Study Links Antidepressant Use to Higher Mortality Risk in IBS Patients

A large observational study analyzing health records of over 669,000 U.S. adults with irritable bowel syndrome (IBS) found an association between antidepressant use and a higher risk of death from any cause. The study, published in Communications Medicine, reported that antidepressant use was linked to a 35% higher risk of all-cause mortality compared to non-use. The research also identified associations between other medication classes and mortality risk, varying by IBS subtype. Researchers noted the study's observational design limits causal conclusions and highlighted the potential for confounding factors.

Study Overview and Methodology

The research analyzed de-identified electronic health records from 106 U.S. healthcare organizations. The study population consisted of a propensity score–matched cohort of 669,083 adults diagnosed with IBS.

The methodology employed a target-trial emulation framework and used active comparators to reduce bias. Negative control outcomes, such as diagnoses for frostbite and acute appendicitis, showed no significant associations, which the researchers noted supports the robustness of the primary findings.

Primary Findings on Medication Use and Mortality

Antidepressants were the most commonly prescribed medication class among the studied IBS patients, used by 52.3% of the cohort.

During the follow-up period, 1.6% of antidepressant users died, compared to 1.01% of non-users.

Antidepressant use was associated with a 35% higher risk of all-cause mortality. This association was observed across subgroups stratified by sex, age, body mass index, and ethnicity. The associated risk increased with the number of prescription refills. At 20 refills, the mortality risk was nearly twice that of non-users.

Findings by Antidepressant Category:

• Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) showed an increased mortality risk of 27% to 32%.
• Mirtazapine use was associated with an observed mortality rate of 5.29%, compared to 2.27% for non-users. The study authors noted this finding may be influenced by residual confounding.

Other Medication Classes:

• Antispasmodics, used by 22.1% of patients, were not associated with an increased mortality risk.
• Kaplan-Meier analysis indicated antidepressant users had lower survival rates after five years compared to antispasmodic users.

Analysis by IBS Subtype

• Use of mu-opioid receptor agonists was associated with higher mortality rates.
  • Diphenoxylate users had a mortality rate of 2.34%, versus 1.38% for non-users.
  • Loperamide users had a mortality rate of 2.1%, versus 0.98% for non-users.
• Patients treated with antispasmodics had better three-year survival than those receiving mu-opioid receptor agonists.
• Antidepressant use within this subgroup was associated with approximately a 50% higher mortality risk.
• No increased mortality risk was observed with rifaximin or bile acid sequestrants.

• Commonly used treatments such as laxatives and secretagogues were not associated with increased mortality risk.
• Antidepressant use in this subgroup was linked to approximately a 56% higher mortality rate.

Secondary Health Outcomes

The study reported that IBS patients prescribed antidepressants were more likely to have certain coexisting conditions compared to other IBS patients, including:

• Cardiovascular disease
• Gastrointestinal bleeding
• Suicidal ideation (five times higher risk)
• Obesity (80% increased risk)
• Hypertension (43% higher chance)

The researchers stated these associations may reflect baseline differences between patient groups, comorbidities, treatment effects, or residual confounding.

Study Limitations and Context

The authors outlined several important limitations:

• The observational design limits causal inference for the identified associations.
• Potential exists for misclassification of cases and unmeasured confounding factors.
• The study could not determine cause-specific mortality.
• Reliance on electronic health record and insurance claims data may introduce classification errors.

Background on IBS Treatment:

• Irritable bowel syndrome is estimated to affect up to 15% of the global population.
• Approved medications for IBS include lubiprostone, rifaximin, eluxadoline, and alosetron. These are used by fewer than 20% of patients with IBS-C and fewer than 10% of patients with IBS-D.
• Non-approved medications, including antidepressants, antispasmodics, and bile acid sequestrants, are frequently used off-label to manage IBS symptoms. Antidepressants are commonly prescribed to help modulate gut-brain signaling and pain perception.

The study concluded that the findings highlight safety differences among commonly prescribed IBS medications and indicate a need for cautious long-term prescribing and further prospective investigation.