Higher mortality risk in IBS patients using antidepressants

A massive real-world study raises new safety questions about widely used IBS treatments, revealing that some commonly prescribed drugs may carry higher long-term risks than previously understood.

Study: Association of pharmacotherapy with all-cause mortality among patients with irritable bowel syndrome. Image credit: Doucefleur/Shutterstock.com

Irritable bowel syndrome (IBS) is a common disorder of the gut that can severely impact the quality of life. Several medications are used long-term to help patients manage their symptoms, but their safety remains unclear. A recent study in Communications Medicine found that antidepressant use in IBS was associated with a higher risk of all-cause mortality.

IBS medications

IBS presents with constipation, diarrhea, or a mixture of both. Its origin is unclear and involves genetic predisposition, gut dysbiosis, social and psychological stress, and immunological and visceral hypersensitivity to trigger factors. As it affects up to 15 % of the world’s population and carries high health-related, economic, and societal costs, its management warrants intensive research.

Approved medications for IBS include those that increase intestinal fluid secretion, such as lubiprostone, antibiotics like rifaximin, and agents that reduce bowel motility, such as eluxadoline and alosetron. These are used by fewer than 20 % of patients with IBS-C and fewer than 10 % of patients with IBS-D.

In contrast, non-approved medications like tricyclic and other antidepressants, antispasmodics, and bile acid sequestrants are often used to treat various IBS symptoms. Antidepressants are commonly prescribed in IBS to help modulate gut–brain signaling and pain perception. Because they are used off-label, their long-term safety in this indication is unknown.

The current study used electronic health records (EHRs) from 106 US healthcare organizations within a large nationwide database, with a propensity score–matched cohort of 669,083 adults with IBS. The most commonly used medication classes were antidepressants, used by 52.3 % of patients. Next came antispasmodics at 22.1 %.

Antidepressants are associated with a higher mortality risk

About 1.6 % of antidepressant users died during the follow-up period, compared to 1.01 % of non-users. The use of antidepressants in IBS was thus associated with a 35 % higher risk of all-cause mortality compared to non-users, irrespective of disease phenotype. This was observed across subgroups stratified by sex, age, body mass index, and ethnicity.

When stratified by drug category, such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), an increase in risk by 27 % to 32 % was observed. In contrast, mirtazapine use was associated with a substantially higher observed mortality rate (5.29 % vs. 2.27 %), although this finding may be influenced by residual confounding compared with non-users.

However, this was not true of antispasmodic use. In addition, when antidepressant users were compared with antispasmodic users (with no history of antidepressant use), the former were shown to have lower survival rates after five years. This Kaplan–Meier analysis showed a divergence in survival over time, though it does not show causality.

With increased antidepressant prescription refills, the associated mortality risk increased. At 20 refills, it was nearly twice that of non-users.

IBS-D subgroup

Patients with IBS-D, characterized by diarrheal symptoms, are commonly treated with mu-opioid receptor agonists such as loperamide and diphenoxylate to reduce bowel motility. In this study, mortality rates were higher among users of these drugs, with 2.34 % of diphenoxylate users and 2.1 % of loperamide users dying from all causes, compared to 1.38 % and 0.98 % of non-users, respectively, indicating an association with increased mortality risk.

Comparative analyses further showed that patients treated with antispasmodics had better three-year survival than those receiving mu-opioid receptor agonists, with survival curves diverging over time. While these findings may reflect known risks such as cardiac arrhythmias at high doses, the relatively small number of events limits any conclusions about causality.

Within the same subgroup, antidepressant use was also associated with increased mortality, with 0.77 % of users dying compared to 0.57 % of non-users, representing an approximately 50 % higher risk. In contrast, no increased mortality risk was observed with rifaximin or bile acid sequestrants.

IBS-C subtype

In patients with IBS-C, the constipation subtype, commonly used treatments such as laxatives and secretagogues were not associated with an increased risk of mortality. However, antidepressant use in this subgroup was linked to a higher mortality rate, with 0.82 % of users dying compared to 0.64 % of non-users, an increase of approximately 56 %.

Other antidepressant-linked outcomes

IBS patients on antidepressants were much more likely to have cardiovascular disease, bleeding from the gut, suicidal ideas, and obesity. For instance, these patients had a 43 % higher chance of hypertension, 80 % increased risk of obesity, and five times higher risk of suicidal ideation. These secondary outcomes were associated with antidepressant use but may reflect baseline differences, comorbidities, treatment effects, or residual confounding, with no data to differentiate them.

Negative controls show no association

A number of unrelated conditions, such as frostbite and acute appendicitis, were also compared across the treatment subgroups to assess for spurious associations. This revealed that negative control outcomes did not show significant associations, supporting the robustness of the findings.

Strengths and limitations

This large study used long-term follow-up with adjusted analyses to identify meaningful associations between IBS drugs and mortality risk. Strengths include propensity score matching across multiple covariates, a target-trial emulation framework, and the use of active comparators to reduce bias.

Some limitations exist, such as the potential for misclassification of cases and unmeasured confounding. The observational design limits causal inference for the associations identified here. Additionally, the study could not determine cause-specific mortality and relied on EHR/claims data, which may introduce classification errors.

Implications of the study

This real-world evaluation of mortality risk associated with commonly used drugs in IBS suggests an association between antidepressant use and higher all-cause mortality risk. The occurrence of increased adverse health outcomes with long-term antidepressant use is supported by other studies. Causality could not be inferred due to the observational nature of the study and the probability of residual confounding.

These findings highlight important safety differences among commonly prescribed IBS medications and underscore the need for cautious long-term prescribing and further prospective investigations.

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