ne IBS, studies that did not state the method of generation of the randomization schedule or method of concealment of allocation, unblinded studies, and studies that used waiting list control as the comparison. A statistically signifi -cant diff erence in treatment eff ect was detected for concealment of allocation and level of blinding only.

Effi cacy of CBT in IBS . Nine trials compared CBT with control therapy in 610 patients ( 36,43,46,50,53,57,59,60,64 ). Symptoms Ta

ble

1 . C

ontin

ued

Stud

y Co

untr

y Se

ttin

g

Dia

gnos

tic

crite

ria u

sed

for

IBS

Crite

ria u

sed

to d

efi n

e sy

mpt

om im

prov

emen

t fo

llow

ing

ther

apy

Sam

ple

size

( %

fem

ale)

An

tidep

ress

ant

used

D

urat

ion

of

ther

apy

Met

hodo

logy

Vahe

di ( 3

4 )

Iran

Seco

ndar

y ca

re

Rom

e II

and

inve

stig

atio

ns

Patie

nt-r

epor

ted

impr

ove-

men

t in

glob

al s

ympt

oms

54 (4

4)

Amitr

ipty

line

10 m

g o.

d.

2 M

onth

s M

etho

d of

rand

omiz

atio

n st

ated

. Met

hod

of c

on-

ceal

men

t of a

lloca

tion

not s

tate

d. D

oubl

e-bl

ind.

U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Abdu

l-Bak

i ( 3

7 )

Leba

non

Prim

ary,

se

cond

ary,

and

te

rtiar

y ca

re

Rom

e II

Patie

nt-r

epor

ted

relie

f of

glob

al s

ympt

oms

107

(42)

Im

pira

min

e 25

mg

o.d.

titra

ted

up to

b.

i.d.

12 W

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of

allo

catio

n st

ated

. Dou

ble-

blin

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Mas

and

( 40 )

U

SA

Terti

ary

care

R

ome

II an

d in

vest

igat

ions

Pa

tient

-rep

orte

d im

prov

e-m

ent i

n gl

obal

sym

ptom

s 72

(88)

Pa

roxe

tine

12.5

mg

o.d.

incr

ease

d to

50

mg

o.d.

12 W

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of

allo

catio

n no

t sta

ted.

Dou

ble-

blin

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Lada

baum

( 3

9 )

USA

Pr

imar

y,

seco

ndar

y, a

nd

terti

ary

care

Rom

e II

and

inve

stig

atio

ns

Patie

nt-r

epor

ted

adeq

uate

re

lief o

f glo

bal s

ympt

oms

54 (8

2)

Cita

lopr

am 2

0 m

g o.

d. fo

r 4 w

eeks

th

en 4

0 m

g o.

d. fo

r 4

wee

ks

8 W

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of

allo

catio

n st

ated

. Dou

ble-

blin

d. F

iber

and

lope

ra-

mid

e al

low

ed

Gha

dir (

38 )

Iran

Seco

ndar

y ca

re

Rom

e III

Pa

tient

-rep

orte

d im

prov

e-m

ent i

n ab

dom

inal

pai

n 62

(Not

re

porte

d)

Dox

epin

or n

ortip

tyl-

ine

10 m

g o.

d.

2 M

onth

s M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of

allo

catio

n st

ated

. Dou

ble-

blin

d. U

ncle

ar if

oth

er

IBS

med

icat

ions

allo

wed

b.i.d

., tw

ice-

daily

; o.d

., on

ce-d

aily

; IB

S, ir

ritab

le b

owel

syn

drom

e.


1356R

EVIE

W Ford et al.

no signifi cant heterogeneity detected between studies ( I 2 = 0 % , P = 0.43). Th e NNT with hypnotherapy was 4 (95 % CI = 3 – 8).

Effi cacy of multicomponent psychological therapy in IBS . Five separate RCTs, again reported in four articles ( 41,48,52,63 ), compared multicomponent psychological therapy with control therapy in 335 patients. Symptoms of IBS were not improved in 96 (57.1 % ) of 168 patients randomized to multicomponent psy-chological therapy, compared with 135 (80.8 % ) of 167 receiving control. Th e RR of IBS symptoms not improving was 0.72 (95 % CI = 0.62 – 0.83; Figure 3 ), with no signifi cant heterogeneity de-tected between studies ( I 2 = 0 % , P = 0.64). Th e NNT with multi-component psychological therapy was 4 (95 % CI = 3 – 7).

Effi cacy of self-administered or minimal-contact CBT in IBS . Th ree trials, involving 144 patients, used self-administered or min-imal-contact CBT ( 54,64,68 ). Overall, 34 (46.6 % ) of 73 patients allocated to receive self-administered or minimal-contact CBT reported no improvement in symptoms, compared with 63 (88.7 % ) of 71 assigned to control. Th e RR of IBS symptoms not improving with self-administered or minimal-contact CBT was 0.53 (95 % CI = 0.17 – 1.66), with signifi cant heterogeneity detected between individual study results ( I 2 = 96 % , P < 0.001).

of IBS did not improve in 145 (41.5 % ) of 349 patients assigned to CBT, compared with 166 (63.6 % ) of 261 patients allocated to control, with an RR of 0.60 (95 % CI = 0.44 – 0.83; Figure 3 ), and statistically signifi cant heterogeneity between studies ( I 2 = 70 % , P < 0.001). Th e NNT with CBT was 3 (95 % CI = 2 – 6).

Effi cacy of relaxation training or therapy in IBS . Six RCTs compared relaxation training or therapy with control therapy in 255 patients ( 42,43,49,51,58,69 ). IBS symptoms did not improve in 96 (72.2 % ) of 133 patients randomized to relaxation training or therapy, compared with 107 (87.7 % ) of 122 patients receiving con-trol therapy. Overall, no benefi t of relaxation training or therapy in IBS was detected (RR of symptoms not improving = 0.77; 95 % CI = 0.57 – 1.04; Figure 3 ), and there was statistically signifi cant heterogeneity between studies ( I 2 = 71 % , P = 0.004).

Effi cacy of hypnotherapy in IBS . Five separate trials, reported in four articles ( 45,56,65,67 ), compared hypnotherapy with con-trol therapy in 278 patients. IBS symptoms did not improve in 77 (54.6 % ) of 141 patients assigned to hypnotherapy, compared with 106 (77.4 % ) of 137 allocated to control therapy. Overall, hypnotherapy was of benefi t in IBS, and the RR of symptoms not improving was 0.74 (95 % CI = 0.63 – 0.87; Figure 3 ), with

1.1.1 Tricyclic antidepressants

1.1.2 Selective serotonin re-uptake inhibitors

Heefner, 1978 105

1416

51460

80

3414

925

655

1515

80

260592

330508

19442211173627

176

21462212163627

180

12361911

52612

121

180 209

223021421925

11527185938

416 328

1210211914203616

53620

22 4.5% 19781982198419881991199120032008200820092011

0.83 (0.46, 1.51)0.52 (0.20, 1.33)0.67 (0.50, 0.92)0.82 (0.50, 1.36)0.30 (0.14, 0.65)0.70 (0.47, 1.04)0.83 (0.63, 1.08)0.50 (0.26, 0.97)0.08 (0.00, 1.36)0.77 (0.58, 1.01)0.44 (0.28, 0.70)0.66 (0.56, 0.79)

0.83 (0.45, 1.51) 2003200420052006200820092010

0.73 (0.54, 0.98)0.32 (0.16, 0.64)0.50 (0.25, 0.97)0.94 (0.33, 2.65)0.58 (0.37, 0.89)1.25 (0.73, 2.15)0.68 (0.51, 0.91)

0.67 [0.58, 0.77]

2.1%9.8%5.6%3.0%7.5%

11.0%3.8%0.3%

10.7%6.5%

4.4%10.0%

3.5%3.7%1.8%6.8%5.1%

35.3%

0.1

Favorsantidepressants

Favors placebo0.2 0.5 1 2 5 10

100.0%

64.7%

31214116255727164824

Myren, 1982Nigam, 1984Boerner, 1988Bergmann, 1991Vij, 1991Drossman, 2003Vahedi, 2008Talley, 2008Abdul-Baki, 2009Ghadir, 2011

Kuiken 2003Tabas 2004Vahedi 2005Tack 2006Talley 2008Masand 2009Ladabaum 2010

Total events

Total events

Subtotal (95% Cl)

Subtotal (95% Cl)Total eventsHeterogeneity: !2 = 0.03; "2 = 15.31, d.f. = 10 (P = 0.12); l2 = 35%Test for overall effect: Z = 4.61 (P < 0.00001)

Heterogeneity: !2 = 0.07; "2 = 11.85, d.f. = 6 (P = 0.07); l2 = 49%

Heterogeneity: !2 = 0.03; "2 = 27.09, d.f. = 17 (P = 0.06); l2 = 37%

Test for overall effect: Z = 2.57 (P = 0.01)

Test for overall effect: Z = 5.39 (P = 0.00001)Test for subgroup differences: "2 = 0.02, d.f. = 1 (P = 0.88), l2 = 0%

Total (95% Cl)

Study or subgroupAntidepressants Placebo

Events Total Events Total Weight M-H, Random, 95% Cl M-H, Random, 95% ClRisk ratio Risk ratio

Year

Figure 2 . Forest plot of randomized controlled trials of antidepressants vs. placebo in irritable bowel syndrome.


1357

REV

IEW


Effi cacy of CBT delivered via the Internet in IBS . Th ere were two trials that delivered CBT via the Internet, containing 140 patients ( 62,66 ). Among 71 patients randomized to CBT via the Internet, 51 (71.8 % ) reported no improvement in symptoms. Th is compared with 68 (98.6 % ) of 69 allocated to control therapy. Th e RR of IBS symptoms not improving with CBT via the Inter-net was 0.75 (95 % CI = 0.48 – 1.17), with signifi cant heterogeneity between the two RCTs ( I 2 = 90 % , P = 0.002).

Effi cacy of dynamic psychotherapy in IBS . Two RCTs compared dynamic psychotherapy with control therapy in 273 patients ( 44,47 ). No improvement in IBS symptoms was reported by 61 (44.2 % ) of 138 patients randomized to dynamic psycho therapy, compared with 95 (70.4 % ) of 135 patients receiving control; the RR of symptoms not improving was 0.60 (95 % CI = 0.39 – 0.93; Figure 3 ), and the NNT was 3.5 (95 % CI = 2 – 25 ). Again there was signifi cant heterogeneity between studies ( I 2 = 72 % , P = 0.06).

Effi cacy of stress management in IBS . Th ere were two trials using this therapy ( 55,60 ), involving 98 patients. Overall, 24 (40.7 % ) of 59 patients assigned to stress management reported no improvement in IBS symptoms, compared with 23 (59.0 % ) of 39 allocated to control. Th ere was no benefi cial eff ect detected for

stress management in IBS (RR = 0.63; 95 % CI = 0.19 – 2.08), and there was signifi cant heterogeneity between studies ( I 2 = 83 % , P = 0.02).

Effi cacy of multicomponent psychological therapy mainly via the telephone or mindfulness meditation training in IBS . Th ere was only one study that used each of these treatment modalities ( 61,63 ). Multicomponent psychological therapy mainly via the telephone appeared to be benefi cial in IBS (RR of symp-toms not improving = 0.78; 95 % CI = 0.64 – 0.93) ( 63 ), but there was no benefi t with mindfulness meditation training (RR = 0.57; 95 % CI = 0.32 – 1.01) ( 61 ).

DISCUSSION Th is updated systematic review and meta-analysis has demon-strated that antidepressants and psychological therapies are eff ec-tive treatments for IBS. Th e NNT for both TCA s and SSRIs was 4, although in the latter instance there was signifi cant heterogeneity between studies and widening of the 95 % CI of eff ect. Adverse events were signifi cantly higher among those taking antidepres-sants, with a number needed to harm of 9. When all psycho-logical therapies, including hypnotherapy, were considered the NNT was again 4. Cognitive behavioral therapy, hypnotherapy,

Table 2 . Subgroup analyses of randomized controlled trials of antidepressants vs. placebo in IBS

Number of

trials Number of patients

Relative risk of IBS symptoms not improving (95 % confi dence interval)

P value for the difference I 2 ( P value)

Setting

Secondary care 8 431 0.55 (0.43 – 0.70) 0.04 39 % (0.12)

Tertiary care 8 508 0.74 (0.63 – 0.86) 0 % (0.51)

Criteria used to defi ne IBS

Rome 12 785 0.66 (0.55 – 0.81) 0.92 48 % (0.03)

Clinical diagnosis 6 315 0.67 (0.54 – 0.83) 12 % (0.34)

Method of randomization

Stated 11 740 0.69 (0.57 – 0.85) 0.53 48 % (0.04)

Not stated 7 360 0.63 (0.51 – 0.77) 8 % (0.37)

Concealment of allocation

Stated 6 518 0.76 (0.61 – 0.94) 0.13 47 % (0.09)

Not stated 12 582 0.61 (0.50 – 0.73) 23 % (0.21)

Blinding

Double 17 1,065 0.69 (0.60 – 0.79) 0.04 28 % (0.38)

Not stated 1 35 0.30 (0.14 – 0.65) NA

Risk of bias

Low 3 288 0.76 (0.46 – 1.27) 0.60 78 % (0.01)

Unclear or high 15 812 0.66 (0.57 – 0.76) 18 % (0.26)

IBS, irritable bowel syndrome; NA, not applicable.


1358R

EVIE

W Ford et al.

Tabl

e 3 .

Cha

ract

eris

tics

of r

ando

miz

ed c

ontr

olle

d tr

ials

of

psyc

holo

gica

l the

rapi

es v

s. c

ontr

ol in

IB

S

Stud

y

Coun

try

Sett

ing

Dia

gnos

tic c

riter

ia

used

for

IB

S

Crite

ria u

sed

to d

efi n

e sy

mpt

om im

prov

emen

t fo

llow

ing

ther

apy

Sam

ple

size

Ps

ycho

logi

cal t

hera

py u

sed

Met

hodo

logy

Nef

f ( 52

) U

SA

Terti

ary

care

Cl

inic

al d

iagn

osis

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

19 (7

9)

Mul

ticom

pone

nt p

sych

olog

ical

ther

apy

cons

istin

g of

two

1-h

sess

ions

per

wee

k fo

r 4 w

eeks

of a

com

-bi

natio

n of

rela

xatio

n th

erap

y, th

erm

al b

iofe

edba

ck,

educ

atio

n an

d tra

inin

g in

stre

ss c

opin

g st

rate

gies

th

en o

ne s

essi

on p

er w

eek

for a

furth

er 4

wee

ks

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Lync

h ( 5

1 )

Cana

da

Terti

ary

care

Cl

inic

al d

iagn

osis

≥ 5

0 % R

educ

tion

in d

iary

ra

ting

of s

ympt

oms

21 (6

7)

One

2-h

rela

xatio

n th

erap

y se

ssio

n pe

r wee

k fo

r 8

wee

ks, w

ith a

udio

tape

s to

pra

ctic

e re

laxa

tion

tech

niqu

es tw

ice

daily

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Gut

hrie

( 47 )

En

glan

d Te

rtiar

y ca

re

Clin

ical

dia

gnos

is

and

inve

stig

atio

ns

Patie

nt-r

epor

ted

impr

ove-

men

t in

glob

al s

ympt

oms

102

(75)

O

ne 2

-h d

ynam

ic p

sych

othe

rapy

ses

sion

follo

wed

by

six

furth

er s

essi

ons

over

3 m

onth

s, a

nd a

rela

xa-

tion

audi

otap

e pr

ovid

ed fo

r use

at h

ome

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. N

o ne

w IB

S m

edic

a-tio

ns a

llow

ed b

ut c

ould

con

tinue

on

cur

rent

ther

apy

Shaw

( 55 )

W

ales

Te

rtiar

y ca

re

Clin

ical

dia

gnos

is

and

inve

stig

atio

ns

Patie

nt-r

epor

ted

over

all

bene

fi t fr

om tr

eatm

ent

35 (5

7)

One

40-

min

stre

ss m

anag

emen

t tec

hniq

ue s

essi

on

per w

eek

for a

t lea

st 4

wee

ks (t

otal

num

ber o

f ses

-si

ons

was

fl ex

ible

)

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Bla

ncha

rd

( 41 )

U

SA

Terti

ary

care

Cl

inic

al d

iagn

osis

an

d in

vest

igat

ions

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

20 (8

5) a

nd

77 (6

6) a

Mul

ticom

pone

nt p

sych

olog

ical

ther

apy

cons

istin

g of

two

1-h

sess

ions

per

wee

k fo

r 4 w

eeks

of a

com

-bi

natio

n of

rela

xatio

n th

erap

y, th

erm

al b

iofe

edba

ck,

educ

atio

n an

d tra

inin

g in

stre

ss c

opin

g st

rate

gies

th

en o

ne s

essi

on p

er w

eek

for a

furth

er 4

wee

ks

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Bla

ncha

rd

( 42 )

U

SA

Terti

ary

care

Cl

inic

al d

iagn

osis

an

d in

vest

igat

ions

≥

50 %

Red

uctio

n in

bas

elin

e sy

mpt

om s

core

23

(78)

Tw

o pr

ogre

ssiv

e m

uscl

e re

laxa

tion

sess

ions

per

w

eek

for 2

wee

ks th

en o

ne s

essi

on p

er w

eek

for a

fu

rther

6 w

eeks

, with

regu

lar h

ome

prac

tice

emph

a-si

zed

(at l

east

25

min

per

day

)

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. O

ther

IBS

med

icat

ions

“ d

isco

urag

ed ”

Gre

ene

( 46 )

U

SA

Terti

ary

care

Cl

inic

al d

iagn

osis

an

d in

vest

igat

ions

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

20 (7

5)

Two

1-h

CBT

sess

ions

per

wee

k fo

r 2 w

eeks

then

on

e se

ssio

n pe

r wee

k fo

r a fu

rther

6 w

eeks

M

etho

d of

rand

omiz

atio

n an

d co

n-ce

alm

ent o

f allo

catio

n no

t sta

ted.

U

nblin

ded.

Unc

lear

if o

ther

IBS

med

icat

ions

allo

wed

Payn

e ( 5

3 )

USA

Te

rtiar

y ca

re

Rom

e I a

nd in

vest

i-ga

tions

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

22 (8

2)

Two

1-h

CBT

sess

ions

per

wee

k fo

r 2 w

eeks

then

on

e se

ssio

n pe

r wee

k fo

r a fu

rther

6 w

eeks

M

etho

d of

rand

omiz

atio

n an

d co

n-ce

alm

ent o

f allo

catio

n no

t sta

ted.

U

nblin

ded.

Unc

lear

if o

ther

IBS

med

icat

ions

allo

wed

Gal

ovsk

i ( 45

) U

SA

Terti

ary

care

Cl

inic

al d

iagn

osis

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

12 (8

3)

One

30-

min

to 1

-h g

ut-d

irect

ed h

ypno

ther

apy

ses-

sion

per

wee

k fo

r 6 w

eeks

M

etho

d of

rand

omiz

atio

n an

d co

n-ce

alm

ent o

f allo

catio

n no

t sta

ted.

U

nblin

ded.

Unc

lear

if o

ther

IBS

med

icat

ions

allo

wed

Vollm

er ( 5

9 )

USA

Te

rtiar

y ca

re

Rom

e I a

nd in

vest

i-ga

tions

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

34 (7

6)

One

1-h

ses

sion

of i

ndiv

idua

l CB

T pe

r wee

k fo

r 10

wee

ks, o

r one

90-

min

ses

sion

of g

roup

CB

T pe

r w

eek

for 1

0 w

eeks

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Tabl

e 3

cont

inue

d on

follo

win

g pa

ge


1359

REV

IEW


Tabl

e 3

cont

inue

d on

follo

win

g pa

ge

Tabl

e 3 .

Con

tinue

d

Stud

y

Coun

try

Sett

ing

Dia

gnos

tic c

riter

ia

used

for

IB

S

Crite

ria u

sed

to d

efi n

e sy

mpt

om im

prov

emen

t fo

llow

ing

ther

apy

Sam

ple

size

Ps

ycho

logi

cal t

hera

py u

sed

Met

hodo

logy

Keef

er ( 4

9 )

USA

Te

rtiar

y ca

re

Clin

ical

dia

gnos

is

≥ 50 %

Red

uctio

n in

bas

elin

e sy

mpt

om s

core

15

(Not

re

porte

d)

One

30-

min

rela

xatio

n re

spon

se m

edita

tion

sess

ion

per w

eek

for 6

wee

ks

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Boy

ce ( 4

3 )

Aust

ralia

Te

rtiar

y ca

re

Rom

e I a

nd in

vest

i-ga

tions

≥ 1

Sta

ndar

d de

viat

ion

de-

crea

se in

bas

elin

e sy

mpt

om

scor

e

105

(81)

O

ne 1

-h C

BT

sess

ion

per w

eek

for 8

wee

ks, o

r one

30

-min

rela

xatio

n th

erap

y se

ssio

n pe

r wee

k fo

r 8

wee

ks

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n st

ated

. In

vest

igat

or b

linde

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Cree

d ( 4

4 )

Engl

and

Terti

ary

care

R

ome

I Pa

tient

-rep

orte

d im

prov

e-m

ent i

n gl

obal

sym

ptom

s 17

1 (7

9)

One

2-h

and

sev

en 4

5-m

in p

sych

odyn

amic

inte

r-pe

rson

al th

erap

y se

ssio

ns o

ver 3

mon

ths

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n st

ated

. In

vest

igat

or b

linde

d. U

ncle

ar if

ot

her I

BS

med

icat

ions

allo

wed

Dro

ssm

an

( 36 )

U

SA

and

Cana

da

Terti

ary

care

R

ome

I ≥ S

core

of 2

8 on

trea

tmen

t sa

tisfa

ctio

n qu

estio

nnai

re

169

(100

) O

ne 1

-h C

BT

sess

ion

per w

eek

for 1

2 w

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of a

lloca

tion

stat

ed.

Inve

stig

ator

blin

ded.

Unc

lear

if

othe

r IB

S m

edic

atio

ns a

llow

ed

Tkac

huk

( 57 )

Ca

nada

Te

rtiar

y ca

re

Rom

e I a

nd in

vest

i-ga

tions

Pa

tient

-rep

orte

d im

prov

e-m

ent i

n gl

obal

sym

ptom

s 28

(96)

Tw

o 90

-min

gro

up C

BT

sess

ions

per

wee

k fo

r 1

wee

k th

en o

ne s

essi

on p

er w

eek

for 8

wee

ks

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Hei

tkem

per

( 48 )

U

SA

Terti

ary

care

R

ome

I ≥ 5

0 % R

educ

tion

in s

ympt

om

scor

e 95

(100

) O

ne 1

-h w

eekl

y m

ultic

ompo

nent

psy

chol

ogic

al

ther

apy

sess

ion

per w

eek

for 8

wee

ks

Met

hod

of ra

ndom

izat

ion

and

con-

ceal

men

t of a

lloca

tion

not s

tate

d.

Unb

linde

d. O

ther

IBS

med

icat

ions

al

low

ed

Sim

ren

( 56 )

Sw

eden

Te

rtiar

y ca

re

Rom

e II

and

inve

sti-

gatio

ns

Patie

nt-r

epor

ted

impr

ove-

men

t in

glob

al s

ympt

oms

28 (6

8)

One

1-h

gut

-dire

cted

hyp

noth

erap

y se

ssio

n pe

r w

eek

for 1

2 w

eeks

M

etho

d of

rand

omiz

atio

n st

ated

. M

etho

d of

con

ceal

men

t of a

lloca

-tio

n no

t sta

ted.

Unb

linde

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Kenn

edy

( 50 )

En

glan

d Pr

imar

y ca

re

Clin

ical

dia

gnos

is

Impr

ovem

ent i

n sy

mpt

om

seve

rity

band

ing

by o

ne b

and

(gra

ded

seve

re to

non

e on

a

four

-poi

nt L

iker

t-sca

le)

149

(not

re

porte

d)

One

50-

min

CB

T se

ssio

n pe

r wee

k fo

r 6 w

eeks

M

etho

d of

rand

omiz

atio

n st

ated

. M

etho

d of

con

ceal

men

t of a

lloca

-tio

n no

t sta

ted.

Unb

linde

d. N

o ne

w

IBS

med

icat

ions

allo

wed

Sand

ers

( 54 )

U

SA

Terti

ary

care

R

ome

II an

d in

vest

i-ga

tions

≥ 5

0 % re

duct

ion

in b

asel

ine

sym

ptom

sco

re

28 (7

9)

Self-

adm

inis

tere

d CB

T m

aile

d as

fi ve

mod

ules

ove

r 10

wee

ks

Met

hod

of ra

ndom

izat

ion

stat

ed.

Met

hod

of c

once

alm

ent o

f al-

loca

tion

not s

tate

d. U

nblin

ded.

U

ncle

ar if

oth

er IB

S m

edic

atio

ns

allo

wed

van

der V

eek

( 58 )

H

olla

nd

Terti

ary

care

R

ome

II R

elia

ble

chan

ge in

dex

≥ 1.9

6 (p

re-th

erap

y sc

ore

min

us

post

-ther

apy

scor

e di

vide

d by

sta

ndar

d er

ror o

f the

di

ffere

nce)

105

(Not

re

porte

d)

One

90-

min

rela

xatio

n tra

inin

g se

ssio

n pe

r wee

k fo

r 4

wee

ks w

ith o

ne b

oost

er s

essi

on a

fter 3

mon

ths

Met

hod

of ra

ndom

izat

ion

not

stat

ed. M

etho

d of

con

ceal

men

t of

allo

catio

n st

ated

. Unb

linde

d. O

ther

IB

S m

edic

atio

ns a

llow

ed


1360R

EVIE

W Ford et al.

Tabl

e 3 .

Con

tinue

d

Stud

y

Coun

try

Sett

ing

Dia

gnos

tic c

riter

ia

used

for

IB

S

Crite

ria u

sed

to d

efi n

e sy

mpt

om im

prov

emen

t fo

llow

ing

ther

apy

Sam

ple

size

Ps

ycho

logi

cal t

hera

py u

sed

Met

hodo

logy

Lack

ner (

64 )

USA

Pr

imar

y,

seco

ndar

y,

and

terti

ary

care

Rom

e II

Patie

nt-r

epor

ted

adeq

uate

re

lief o

f glo

bal s

ympt

oms

75 (8

7)

One

1-h

CB

T se

ssio

n pe

r wee

k fo

r 10

wee

ks, o

r one

1-

h CB

T se

ssio

n on

four

occ

asio

ns o

ver 1

0 w

eeks

M

etho

d of

rand

omiz

atio

n st

ated

. M

etho

d of

con

ceal

men

t of a

lloca

-tio

n no

t sta

ted.

Unb

linde

d. O

ther

IB

S m

edic

atio

ns a

llow

ed

Hun

t ( 62

) U

SA

Not

re-

porte

d Cl

inic

al d

iagn

osis

Pa

tient

repo

rted

they

had

“ r

ecov

ered

” ac

cord

ing

to th

e ga

stro

inte

stin

al s

ympt

om-

ratin

g sc

ale

54 (8

2)

One

mod

ule

of C

BT

deliv

ered

via

the

Inte

rnet

per

w

eek

for 5

wee

ks, w

ith h

omew

ork

assi

gnm

ents

M

etho

d of

rand

omiz

atio

n an

d co

n-ce

alm

ent o

f allo

catio

n no

t sta

ted.

U

nblin

ded.

Unc

lear

if o

ther

IBS

med

icat

ions

not

allo

wed

Jarr

ett (

63 )

USA

N

ot re

-po

rted

Rom

e II

≥ 50 %

Red

uctio

n in

bas

elin

e sy

mpt

om s

core

18

8 (8

6)

One

1-h

mul

ticom

pone

nt p

sych

olog

ical

ther

apy

ses-

sion

per

wee

k de

liver

ed in

-per

son

for 9

wee

ks, o

r on

e 1-

h se

ssio

n pe

r wee

k de

liver

ed in

-per

son

for 2

w

eeks

, the

n si

x se

ssio

ns d

eliv

ered

via

the

tele

phon

e w

ith th

e fi n

al s

essi

on d

eliv

ered

in-p

erso

n

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n no

t st

ated

. Unb

linde

d. N

o ot

her I

BS

med

icat

ions

allo

wed

Ljot

tson

( 66 )

Sw

eden

N

ot re

-po

rted

Rom

e III

≥ 5

0 % R

educ

tion

in b

asel

ine

sym

ptom

sco

re

86 (N

ot

repo

rted)

A

CBT

prot

ocol

con

sist

ing

of fi

ve s

teps

and

del

iv-

ered

via

the

Inte

rnet

ove

r 10

wee

ks

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n st

ated

. U

nblin

ded.

Unc

lear

if o

ther

IBS

med

icat

ions

allo

wed

Mos

s-M

orris

( 6

8 )

New

Ze

alan

d Pr

imar

y ca

re

Rom

e I o

r Rom

e II

Patie

nt-r

epor

ted

adeq

uate

re

lief o

f glo

bal s

ympt

oms

64 (7

2)

A se

lf-ad

min

iste

red

CBT

prog

ram

div

ided

into

sev

en

chap

ters

and

com

plet

ed o

ver 7

– 8 w

eeks

M

etho

d of

rand

omiz

atio

n an

d co

ncea

lmen

t of a

lloca

tion

stat

ed.

Unb

linde

d. U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

llow

ed

Shin

ozak

i ( 6

9 )

Japa

n Te

rtiar

y ca

re

Rom

e II

and

inve

sti-

gatio

ns

Patie

nt-r

epor

ted

adeq

uate

re

lief o

f glo

bal s

ympt

oms

21 (5

2)

One

30-

to 4

0-m

in re

laxa

tion

train

ing

sess

ion

per

wee

k fo

r 8 w

eeks

M

etho

d of

rand

omiz

atio

n an

d co

n-ce

alm

ent o

f allo

catio

n no

t sta

ted.

U

nblin

ded.

Unc

lear

if o

ther

IBS

med

icat

ions

allo

wed

Cras

ke ( 6

0 )

USA

Pr

imar

y an

d te

rtiar

y ca

re

Rom

e II

≥ 50 %

Red

uctio

n in

bas

elin

e sy

mpt

om s

core

11

0 (N

ot

repo

rted)

O

ne 5

0-m

in C

BT

or s

tress

man

agem

ent s

essi

on p

er

wee

k fo

r 10

wee

ks

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n st

ated

. U

nblin

ded.

Oth

er IB

S m

edic

atio

ns

allo

wed

Gay

lord

( 61 )

U

SA

Not

re-

porte

d R

ome

II ≥ 5

0 Po

int r

educ

tion

in th

e IB

S sy

mpt

om s

ever

ity s

core

75

(100

) O

ne 2

-h m

indf

ulne

ss m

edita

tion

train

ing

sess

ion

per w

eek

for 8

wee

ks p

lus

one

half-

day

retre

atm

ent

sess

ion

Met

hod

of ra

ndom

izat

ion

stat

ed.

Met

hod

of c

once

alm

ent o

f allo

ca-

tion

not s

tate

d. In

vest

igat

or b

linde

d.

Oth

er IB

S m

edic

atio

ns a

llow

ed

Lind

fors

( 65 )

Sw

eden

Se

cond

ary

or te

rtiar

y ca

re

Rom

e II

and

inve

sti-

gatio

ns

≥ 25 %

Red

uctio

n of

tota

l sc

ore

on th

e G

I sym

ptom

qu

estio

nnai

re

48 (8

1) a

nd

90 (7

9) a

One

1-h

gut

-dire

cted

hyp

noth

erap

y se

ssio

n pe

r w

eek

for 1

2 w

eeks

, with

enc

oura

gem

ent t

o pr

actic

e at

hom

e on

a re

gula

r bas

is a

nd a

udio

tape

s pr

ovid

ed

in o

ne s

tudy

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n st

ated

. U

nblin

ded.

Oth

er IB

S m

edic

atio

ns

allo

wed

Mos

er ( 6

7 )

Aust

ria

Prim

ary

and

terti

ary

care

R

ome

III

Patie

nt-r

epor

ted

adeq

uate

re

lief o

f glo

bal s

ympt

oms

90 (7

9)

Ten

45-m

in g

ut-d

irect

ed h

ypno

ther

apy

sess

ions

ov

er 1

2 w

eeks

, with

enc

oura

gem

ent t

o pr

actic

e at

ho

me

on a

regu

lar b

asis

and

com

pact

dis

c pr

ovid

ed

Met

hod

of ra

ndom

izat

ion

and

conc

ealm

ent o

f allo

catio

n st

ated

. In

vest

igat

or b

linde

d. O

ther

IBS

med

icat

ions

allo

wed

CBT,

cog

nitiv

e be

havi

oral

the

rapy

; IB

S, ir

ritab

le b

owel

syn

drom

e.

a Tw

o se

para

te s

tudi

es r

epor

ted

in o

ne p

aper

.


1361

REV

IEW


Psychological therapies ControlStudy or Subgroup1.1.1 Cognitive behavioural therapy

1.1.2 Relaxation training or therapy

1.1.3 Hypnotherapy

1.1.4 Multi-component psychological therapy

1.1.5 Self-administered / minimal contact cognitive behavioural therapy

1.1.6 Cognitive behavioural therapy via internet

1.1.7 Dynamic psychotherapy

1.1.8 Stress management

1.1.9 Multi-component psychological therapy via telephone

1.1.10 Mindfulness meditation training

Greene 1994 23

110

51

4103

3146

34

281923

4224

2541

96

16108

34

2526

284371

2642

264369

6851

1725

7331

1027

63

26

11273371

1038104862

168

8 1.4% 0.45 (0.20, 0.99) 19871992199220042009

200720082010

0.78 (0.56, 1.08)0.50 (0.22, 1.14)0.70 (0.51, 0.96)0.75 (0.61, 0.91)0.72 (0.62, 0.83)

1.04 (0.83, 1.29)0.41 (0.26, 0.66)0.33 (0.18, 0.61)

0.90 (0.78, 1.04) 200920100.62 (0.48, 0.79)

0.75 (0.48, 1.17)

0.53 (0.17, 1.66)

3.6%1.4%3.7%4.5%

14.5%

4.3%2.7%2.0%9.0%

4.8%4.2%8.9%

2041

61

5385

138

3956

4986

135

95

0.47 (0.33, 0.69) 199120030.74 (0.57, 0.97)

0.60 (0.39, 0.93)

0.34 (0.16, 0.73) 19912011

2009

1.13 (0.62, 2.07)0.63 (0.19, 2.08)

0.78 (0.64, 0.93)0.78 (0.64, 0.93)

20110.57 (0.32, 1.01)0.57 (0.32, 1.01)

0.68 (0.61, 0.76)

0.1 0.2

Favors psychological Favors control

0.5 1 2 5 10

3.3%4.0%7.3%

519

24

44

44

11

639

1232

839

1102

11

3636

21

21

3939

64 55

55

626264

184159

149

172239

23

1.5%2.1%3.6%

4.5%4.5%

2.2%2.2%

100.0%

298

3555

939104762

167135

77

6 69

402031

6 1.5%1.2%4.1%4.0%3.3%

14.1%

0.54 (0.25, 1.16) 19982004201220122013

0.44 (0.18, 1.11)0.70 (0.55, 0.90)0.87 (0.67, 1.15)0.71 (0.49, 1.03)0.74 (0.63, 0.87)

14452349

137106

14452551

141

2

1114

7365411

1087

25507

10 1.6% 0.39 (0.19, 0.82) 198919932001200320072010

0.80 (0.54, 1.20)0.49 (0.20, 1.20)1.17 (0.92, 1.49)0.87 (0.77, 0.98)0.26 (0.07, 0.97)0.77 (0.57, 1.04)

3.1%1.2%4.2%4.9%0.6%

15.6%

98

345110

122107

13396

27249

18

10122414

112357223

349166145

47

9996

362536279

10 0.7% 0.22 (0.06, 0.78) 199419951998200320032003200520082011

0.28 (0.10, 0.76)0.51 (0.31, 0.82)0.08 (0.00, 1.25)0.72 (0.54, 0.96)1.05 (0.80, 1.38)0.71 (0.48, 1.07)0.40 (0.25, 0.66)0.94 (0.50, 1.74)0.60 (0.44, 0.83)

1.0%2.7%0.2%3.9%4.0%3.1%2.6%2.0%

20.1%

1010145734772722

261

Payne 1995Vollmer 1998Tkachuk 2003Drossman 2003Boyce 2003Kennedy 2005Lackner 2008Craske 2011Subtotal (95% Cl)Total events

Lynch 1989Blanchard 1993Keefer 2001Boyce 2003Van der Veek 2007Shinozaki 2010Subtotal (95% Cl)Total events

Galovski 1998Simren 2004Lindfors 2012aLindfors 2012bMoser 2013Subtotal (95% Cl)Total events

Neff 1987Blanchard 1992bBlanchard 1992aHeitkemper 2004Jarrett 2009Subtotal (95% Cl)Total events

Total events

Total events

Total events

Total events

Total events

Total events

Gaylord 2011

Total (95% Cl)

Jarrett 2009

Total events

Sanders 2007Lackner 2008

Hunt 2009

Guthrie 1991Creed 2003

Shaw 1991Craske 2011

Ljotsson 2010Subtotal (95% Cl)

Subtotal (95% Cl)

Subtotal (95% Cl)

Subtotal (95% Cl)

Subtotal (95% Cl)

Moss-Morris 2010Subtotal (95% Cl)

Heterogeneity: !2 = 0.00; "2 = 2.53, d.f. = 4 (P = 0.64); l 2 = 0%

Heterogeneity: !2 = 0.97; "2 = 44.54, d.f. = 2 (P < 0.00001); l 2 = 96%




Heterogeneity: !2 = 0.06; "2 = 119.98, d.f. = 35 (P < 0.00001); l 2 = 71

Heterogeneity: Not applicable

Heterogeneity: Not applicable

Test for overall effect: Z = 4.43 (P < 0.00001)





Test for overall effect: Z = 6.66 (P < 0.00001)Test for subgroup differences: "2 = 3.74, d.f. = 9 (P = 0.93), l 2 = 0%





Heterogeneity: !2 = 0.00; "2 = 3.84, d.f. = 4 (P = 0.43); l 2 = 0%Test for overall effect: Z = 3.74 (P = 0.0002)



Events EventsTotal WeightRisk ratio

M-H, Random, 95% ClRisk ratio

M-H, Random, 95% ClYearTotal

Figure 3 . Forest plot of randomized controlled trials of psychological therapies vs. control in irritable bowel syndrome.


1362R

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W Ford et al.

via the Internet were of no benefi t, it should be noted that in most cases the proportions with an improvement in symptoms were higher with active therapy, and the number of included individu-als in the eligible trials was small. Adverse events data were poorly reported among trials of psychological therapies. Th e assumption that the administration of psychological therapies is without the potential for adverse events is probably unrealistic. In the future, RCTs should report these data more completely.

A strength of this systematic review and meta-analysis is our use of rigorous methodology. We reported our search strategy, which included searching the “ gray ” literature, and assessment of eligibility and data extraction was performed independently by two reviewers. We also used an intention-to-treat analysis and pooled data with a random-eff ects model to minimize the likeli-hood that treatment eff ect would be overestimated. 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 gastrointestinal disorders from the analysis. Th is inclusive approach has pro-vided us with access to data for > 1,000 IBS patients treated with antidepressants vs. placebo, and > 2,100 patients randomized to psychological therapies vs. control. We also performed sub-group analyses to explore the reasons for heterogeneity between studies, and to assess treatment eff ect according to individual therapy used, study setting, criteria used to defi ne IBS, and

multicomponent psychological therapy, either in person or mainly via the telephone, and dynamic psychotherapy were all more eff ective than control therapy, with NNTs of between 3 and 4, and there was a trend toward a benefi t of mindfulness medita-tion training. Although relaxation training, stress management, self-administered or minimal-contact CBT, and CBT delivered

Bias assessment plot

–4.0 –2.4 –0.8 0.8 2.4 4.0 5.61.5

1.0

0.5

0.0

Log(relative risk)

Sta

ndar

d er

ror

Figure 4 . Funnel plot of randomized controlled trials of psychological therapies vs. control in irritable bowel syndrome.

Table 4 . Subgroup analyses of randomized controlled trials of psychological therapies vs. control in IBS

Number of

trials Number of patients

Relative risk of IBS symptoms not improving (95 % confi dence interval)

P value for the difference I 2 ( P value)

Setting

Tertiary care 22 1,103 0.65 (0.55 – 0.78) 0.53 75 % ( < 0.001)

Other 14 1,231 0.70 (0.60 – 0.81) 65 % ( < 0.001)

Criteria used to defi ne IBS

Rome 24 1,787 0.72 (0.63 – 0.81) 0.16 72 % ( < 0.001)

Clinical diagnosis 12 547 0.58 (0.44 – 0.76) 73 % ( < 0.001)

Method of randomization

Stated 18 1,411 0.75 (0.65 – 0.87) 0.06 74 % ( < 0.001)

Not stated 18 923 0.60 (0.50 – 0.71) 67 % ( < 0.001)

Concealment of allocation

Stated 12 1,104 0.80 (0.70 – 0.93) 0.007 67 % ( < 0.001)

Not stated 24 1,230 0.59 (0.50 to 0.70) 73 % ( < 0.001)

Blinding

Investigator 6 654 0.83 (0.67 – 1.04) 0.05 68 % (0.008)

Unblinded 30 1,680 0.64 (0.56 – 0.73) 73 % ( < 0.001)

Handling of control arm

Waiting list control 18 693 0.61 (0.49 – 0.76) 0.17 76 % ( < 0.001)

Usual management / supportive 17 1,472 0.73 (0.63 – 0.83) 71 % ( < 0.001)

IBS, irritable bowel syndrome.


1363

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study methodology and design. Finally, we extracted and pooled adverse events data, where reported.

Th ere are limitations to this systematic review and meta-analy-sis, which arise from the nature of the studies available for syn-thesis. Th ere were very few trials at a low risk of bias, and there was evidence of heterogeneity between RCTs in many of our analyses, although not for TCAs, hypnotherapy, or multicompo-nent psychological therapy. In addition, the diff erence in favor of antidepressants was no longer statistically signifi cant when trials at high or unclear risk of bias were excluded from the analysis, although there were only three studies at a low risk of bias, con-taining 288 patients. Th ere was evidence of publication bias, or other small study eff ects, for both antidepressants and psycho-logical therapies. For antidepressants, this disappeared when one small outlying RCT was excluded from the analysis. Subgroup analyses demonstrated that treatment eff ect was generally lower in studies that reported the method of generation of the rand-omization schedule and concealment of allocation, which is in line with reports from the systematic review literature in gen-eral ( 70 ). Th ese issues may mean that the true treatment eff ect of both antidepressants and psychological therapies has been overestimated.

Our previous meta-analysis examining this issue demonstrated similar fi ndings, in terms of the effi cacy of both antidepressants and psychological therapies ( 18 ). Despite the addition of 4 trials of antidepressants ( 37 – 40 ), and 10 studies of psychological therapies ( 60 – 69 ), since its publication, the overall estimates of the effi cacy of these treatments remain almost identical. However, more trials of antidepressants now report adverse events than previously, and these were signifi cantly more common with active therapy than with placebo, which was not the case previously. In addition, there was a signifi cant eff ect of antidepressant therapy on abdominal pain, an outcome that was reported by more RCTs in this updated meta-analysis ( 26,27,30,33 – 35,38 ).

It remains unclear whether antidepressants or psychological therapies are eff ective for the treatment of IBS in primary care, with only two of the RCTs we identifi ed conducted entirely within this setting ( 50,68 ). Th e effi cacy of these therapies according to predominant stool pattern reported by the patient has also not been well studied. TCAs have been shown to prolong orocecal and whole gut transit times, whereas SSRIs decreases orocecal transit time ( 71 ). It would therefore seem biologically plausible that TCAs would be more eff ective in diarrhea-predominant IBS, and SSRIs of greater benefi t in constipation-predominant IBS, but this has only been assessed in two studies to date ( 33,34 ).

In addition, whether the benefi t of antidepressants arises from the treatment of coexistent depression is controversial ( 72 ). Th ree studies reported that there was no signifi cant relationship between depression scores and improvement in IBS symptoms ( 30,31,35 ), and one RCT showed that treatment eff ect with desipramine was greater in those without evidence of coexistent depression ( 36 ). Overall, in our meta-analysis, there appeared to be a benefi t of antidepressants in IBS, but there was signifi cant heterogeneity between studies of SSRIs. However, in one RCT of citalopram, the authors screened for and excluded depressed individuals from the

study, and in this trial there was no benefi t of active therapy over placebo ( 39 ), leading to the conclusion that there was only weak evidence that citalopram was superior to placebo in achieving response in nondepressed patients with IBS. For SSRIs, this theory is plausible, as the doses used in treatment trials for IBS are very similar to those used to treat depression; however, this would seem less likely for TCAs, where the doses used are considerably lower than the therapeutic range considered as eff ective for the treatment of mood disorders.

Th ere remains, therefore, a clear need for larger trials of both anti-depressants and psychological therapies, perhaps in combination, that use rigorous methodology, are conducted among IBS patients in primary care, recruit patients based on predominant stool pat-tern, either exclude depressed or anxious individuals, or stratify for co-existent depression, anxiety, and other co-morbidities, and which use outcome measures in accordance with recommendations for the design of treatment trials for the functional gastrointesti-nal disorders from the Rome committee ( 73 ), or Food and Drug Administration-approved end points. It would also be insightful to understand more about the exact mechanisms by which these therapies have their benefi cial eff ects in IBS. Functional magnetic resonance imaging studies have demonstrated that hypnotherapy appears to lead to normalization of abnormal central pain process-ing ( 74 ), and that amitriptyline reduces brain activation during painful rectal distension ( 75 ), but there are a few other studies that advance our understanding of how antidepressants and other psy-chological therapies may improve the symptoms of IBS patients.

In summary, this updated systematic review and meta-analysis has demonstrated that TCAs, SSRIs, CBT, hypnotherapy, multi-component psychological therapy, either in person or mainly via the telephone, and dynamic psychotherapy are all eff ective treat-ments for IBS. Despite the considerable number of studies pub-lished in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment eff ect have remained almost identical. Th e fi nding that antidepressants, as well as many of the psychological therapies we studied, are benefi cial in IBS has implications for the management of a condition that clinicians oft en fi nd challenging, and should encourage increased use of anti-depressants by gastroenterologists and promote eff orts to improve access for both patients and physicians to psychological therapies.

ACKNOWLEDGMENTS Th is study was performed to inform the American College of Gastroenterology Monograph on irritable bowel syndrome. We are grateful to Payman Moayedi for translation of foreign language arti-cles, and Dr Maxine Lewis for assistance with interpretation of RCTs of psychological therapies in IBS.

CONFLICTS OF INTEREST Guarantor of the article: Alexander C. Ford, MBChB, MD. Specifi c author contributions: A.C.F., E.M.M.Q., B.E.L., A.J.L., Y.A.S., L.R.S., E.E.S., B.M.R.S., and P.M. conceived the study. A.C.F. and P.M. collected all data, analyzed and interpreted the data. A.C.F. draft ed the manuscript. All authors commented on draft s of the paper. All authors have approved the fi nal draft of the manuscript.


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Financial support: Th is work was supported by American College of Gastroenterology. Potential competing interests: None.

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Effect of Antidepressants and Psychological Therapies, Including Hypnotherapy, in Irritable Bowel Syndrome: Systematic Review and Meta-Analysis

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