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

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Ford AC, et al. "Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis". American Journal of Gastroenterology. 2014. 109(9):1350-1365.
PubMed

Clinical Question

In patients with Irritable Bowel Syndrome (IBS), are the use of antidepressants safe and more effective at reducing symptoms compared to placebo alone?

Bottom Line

Antidepressants are effective at treating the symptoms of irritable bowel syndrome (IBS) and were found safe, causing no serious adverse events but more adverse events than placebo.

Major Points

With a prevalence of between 5 and 20%, irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders worldwide.[1] Patients with IBS consume >50% more health care resources than matched controls without IBS.[2] Patients with IBS demonstrate visceral hypersensitivity to painful stimuli,[3] [4] abnormal central processing of pain,[5] and higher levels of psychological comorbidity compared with non IBS patients.[6] [7] Exercise, antidiarrheals, antispasmodics, and antidepressants are common treatment options for IBS.

In this systematic review and meta analysis, there were 17 randomized controlled trials (RCTs) comparing antidepressants with placebo in the treatment of IBS. The trials evaluated a total of 1,084 patients, 592 of whom received antidepressant therapy and 492 received placebo.[8] Ten trials included tricyclic antidepressants (TCAs), six included selective serotonin reuptake inhibitor (SSRIs), and one trial studied both. 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. The NNT with antidepressants was 4 (95 % CI = 3 – 6). There were no serious adverse events reported with the use of antidepressants, however there was a significantly higher incidence of adverse events reported compared to placebo (NNH=9, 95 % CI 5 – 111).


Guidelines

American Gastroenterological Association (updated 2014)[9] The AGA recommends the use of tricyclic antidepressants over no therapy in patients with IBS (conditional recommendation, low-quality evidence) The AGA recommends against the use of selective serotonin reuptake inhibitors in patients with IBS (conditional recommendation, low-quality evidence)

Design

  • Systematic Review, Meta-analysis of 17 Randomized Controlled Trials
  • N= 1,084
    • Antidepressant therapy (n=592)
    • Placebo (n=492)
  • Setting: 17 Centers in the US, Norway, India, Germany, Holland, Iran, Belgium, Australia, Lebanon
  • Enrollment: studies published 1978-2010
  • Analysis: Intention-to-treat
  • Primary outcome: IBS symptoms cure or improvement or abdominal pain cure or improvement after completion of therapy

Population

Inclusion Criteria

  • Adults, over the age of 16 years
  • Diagnosis of IBS based on either a clinician’s opinion or meeting specific diagnostic criteria
  • Age 40-79 years with CAD or 55-79 years with
  • Minimum duration of therapy 7 days
  • Minimum duration of follow up 7 days


Exclusion Criteria

  • No specific exclusion criteria for trials


Baseline Characteristics

  • Individual study baseline characteristics not reported


Interventions

  • 17 randomized control trials in which antidepressants were compared to placebo.
    • 10 trials used tricyclic antidepressants.
    • 6 trials used selective serotonin reuptake inhibitors.
    • 1 trial used both antidepressants
  • Each trial assessed stated the percentage of female patients, antidepressant used, dose, duration of therapy, and method of randomization.
  • The majority of trials did not state the type of IBS assessed

Outcomes

Comparisons are antidepressants vs. placebo.

Primary Outcomes

No improvement in abdominal pain after cessation of therapy
47.8% vs. 72.8% in 7 RCTs (RR 0.62; 95% CI 0.43-0.88, I2=72.4%) (NNT=4)


Secondary Outcomes

Secondary outcomes assessing efficacy according to specific type of antidepressant

Tricyclic antidepressants vs. placebo

No improvement in abdominal pain after cessation of therapy
43.3% vs. 63.7% in 11 RCTs (RR 0.66; 95% CI 0.56-0.79, I2=35%) (NNT=5)

Selective serotonin reuptake inhibitors vs. placebo

No improvement in abdominal pain after cessation of therapy
45.5% vs. 67.2% in 7 RCTs (RR 0.68; 95% CI 0.51-0.91, I2=49%) (NNT=5)

Antidepressants vs. placebo

Incidence of adverse events
31.3% vs. 16.5% (RR 1.63; 95% CI 1.18-2.25) (NNH=7)

Subgroup Analysis

Analysis of RCTs comparing antidepressants vs. placebo on no improvement in IBS symptoms based on trial methodology

Setting 
  • Secondary care: RR 0.55; 95% CI 0.43-0.70 in 8 trials
  • Tertiary care: RR 0.74; 95% CI 0.63-0.86 in 8 trials
Criteria used to define IBS 
  • Rome: RR 0.66; 95% CI 0.55-0.81 in 12 trials
  • Clinical diagnosis: RR 0.67; 95% CI 0.54-0.83 in 6 trials
Method of randomization 
  • Stated: RR 0.69; 95% CI 0.57-0.85 in 11 trials
  • Not stated: RR 0.63; 95% CI 0.51-0.77 in 7 trials
Concealment of allocation 
  • Stated: RR 0.76; 95% CI 0.61-0.94 in 6 trials
  • Not stated: RR 0.61: 95% CI 0.50-0.73 in 12 trials
Blinding 
  • Double: RR 0.69; 95% CI 0.60-0.79 in 17 trials
  • Not stated: RR 0.30; 95% CI 0.14-0.65 in 1 trial
Risk of bias 
  • Low: RR 0.76; 95% CI 0.46-1.27 in 3 trials
  • Unclear or high: RR 0.66; 95% CI 0.57-0.76 in 15 trials

Adverse Events

  • No significant adverse events were reported

Criticisms

  • There was evidence of publication bias and other small study effects for both antidepressants. For antidepressants, this disappeared when one small outlying RCT was excluded from the analysis.
  • There was evidence of heterogeneity between RCTs for the use of antidepressants in reducing global IBS symptoms and abdominal pain.
  • Subgroup analyses demonstrated that treatment effect was generally lower in studies that reported the method of generation of the randomization schedule and concealment of allocation.

Funding

American College of Gastroenterology

Further Reading

  1. Lovell RM & Ford AC Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin. Gastroenterol. Hepatol. 2012. 10:712-721.e4.
  2. Inadomi JM et al. Systematic review: the economic impact of irritable bowel syndrome. Aliment. Pharmacol. Ther. 2003. 18:671-82.
  3. Moriarty KJ & Dawson AM Functional abdominal pain: further evidence that whole gut is affected. Br Med J (Clin Res Ed) 1982. 284:1670-2.
  4. Trimble KC et al. Heightened visceral sensation in functional gastrointestinal disease is not site-specific. Evidence for a generalized disorder of gut sensitivity. Dig. Dis. Sci. 1995. 40:1607-13.
  5. Tillisch K et al. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology 2011. 140:91-100.
  6. Osterberg E et al. A population study on irritable bowel syndrome and mental health. Scand. J. Gastroenterol. 2000. 35:264-8.
  7. Whitehead WE et al. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?. Gastroenterology 2002. 122:1140-56.
  8. Ford AC 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; quiz 1366.
  9. Weinberg DS et al. American Gastroenterological Association Institute Guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology 2014. 147:1146-8.