Irritable bowel syndrome (IBS) is a chronic functional bowel disorder, defined as abdominal pain in association with disordered defecation (1). The prevalence in the community is between 5% and 20% (2), depending on the criteria used to define its presence, and it is more common in women and younger individuals (2,3). Although the pathophysiology is unknown, there have been recent attempts to redefine functional gastrointestinal (GI) conditions as disorders of gut–brain interaction (4), characterized by one or more pathophysiological processes including, but not limited to, disturbed motility, visceral hypersensitivity, altered mucosal immune function, perturbations in the intestinal microbiota, and altered central nervous system (CNS) processing.
Psychiatric conditions including depression, anxiety, and somatization often coexist in IBS (5,6). However, antidepressants and psychological therapies may be beneficial in functional GI disorders (7), such as IBS, not only because they have effects within the CNS, but also because they have peripheral effects on pain perception, visceral hypersensitivity, and GI motility (8–14). These peripheral and central effects may make them ideal candidates to treat the heterogeneous etiologies that likely cause the symptoms of IBS. Although the use of antidepressants in IBS is widespread in some healthcare settings (15), access to psychological therapies may be limited (16). There may also be a reluctance on the part of physicians to consider recommending either, perhaps due to doubts about their efficacy (17,18), or because their use is perceived to be stigmatizing (19).
Previous meta-analyses by our group (20,21), conducted to inform the American College of Gastroenterology’s (ACG) monograph on the management of IBS (22,23), have suggested that both antidepressants and psychological therapies are effective treatments for IBS. Prior to these meta-analyses, evidence for their efficacy was disputed (24), partly due to the fact that previous systematic reviews and meta-analyses that had examined this issue had important limitations (25). In the intervening 4 years since our last meta-analysis, further studies have been published. We have therefore re-examined this issue once again to update the latest iteration of the ACG monograph.
Search strategy and study selection
This was an update of our previous systematic review and meta-analysis (20). The medical literature was searched using MEDLINE (1946 to July 2017), EMBASE and EMBASE Classic (1947 to July 2017), PsychINFO (1806 to July 2017), and the Cochrane central register of controlled trials. Randomized controlled trials (RCTs) examining the effect of antidepressants and psychological therapies in adult patients (over the age of 16 years) with IBS were eligible for inclusion (Box 1), including the first period of crossover RCTs, prior to cross-over to the second treatment. In the case of antidepressant trials the control arms were 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 management”.
Duration of therapy had to be ≥7 days. The diagnosis of IBS could be based on either a physician’s opinion or accepted symptom-based diagnostic criteria, supplemented by the results of investigations to exclude organic disease, where investigators deemed this necessary. Subjects were required to be followed up for ≥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 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 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.
The literature search was performed as part of a broader exercise to inform an update of the ACG monograph on the management of IBS (26). Specifically, studies on IBS were identified with the terms irritable bowel syndrome and functional diseases, colon (both as medical subject heading (MeSH) and free text terms), and IBS, spastic colon, irritable colon, or 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, selective serotonin re-uptake inhibitors (SSRIs), paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram, serotonin uptake inhibitors, venlafaxine, duloxetine, mianserin, trazodone, sulpiride, quetiapine, aripiprazole, cognitive therapy, psychotherapy, behavior therapy, relaxation techniques, or hypnosis (both as MeSH terms and free text terms), and the following free text terms: escitalopram, serotonin norepinephrine reuptake inhibitors, milnacipran, tetracyclic antidepressants, mirtazapine, atypical antipsychotics, levosulpiride, olanzapine, behavioral therapy, relaxation therapy, or hypnotherapy.
There were no language restrictions. 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. In order to identify potentially eligible studies published only in abstract form, conference proceedings (Digestive Diseases Week, American College of Gastroenterology, and United European Gastroenterology Week) between 2001 and 2017 were also hand-searched. A recursive search of the literature was performed using the bibliographies of all relevant studies. Two reviewers assessed all articles independently using pre-designed eligibility forms, according to the eligibility criteria, which were defined prospectively. Disagreements between investigators were resolved by consensus.
RCTs conducted in adults (participants aged >16 years)
Diagnosis of IBS based on either a clinician’s opinion, or meeting specific diagnostic criteria*, supplemented by negative investigations where trials deemed this necessary.
Compared 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, III, or IV.
†Preferably patient-reported, but if this was not available then as assessed by a physician or questionnaire data.
The primary outcomes assessed were the effects of antidepressants compared with placebo, and the effects of psychological therapies compared with control therapy or a physician’s “usual management”, on global IBS symptoms or abdominal pain at study end. Secondary outcomes included assessing efficacy according to specific type of antidepressant or psychological therapy, and adverse events occurring as a result of antidepressant therapy.
All data were extracted independently by two reviewers on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA, USA) as dichotomous outcomes (global IBS symptoms 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 define IBS, primary outcome measure used to define symptom improvement or cure following therapy, duration of follow-up, proportion of female patients, and proportion of patients according to predominant stool pattern (IBS with constipation (IBS-C), diarrhea (IBS-D), or mixed stool pattern (IBS-M)). 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.
Data Extraction Methodology Cited Here...
Outcome of interest : improvement in global IBS symptoms preferable, if not reported then improvement in abdominal pain.
Reporting of outcomes : patient-reported preferable, if not available then investigator-reported.
Time of assessment : upon completion of therapy.
Denominator used : true intention-to-treat analysis, if not available then all evaluable patients.
Cut off used for dichotomization : any improvement in global IBS symptoms or abdominal pain for Likert-type scales, investigator-defined improvement for continuous scales, if no investigator definition available then we used ≥1 standard deviation decrease in symptom score from baseline to completion of therapy (we assessed if the use of any decrease in symptom score from baseline to completion of therapy altered our analysis).
Assessment of risk of bias
Two investigators performed this independently. Disagreements were resolved by consensus. The Cochrane handbook was used to assess risk of bias (27), by recording the method used to generate the randomization schedule and conceal treatment allocation, whether blinding was implemented for participants, personnel, and outcomes assessment, 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.
Data synthesis and statistical analysis
Data were pooled using a random effects model (28), to provide a more conservative estimate of the range of effects of antidepressants and psychological therapies, if there was 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 (CI). RRs were also used to summarize adverse events data. The number needed to treat (NNT) and the number needed to harm (NNH), with 95% CIs, were calculated using the formula NNT or NNH = 1/(control event rate x (1−RR)).
Heterogeneity, which is variation between individual study results arising as a result of either differences in study participants or methodology, was assessed using both the I 2 statistic with a cut off of ≥ 50%, and the chi-squared test with a P value <0.10, used to define a significant degree of heterogeneity (29). Review Manager version 5.3.5 (RevMan for Windows 2014, the Nordic Cochrane Centre, Copenhagen, Denmark) and StatsDirect version 2.7.7 (StatsDirect Ltd, Sale, Cheshire, England) were used to generate Forest plots of pooled RRs 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 or other small study effects, using the Egger test (30), if there were sufficient (≥10) eligible studies included in the meta-analysis, in line with recommendations (31).
The search strategy identified a total of 5316 citations, of which 114 published articles appeared to be relevant, and were retrieved for further assessment (Fig. 1). Of these 114, 63 were excluded for various reasons leaving 53 RCTs, reported in 51 eligible articles, 35 of which compared psychological therapies with control therapy in the form of symptom monitoring, physician’s “usual management”, or supportive therapy, and were reported in 33 separate articles (10,32–63), 17 RCTs, reported in 17 articles, compared antidepressants with placebo (64–80), and one RCT, reported in one article, compared both psychological therapies and antidepressants with placebo (81). Agreement between reviewers for assessment of trial eligibility was good (kappa statistic = 0.77). Two of the RCTs were conducted amongst mixed populations of patients with functional disorders (80,81). In both instances, we contacted the original investigators to obtain the data for only the patients with IBS. Four of the trials of psychological therapies (47,48,61,62), and one of the RCTs of antidepressants (80), were identified since our previous meta-analysis. One of these had been missed by literature searches that informed prior versions of this meta-analysis (62), but was identified in the bibliography of one of the other newly identified articles.
Efficacy of antidepressants in the treatment of IBS
In total, there were 18 RCTs comparing antidepressants with placebo in the treatment of IBS (64–81), which evaluated 1127 patients, 612 of whom received active therapy and 515 placebo. Eleven trials used tricyclic antidepressants (TCAs) (71–81), six SSRIs (65–70), and one studied both (64). Only four of the RCTs were at low risk of bias (66,79–81). The proportion of female patients recruited by trials ranged from 42 to 100%. The majority of trials did not differentiate between the type of IBS patients recruited, with only seven studies providing data on this (65–68,70,75,77), one of which recruited only IBS-C patients (70), and another only IBS-D patients (77). Detailed characteristics of individual RCTs are provided in Table 1.
Overall, 266 (43.5%) of 612 patients assigned to antidepressant therapy reported unimproved IBS symptoms following therapy, compared with 340 (66.0%) of 515 allocated to placebo. The RR of IBS symptoms not improving after treatment with antidepressant therapy versus placebo was 0.66 (95% CI 0.57–0.76), with significant heterogeneity detected between studies (I 2 = 37%, P = 0.06) (Fig. 2). There was statistically significant asymmetry in the funnel plot (Egger test, P = 0.03), suggesting publication bias or other small study effects, but this was driven by the TCA arm of one small study (64), and disappeared with its exclusion from the analysis (Egger test, P = 0.13), with no impact on the overall efficacy estimate. The NNT with antidepressants was 4.5 (95% CI 3.5–6).
The effect of antidepressant therapy on abdominal pain was reported by seven RCTs (67,68,70,71,75,77,79), 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, giving a RR of abdominal pain not improving of 0.62 (95% CI 0.43–0.88), but with considerable heterogeneity between studies (I 2 = 72%, P = 0.001) (Fig. 3). This beneficial effect on abdominal pain appeared to be limited to TCAs (RR = 0.59; 95% CI 0.42–0.83, I 2 = 35%), with no statistically significant effect of SSRIs (RR = 0.64; 95% CI 0.32–1.27, I 2 = 86%), although the point estimate of effect was similar for both drug classes, and there was no statistically significant difference between them (subgroup differences, I 2 = 0%, P = 0.85).
Efficacy of TCAs in the treatment of IBS
Twelve RCTs compared TCAs with placebo, including a total of 787 patients (64,71–81). Of 436 patients receiving active therapy, 186 (42.7%) had no improvement in symptoms after treatment, compared with 224 (63.8%) of 351 receiving placebo. The RR of IBS symptoms not improving with TCAs compared with placebo was 0.65 (95% CI 0.55–0.77), with no statistically significant heterogeneity detected between studies (I 2 = 34%, P = 0.12) (Fig. 2), and evidence of funnel plot asymmetry (Egger test, P = 0.01). The NNT with TCAs was 4.5 (95% CI 3.5–7).
Efficacy of SSRIs in the treatment of IBS
There were seven trials comparing SSRIs with placebo, recruiting a total of 356 patients (64–70). In total, 80 (45.5%) of 176 patients allocated to SSRIs reported no improvement in symptoms following therapy, compared with 121 (67.2%) of 180 placebo patients. The RR of IBS symptoms not improving with SSRIs compared with placebo was 0.68 (95% CI 0.51–0.91), but with statistically significant heterogeneity between studies (I 2 = 49%, P = 0.07) (Fig. 2). The NNT with SSRIs was 5 (95% CI 3–16.5).
Adverse events with antidepressant therapy
Eight trials reported on overall adverse events with antidepressants versus placebo (65,68,71,72,74,75,78,80). In total, 83 (36.4%) of 228 patients assigned to antidepressants experienced adverse events, compared with 47 (21.1%) of 223 allocated to placebo. When data were pooled the incidence of adverse events was significantly higher among those taking antidepressants (RR of experiencing any adverse event = 1.56; 95% CI 1.23–1.98) (Fig. 4). The NNH was 8.5 (95% CI 5–21). There were no serious adverse events. Six of the RCTs used TCAs (71,72,74,75,78,80) and, in these trials, there was a significantly higher rate of adverse events (RR = 1.59; 95% CI 1.23–2.06). Drowsiness and dry mouth were more common in patients randomized to TCAs than those receiving placebo.
Efficacy of psychological therapies in the treatment of IBS
There were a total of 34 articles, reporting on 36 separate RCTs, comparing various psychological therapies with control therapy in the form of symptom monitoring, physician’s “usual management”, supportive therapy, or placebo for the treatment of IBS in a total of 2487 patients (10,32–63,81). Six RCTs used cognitive behavioral therapy (CBT) (35,39,41,42,53,81), six trials used relaxation training or therapy (33,36,37,55,60,61), five RCTs, reported in four separate articles, used hypnotherapy (10,34,57,58), four trials, reported in three separate articles, used multi-component psychological therapy (32,38,52), two RCTs used self-administered or minimal contact CBT (40,59), two trials used internet-delivered CBT (44,46), two RCTs used dynamic psychotherapy (50,51), two trials used mindfulness meditation training (47,63), one RCT used stress management (54), one trial used stress management or CBT (43), one RCT used stress management or contingency management (62), one RCT used CBT or self-administered CBT (45), one trial used multi-component psychological therapy delivered in-person or mainly via the telephone (56), one RCT used CBT or relaxation therapy (49), and one RCT used emotional awareness and expression training or relaxation therapy (48).
The control arm received symptom monitoring in 18 RCTs, reported in 17 articles (32–48), usual care in 15 trials, reported in 14 articles (49–62), supportive therapy in two RCTs (10, 63), and placebo in one trial (81). None of the trials were at low risk of bias, due to the inability to blind participants to the nature of the intervention received. The proportion of female patients recruited by trials ranged from 52 to 100%. Detailed characteristics of individual trials are provided in Table 2. Adverse events data were poorly reported by included RCTs, precluding any meaningful analysis.
Overall, IBS symptoms did not improve in 735 (52.2%) of 1407 patients receiving psychological therapies, compared with 820 (75.9%) of 1080 receiving control in the form of symptom monitoring, physician’s “usual management”, supportive therapy, or placebo. The RR of IBS symptoms not improving with psychological therapies was 0.69 (95% CI 0.62–0.76) (Fig. 5), with considerable heterogeneity detected between studies (I 2 = 69%, P < 0.001), and evidence of funnel plot asymmetry, or other small study effects (Egger test, P<0.001), with a lack of small studies showing no effect of psychological therapies on the symptoms of IBS. The NNT with psychological therapies was 4 (95% CI 3.5–5.5).
Efficacy of CBT in IBS
Nine trials compared CBT with control therapy in 610 patients (35,39,41–43,45,49,53,81). Symptoms of IBS did not improve in 145 (41.5%) of 349 assigned to CBT, compared with 166 (63.6%) of 261 allocated to control, with a RR of 0.60 (95% CI 0.44–0.83) (Fig. 5), and statistically significant heterogeneity between studies (I 2 = 70%, P < 0.001). The NNT with CBT was 4 (95% CI 3–9).
Efficacy of relaxation training or therapy in IBS
Eight RCTs compared relaxation training or therapy with control therapy in 360 patients (33,36,37,48,49,55,60,61). IBS symptoms did not improve in 126 (68.1%) of 185 patients randomized to relaxation training or therapy, compared with 147 (84.0%) of 175 receiving control therapy. Overall, there was a benefit of relaxation training or therapy in IBS (RR of symptoms not improving = 0.80; 95% CI 0.65–0.98) (Fig. 5), but with statistically significant heterogeneity between studies (I 2 = 61%, P = 0.01). The NNT was 6 (95% CI 3–60).
Efficacy of multi-component psychological therapy in IBS
Five separate RCTs, reported in four articles (32,38,52,56), compared multi-component psychological therapy with control therapy in 335 patients. Symptoms of IBS were not improved in 96 (57.1%) of 168 patients randomized to multi-component psychological therapy, compared with 135 (80.8%) of 167 receiving control. The RR of IBS symptoms not improving was 0.72 (95% CI 0.62–0.83) (Fig. 5), with no significant heterogeneity detected between studies (I 2 = 0%, P = 0.64). The NNT with multi-component psychological therapy was 4 (95% CI 3–7).
Efficacy of hypnotherapy in IBS
Five separate trials, again reported in four articles (10,34,57,58), compared hypnotherapy with control 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 benefit in IBS, with a RR of symptoms not improving of 0.74 (95% CI 0.63–0.87) (Fig. 5), with no significant heterogeneity detected between studies (I 2 = 0%, P = 0.43). The NNT with hypnotherapy was 5 (95% CI 3.5–10).
Efficacy of self-administered or minimal contact CBT in IBS
Three trials, involving 144 patients, used self-administered or minimal contact CBT (40,45,59). 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. The RR of IBS symptoms not improving with self-administered or minimal contact CBT was 0.53 (95% CI 0.17–1.66) (Fig. 5), with significant heterogeneity detected between individual study results (I 2 = 96%, P < 0.001).
Efficacy of stress management in IBS
There were three trials using this therapy (43,54,62), involving 142 patients. Overall, 37 (46.3%) of 80 patients assigned to stress management reported no improvement in IBS symptoms, compared with 43 (69.4%) of 62 allocated to control. There was no beneficial effect detected for stress management in IBS (RR = 0.68; 95% CI 0.39–1.20) (Fig. 5), and there was significant heterogeneity between studies (I 2 = 66%, P = 0.05).
Efficacy of dynamic psychotherapy in IBS
Two RCTs compared dynamic psychotherapy with control therapy in 273 patients (50,51). No improvement in IBS symptoms was reported by 61 (44.2%) of 138 randomized to dynamic psychotherapy, compared with 95 (70.4%) of 135 receiving control, with a RR of symptoms not improving of 0.60 (95% CI 0.39–0.93) (Fig. 5), and a NNT of 4 (95% CI 2–20). Again there was significant heterogeneity between studies (I 2 = 72%, P = 0.06).
Efficacy of mindfulness meditation training in IBS
There were two studies, recruiting 165 patients (47,63). Overall, 44 (55.7%) of 79 patients assigned to mindfulness meditation symptoms were not improved, compared with 58 (67.4%) of 86 allocated to control, with no beneficial effect detected (RR = 0.78; 95% CI 0.44–1.41) (Fig. 5), and with significant heterogeneity between studies (I 2 = 74%, P = 0.05).
Efficacy of CBT delivered via the internet in IBS
There were two trials that delivered CBT via the internet, containing 140 patients (44,46). Among 71 patients randomized to CBT via the internet, 51 (71.8%) reported no improvement in symptoms. This compared with 68 (98.6%) of 69 allocated to control therapy. The RR of IBS symptoms not improving with CBT via the internet was 0.75 (95% CI 0.48–1.17) (Fig. 5), with significant heterogeneity between the two RCTs (I 2 = 90%, P = 0.002).
Efficacy of multi-component psychological therapy mainly via the telephone, contingency management in IBS, or emotional awareness and expression training
There was only one study using each of these treatment modalities (48,56,62). Multi-component psychological therapy mainly via the telephone (RR of symptoms not improving = 0.78; 95% CI 0.64–0.93) (56), contingency management (RR = 0.45; 95% CI 0.26–0.77) (62), and emotional awareness and expression training (RR = 0.49; 95% CI 0.28–0.87) (48) all appeared to be beneficial in IBS (Fig. 5).
This updated systematic review and meta-analysis has once again demonstrated that antidepressants and psychological therapies appear to be effective treatments for IBS. The NNT for TCAs and SSRIs was 4.5 and 5 respectively, although in the latter instance there was significant heterogeneity between studies, several negative RCTs, and a widening of the 95% CI of effect. Adverse events were significantly higher among those taking antidepressants, particularly among those allocated to TCAs, with a NNH of 8.5. When all psychological therapies, including hypnotherapy, were considered the NNT was 4. CBT, relaxation therapy, multicomponent psychological therapy, hypnotherapy, and dynamic psychotherapy were all more effective than control therapy, when data from two or more RCTs were pooled, with NNTs of between 4 and 6. Self-administered or minimal contact CBT, stress management, mindfulness meditation training, and CBT delivered via the internet were of no benefit, although 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 individuals in the eligible trials was small. Multi-component psychological therapy delivered mainly via the telephone, contingency management, and emotional awareness and expression training also appeared beneficial, although there was only one RCT for each of these treatment modalities. Finally, adverse events data were poorly reported among trials of psychological therapies.
We used an exhaustive search strategy, which involved searching the “gray” literature. Assessment of eligibility and data extraction was performed independently by two reviewers. We used an intention-to-treat analysis and pooled data with a random effects model, to minimize the likelihood that treatment effect 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 disorders from the analysis. This inclusive approach has provided us with access to data for >1000 IBS patients treated with antidepressants versus placebo, and almost 2500 patients randomized to psychological therapies versus control. We also performed subgroup analyses to assess treatment effect according to individual therapy used. Finally, we extracted and pooled adverse events data, where reported.
Limitations of this systematic review and meta-analysis arise from the studies available for synthesis. There were very few trials at low risk of bias, and there was evidence of heterogeneity between RCTs of SSRIs and psychological therapies as a whole, although not for TCAs, hypnotherapy, or multi-component psychological therapy. There was also evidence of publication bias, or other small study effects, for both antidepressants and psychological therapies. For antidepressants, this disappeared when one small outlying RCT was excluded from the analysis. As we have highlighted in previous versions of this meta-analysis, this may have led to overestimation of the treatment effect for both antidepressants and psychological therapies, but this is likely to be more pronounced for psychological therapies.
It is interesting that there was no evidence for any benefit of psychological therapies that minimize personal contact with patients, such as internet-delivered therapies or minimal contact CBT. This suggests that more intensive personal contact is needed for psychological therapies to be effective. There is, however, a paucity of data on which patients and what type of IBS symptoms respond best to therapy, and in which setting. Only two of the RCTs we identified were conducted entirely within primary care (53,59), and definitive trials in this setting are needed. The efficacy of these therapies according to predominant stool pattern reported by the patient has also not been well studied. TCAs prolong orocecal and whole gut transit times (12,82), whereas SSRIs decrease orocecal transit time (12,14). It would, therefore, seem biologically plausible that TCAs would be more effective in diarrhea-predominant IBS, and SSRIs of greater benefit in constipation-predominant IBS, but only two published RCTs have assessed this approach (70,77). Antidepressants may have their beneficial effects in IBS in other ways. Although evidence for any effect of antidepressants on visceral hypersensitivity in the GI tract is limited (68,83), there are data demonstrating the efficacy of TCAs in other painful functional disorders, such as fibromyalgia (84), and chronic headache (85), but high quality data for SSRIs in these conditions are lacking (86,87). Interestingly, some of the strongest evidence for the painmodifying effects of antidepressants in chronic painful disorders comes from high quality RCTs of the serotonin and norepinephrine re-uptake inhibitors (SNRIs) duloxetine and milnacipran (88–92), neither of which have been tested in IBS trials to date.
Whether the benefit of antidepressants arises from the treatment of co-existent depression is controversial. Data from the RCTs included in this meta-analysis are conflicting, with three studies reporting no significant relationship between depression scores and improvement in IBS symptoms (65,67,75), one trial demonstrating that treatment effect with desipramine was actually greater in those without evidence of co-existent depression (81), and a fifth RCT of citalopram, where depressed individuals were excluded, showing no benefit of the drug in IBS (66). In treatment trials of SSRIs in IBS, the doses used were almost identical to those used to treat depression, but any effect on mood would seem less likely for TCA trials, where the doses used were considerably lower than those used for mood disorders. Interestingly, in a recent study, presence of depression seemed to modify the central response to pain in patients with IBS (93), suggesting that if antidepressants are indeed improving mood in patients with IBS this may have other beneficial effects.
In terms of future research, there remains a clear need for larger, high quality trials of both antidepressants and psychological therapies that are conducted in primary care, and which stratify patients according to both predominant stool pattern and presence or absence of mood disorder. Psychological therapies, such as CBT, work differently to pharmacological therapies in IBS, by acting on frontal “executive” areas of the brain in order to modify cognitive, behavioral, and emotional responses to symptoms. This may lead to a reduction in the anxiety that results from such symptoms, which can itself drive exacerbations of IBS via the enteric nervous system, and also improved social functioning. Trials that also test the hypothesis that there is an augmentative effect of combining psychological therapies with antidepressants, as appears to be the case in the treatment of chronic headache (94), are therefore also warranted. Perhaps surprisingly, to date, there have been no trials of SNRIs in IBS, and this should also be addressed, given their known efficacy in other painful functional disorders.
In summary, this updated systematic review and meta-analysis has demonstrated that TCAs, SSRIs, CBT, relaxation therapy, hypnotherapy, multi-component psychological therapy, and dynamic psychotherapy are probably effective treatments for IBS. Adverse effects are more common with antidepressants, particularly TCAs. Despite another five studies identified in the years since we last examined this issue, the overall summary estimates of treatment effect have remained very similar. Better knowledge of the point in the natural history at which to consider these therapies, as well as those subgroups of patients who are more likely to respond, could lead to improved treatment outcomes for patients with this difficult to treat chronic disorder
CONFLICTS OF INTEREST
Guarantor of the article: Alexander C. Ford, MBChB, MD, FRCP.
Specific author contributions: ACF, BEL, LAH, EMMQ, and PM conceived the study. ACF and PM collected all data. ACF and PM analyzed and interpreted the data. ACF drafted the manuscript. All authors commented on drafts of the paper. All authors have approved the final draft of the manuscript.
Financial support: American College of Gastroenterology.
Potential competing interests: None.
This study was performed to inform the American College of Gastroenterology Monograph on IBS. We would like to thank Dr. Johanne Agger, Dr. Doron Boltin, Professor Ram Dickman, and Dr. Elyse Thakur for responding to our queries about their papers and, in some instances, providing us with extra data. The work was supported by the American College of Gastroenterology Institute and the Canadian Institute for Health Research. Paul Moayyedi is the Principal Investigator for the Inflammation, microbiome, and alimentation: gastro-intestinal and neuropsychiatric effects (IMAGINE) - a Strategy for Patient Oriented Research (SPOR) chronic disease network that evaluates the impact of psychological interventions in GI disease.
1. Mearin F, Lacy BE, Chang L, et al Bowel disorders. Gastroenterology. 2016;150:1393–407.
2. Lovell RM, Ford AC. Global prevalence of, and risk factors for, irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10:712–21.
3. Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the community: systematic review and meta-analysis. Am J Gastroenterol. 2012;107:991–1000.
4. Drossman DA. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology. 2016;148:1262–79.
5. Osterberg E, Blomquist L, Krakau I, et al A population study on irritable bowel syndrome and mental health. Scand J Gastroenterol. 2000;35:264–8.
6. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122:1140–56.
7. Drossman DA, Tack J, Ford AC, et al Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome Foundation working team report. Gastroenterology. 2018;154:1140–1171.e1.
8. Lowen MB, Mayer EA, Sjoberg M, et al Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome. Aliment Pharmacol Ther. 2013;37:1184–97.
9. Morgan V, Pickens D, Gautam S, et al Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome. Gut. 2005;54:601–7.
10. Simren M, Ringstrom G, Bjornsson ES, et al Treatment with hypnotherapy reduces the sensory and motor component of the gastrocolonic response in irritable bowel syndrome. Psychosom Med. 2004;66:233–8.
11. Cannon RO 3rd, Quyyumi AA, Mincemoyer R, et al Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med. 1994;330:1411–7.
12. Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther. 1994;8:159–66.
13. Broekaert D, Fischler B, Sifrim D, et al Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2006;23:365–70.
14. Chial HJ, Camilleri M, Burton D, et al Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health. Am J Physiol Gastrointest Liver Physiol. 2003;284:G130–7.
15. Ladabaum U, Boyd E, Zhao WK, et al Diagnosis, comorbidities, and management of irritable bowel syndrome in patients in a large health maintenance organization. Clin Gastroenterol Hepatol. 2012;10:37–45.
16. Everitt H, Landau S, Little P, et al Assessing Cognitive Behavioural Therapy in Irritable Bowel (ACTIB): protocol for a randomised controlled trial of clinical-effectiveness and cost-effectiveness of therapist delivered cognitive behavioural therapy and web-based self-management in irritable bowel syndrome in adults. BMJ Open. 2015;5:e008622.
17. Harkness EF, Harrington V, Hinder S, et al GP perspectives of irritable bowel syndrome–an accepted illness, but management deviates from guidelines: a qualitative study. BMC Fam Pract. 2013;14:92.
18. Shivaji UN, Ford AC. Beliefs about management of irritable bowel syndrome in primary care: cross-sectional survey in one locality. Prim Health Care Res Dev. 2014;16:263–9.
19. Drossman DA. Functional GI disorders: what's in a name? Gastroenterology. 2005;128:1771–2.
20. Ford AC, Quigley EM, Lacy BE, et al Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2014;109:1350–65.
21. Ford AC, Talley NJ, Schoenfeld PS, et al Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58:367–78.
22. Ford AC, Moayyedi P, Lacy BE, et al American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109 (Suppl 1):S2–26.
23. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al An evidence-based systematic review on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl I):S8–35.
24. Chang L, Lembo A, Sultan S. American Gastroenterological Association Institute Technical Review on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014;147:1149–72.e2.
25. Ford AC, Guyatt GH, Talley NJ, et al Errors in the conduct of systematic reviews of pharmacological interventions for irritable bowel syndrome. Am J Gastroenterol. 2010;105:280–8.
26. Ford AC, Moayyedi P, Chey WD, et al American College of Gastroenterology's monograph on the management of irritable bowel syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1–18.
28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.
29. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.
30. Egger M, Davey-Smith G, Schneider M, et al Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.
31. Sterne JA, Sutton AJ, Ioannidis JP, et al Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.
32. Blanchard EB, Schwarz SP, Suls JM, et al Two controlled evaluations of multicomponent psychological treatment of irritable bowel syndrome. Behav Res Ther. 1992;30:175–89.
33. Blanchard EB, Greene B, Scharff L, et al Relaxation training as a treatment for irritable bowel syndrome. Biofeedback Self Regul. 1993;18:125–31.
34. Galovski TE, Blanchard EB. The treatment of irritable bowel syndrome with hypnotherapy. Appl Psychophysiol Biofeedback. 1998;23:219–32.
35. Greene B, Blanchard EB. Cognitive therapy for irritable bowel syndrome. J Consult Clin Psychol. 1994;62:576–82.
36. Keefer L, Blanchard EB. The effects of relaxation response meditation on the symptoms of irritable bowel syndrome: results of a controlled treatment study. Behav Res Ther. 2001;39:801–11.
37. Lynch PM, Zamble E. A controlled behavioral treatment study of irritable bowel syndrome. Behav Ther. 1989;20:509–23.
38. Neff DF, Blanchard EB. A multi-component treatment for irritable bowel syndrome. Behav Ther. 1987;18:70–83.
39. Payne A, Blanchard EB. A controlled comparison of cognitive therapy and self-help support groups in the treatment of irritable bowel syndrome. J Consult Clin Psychol. 1995;63:779–86.
40. Sanders KA, Blanchard EB, Sykes MA. Preliminary study of a self-administered treatment for irritable bowel syndrome: comparison to a wait list control group. Appl Psychophysiol Biofeedback. 2007;32:111–9.
41. Tkachuk GA, Graff LA, Martin GL, et al Randomized controlled trial of cognitive-behavioral group therapy for irritable bowel syndrome in a medical setting. J Clin Psychol Med Settings. 2003;10:57–69.
42. Vollmer A, Blanchard EB. Controlled comparison of individual versus group cognitive therapy for irritable bowel syndrome. Behav Ther. 1998;29:19–33.
43. Craske MG, Wolitzky-Taylor KB, Labus J, et al A cognitive-behavioral treatment for irritable bowel syndrome using interoceptive exposure to visceral sensations. Behav Res Ther. 2011;49:413–21.
44. Hunt MG, Moshier S, Milonova M. Brief cognitive-behavioral internet therapy for irritable bowel syndrome. Behav Res Ther. 2009;47:797–802.
45. Lackner JM, Jaccard J, Krasner SS, et al Self-administered cognitive behavior therapy for moderate to severe irritable bowel syndrome: clinical efficacy, tolerability, feasibility. Clin Gastroenterol Hepatol. 2008;6:899–906.
46. Ljotsson B, Falk L, Wibron Vesterlund A, et al Internet-delivered exposure and mindfulness based therapy for irritable bowel syndrome - a randomized controlled trial. Behav Res Ther. 2010;48:531–9.
47. Zernicke KA, Campbell TS, Blustein PK, et al Mindfulness-based stress reduction for the treatment of irritable bowel syndrome symptoms: a randomized wait-list controlled trial. Int J Behav Med. 2013;20:385–96.
48. Thakur ER, Holmes HJ, Lockhart NA, et al Emotional awareness and expression training improves irritable bowel syndrome: a randomized controlled trial. Neurogastroenterol Motil 2017;29: https://doi.org/10.1111/nmo
49. Boyce PM, Talley NJ, Balaam B, et al A randomized controlled trial of cognitive behavior therapy, relaxation training, and routine clinical care for the irritable bowel syndrome. Am J Gastroenterol. 2003;98:2209–18.
50. Creed F, Fernandes L, Guthrie E, et al The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology. 2003;124:303–17.
51. Guthrie E, Creed F, Dawson D, et al A controlled trial of psychological treatment for the irritable bowel syndrome. Gastroenterology. 1991;100:450–7.
52. Heitkemper M, Jarrett ME, Levy RL, et al Self-management for women with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:585–96.
53. Kennedy T, Jones R, Darnley S, et al Cognitive behaviour therapy in addition to antispasmodic treatment for irritable bowel syndrome in primary care: randomised controlled trial. BMJ. 2005;331:435–7.
54. Shaw G, Srivastava ED, Sadlier M, et al Stress management for irritable bowel syndrome: a controlled trial. Digestion. 1991;50:36–42.
55. van der Veek PPJ, van Rood YR, Masclee AAM. Clinical trial: short- and long-term benefit of relaxation training for irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:943–52.
56. Jarrett ME, Cain KC, Burr RL, et al Comprehensive self-management for irritable bowel syndrome: Randomized trial of in-person vs. combined in-person and telephone sessions. Am J Gastroenterol. 2009;104:3004–14.
57. Lindfors P, Unge P, Arvidsson P, et al Effects of gut-directed hypnotherapy on IBS in different clinical settings - results from two randomized, controlled trials. Am J Gastroenterol. 2012;107:276–85.
58. Moser G, Tragner S, Elwira Gajowniczek E, et al Long-term success of GUT-directed group hypnosis for patients with refractory irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2013;108:602–9.
59. Moss-Morris R, McAlpine L, Didsbury LP, et al A randomized controlled trial of a cognitive behavioural therapy-based self-management intervention for irritable bowel syndrome in primary care. Psychol Med. 2010;40:85–94.
60. Shinozaki M, Kanazawa M, Kano M, et al Effect of autogenic training on general improvement in patients with irritable bowel syndrome: a randomized controlled trial. Appl Psychophysiol Biofeedback. 2010;35:189–98.
61. Boltin D, Sahar N, Gil E, et al Gut-directed guided affective imagery as an adjunct to dietary modification in irritable bowel syndrome. J Health Psychol. 2015;20:712–20.
62. Fernandez C, Perez M, Amigo I, et al Stress and contingency management in the treatment of irritable bowel syndrome. Stress Med. 1998;14:31–42.
63. Gaylord SA, Palsson OS, Garland EL, et al Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial. Am J Gastroenterol. 2011;106:1678–88.
64. Talley NJ, Kellow JE, Boyce P, et al Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial. Dig Dis Sci. 2008;53:108–15.
65. Tack J, Broekaert D, Fischler B, et al A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006;55:1095–103.
66. Ladabaum U, Sharabidze A, Levin TR, et al Citalopram is not effective therapy for nondepressed patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2010;8:42–8.
67. Tabas G, Beaves M, Wang J, et al Paroxetine to treat irritable bowel syndrome not responding to high fiber diet: a double-blind placebocontrolled trial. Am J Gastroenterol. 2004;99:914–20.
68. Kuiken SD, Tytgat GNJ, Boeckxstaens GEE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: A double-blind, randomized, placebo-controlled study. Clin Gastroenterol Hepatol. 2003;1:219–28.
69. Masand PS, Pae CU, Krulewicz S, et al A double-blind, randomized, placebo-controlled trial of paroxetine controlled-release in irritable bowel syndrome. Psychosomatics. 2009;50:78–86.
70. Vahedi H, Merat S, Rashidioon A, et al The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther. 2005;22:381–5.
71. Heefner JD, Wilder RM, Wilson ID. Irritable colon and depression. Psychosomatics. 1978;19:540–7.
72. Myren J, Groth H, Larssen SE, et al The effect of trimipramine in patients with the irritable bowel syndrome: a double-blind study. Scand J Gastroenterol. 1982;17:871–5.
73. Nigam P, Kapoor KK, Rastog CK, et al Different therapeutic regimens in irritable bowel syndrome. J Assoc Physicians India. 1984;32:1041–4.
74. Boerner D, Eberhardt R, Metz K, et al Wirksamkeit und vertraglichkeit eines antidepressivuns beim colon irritabile. Therapiewoche. 1988;38:201–8.
75. Vij JC, Jiloha RC, Kumar N, et al Effect of antidepressant drug (doxepin) on irritable bowel syndrome patients. Indian J Psychiatry. 1991;33:243–6.
76. Bergmann M, Heddergott A, Schlosser T. [Die therapie des colon irritabile mit trimipramin (Herphonal) - Eine kontrollierte studie]. Z Klin Med. 1991;46:1621–8.
77. Vahedi H, Merat S, Momtahen S, et al Clinical trial: the effect of amitriptyline in patients with diarrhea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2008;27:678–84.
78. Abdul-Baki H, Hajj EL II, El Zahabi L, et al A randomized controlled trial of imipramine in patients with irritable bowel syndrome. World J Gastroenterol. 2009;15:3636–42.
79. Ghadir MR, Habibinejad H, Heidari A, et al Doxepin is more effective than nortriptyline and placebo for the treatment of diarrhea-predominant irritable bowel syndrome: a randomized triple-blind placebo-controlled trial. Tehran Univ Med J. 2011;69:352–8.
80. Agger JL, Schroder A, Gormsen LK, et al Imipramine versus placebo for multiple functional somatic syndromes (STreSS-3): a double-blind, randomised study. Lancet Psychiatry. 2017;4:378–88.
81. Drossman DA, Toner BB, Whitehead WE, et al Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003;125:19–31.
82. Gorard DA, Libby GW, Farthing MJ. Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea-predominant irritable bowel syndrome. Dig Dis Sci. 1995;40:86–95.
83. Siproudhis L, Dinasquet M, Sebille V, et al Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception. Aliment Pharmacol Ther. 2004;20:689–95.
84. Moore RA, Derry S, Aldington D, et al Amitriptyline for fibromyalgia in adults. Cochrane Database Syst Rev. 2015;7:CD008242.
85. Jackson JL, Shimeall W, Sessums L, et al Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222.
86. Walitt B, Urrutia G, Nishishinya MB, et al Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015:CD011735.
87. Banzi R, Cusi C, Randazzo C, et al Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev. 2015:CD011681.
88. Cording M, Derry S, Phillips T, et al Milnacipran for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2015:CD008244.
89. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014:CD007115.
90. Skljarevski V, Ossanna M, Liu-Seifert H, et al A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain. Eur J Neurol. 2009;16:1041–8.
91. Skljarevski V, Zhang S, Desaiah D, et al Duloxetine versus placebo in patients with chronic low back pain: A 12-week, fixed-dose, randomized, double-blind trial. J Pain. 2010;11:1282–90.
92. Konno S, Oda N, Ochiai T, et al Randomized, double-blind, placebo controlled phase III trial of duloxetine monotherapy in Japanese patients with chronic low back pain. Spine (Phila Pa 1976). 2016;41:1709–17.
93. Schmid J, Langhorst J, Gass F, et al Placebo analgesia in patients with functional and organic abdominal pain: a fMRI study in IBS, UC and healthy volunteers. Gut. 2015;64:418–27.
© The American College of Gastroenterology 2019. All Rights Reserved.
94. Holroyd KA, O'Donnell FJ, Stensland M, et al Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA. 2001;285:2208–15.