Common IBS Medications Linked to Increased Mortality Risk in Large US Cohort Study

Long-term use of some commonly prescribed medications for irritable bowel syndrome (IBS), including antidepressants and select antidiarrheal agents, was associated with an increased risk of all-cause mortality in a large retrospective cohort study of US adults.

The findings, published in Communications Medicine, are based on analysis of 669 083 adults aged 18 to 65 years with IBS using a nationwide electronic health record database spanning 2005 to 2023.

Antidepressants Associated With Higher Mortality Across Subgroups

Antidepressant use was associated with a significantly increased risk of all-cause mortality compared with nonuse (hazard ratio [HR], 1.35; 95% CI, 1.26–1.45), with mortality rates of 1.6% vs 1.0%, respectively.

The association was consistent across antidepressant classes, including:

• Selective serotonin reuptake inhibitors (HR, 1.32; 95% CI, 1.22–1.44)
• Tricyclic antidepressants (HR, 1.27; 95% CI, 1.14–1.43)
• Serotonin-norepinephrine reuptake inhibitors (HR, 1.32; 95% CI, 1.19–1.46)
• Mirtazapine (HR, 2.05; 95% CI, 1.73–2.43)

Notably, the increased mortality risk persisted across demographic subgroups, including stratification by age, sex, body mass index, and race/ethnicity.

A dose-response relationship was also observed, with higher numbers of antidepressant refills associated with progressively increased mortality risk, reaching an HR of 1.91 with 20 refills.

Antidiarrheal Agents Show Variable Risk in IBS-D

Among patients with diarrhea-predominant IBS (IBS-D), certain commonly used agents were associated with increased mortality risk:

• Loperamide (HR, 2.39; 95% CI, 1.48–3.90)
• Diphenoxylate (HR, 1.89; 95% CI, 1.02–3.51)

In contrast, other therapies were not associated with increased mortality, including rifaximin, eluxadoline, bile acid sequestrants, and antispasmodics.

Kaplan–Meier analyses (Figure 3, page 6) demonstrated divergence in survival curves over time between patients receiving mu receptor agonists and those receiving antispasmodics, suggesting a potential long-term safety signal.

No Increased Risk With IBS-C Therapies

For constipation-predominant IBS (IBS-C), commonly used therapies—including polyethylene glycol 3350 and secretagogues—were not associated with increased mortality risk.

Antispasmodics, including dicyclomine and hyoscyamine, were also not linked to increased mortality and served as a comparator group in the analysis.

Secondary Outcomes Suggest Broader Safety Signals

Antidepressant use was associated with increased risks of several adverse outcomes, including hypertension, cardiac arrhythmias, heart failure, stroke, gastrointestinal bleeding, and falls, with hazard ratios ranging from 1.21 to 5.19.

Investigators noted increased risks of aspiration pneumonitis, serotonin syndrome, and suicidal ideation, further underscoring potential safety concerns with long-term use.

Study Design and Limitations

The study used a propensity score–matched design with 1:1 matching across 56 covariates to reduce confounding and incorporated a target trial emulation framework.

However, as an observational study using electronic health record data, findings are subject to residual confounding, potential misclassification, and inability to determine cause-specific mortality.

Clinical Implications for Primary Care

IBS affects approximately 10% to 15% of the global population and is frequently managed in primary care, where antidepressants and symptomatic therapies are commonly prescribed.

The findings raise questions about long-term safety of certain pharmacotherapies and suggest that clinicians should carefully weigh risks and benefits when prescribing antidepressants and opioid receptor agonists for IBS, particularly for chronic use.

At the same time, the absence of increased mortality risk with several guideline-recommended and FDA-approved therapies may help inform safer treatment selection.

References:

1. Mehravar S, Yeo YH, Pimentel M, Naji P, Ng WH, Burger N, Takakura W, Rezaie A. Association of pharmacotherapy with all-cause mortality among patients with irritable bowel syndrome. Commun Med (Lond). 2026 Apr 8;6(1):176. doi: 10.1038/s43856-026-01498-6
2. Cedars-Sinai Medical Center. Some common IBS treatments linked to higher risk of death. News release. April 8, 2026. Accessed April 9, 2026. https://www.eurekalert.org/news-releases/1122913