Antidepressants and certain antidiarrheal drugs, such as loperamide and diphenoxylate, were linked to a slightly higher risk for death in adults with irritable bowel syndrome (IBS), according to findings of a recent study.

The findings, published in Communications Medicine, raise concerns about the safety of antidepressants and mu receptor agonists in IBS treatment and call for new considerations in long-term prescribing, the authors wrote.

Researchers performed a retrospective cohort study using the TriNetX Analytics US electronic health record (EHR) database from 2005 to 2023. The database compiles EHR data from 106 US healthcare organizations across all 50 states. The 1:1 propensity score-matched cohort included 669,083 adults (age, 18-65 years) with IBS. Patients were grouped by medication use and IBS subtype: IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). Exposures included therapies for IBS, IBS-D, or IBS-C recommended in guidelines and the primary outcome was all-cause mortality.

Antispasmodics Not Linked to Higher Mortality Risk

Antidepressants were linked to an increased risk for all-cause mortality (hazard ratio [HR], 1.35; 95% CI, 1.26-1.45; mortality rate, 1.6% vs 1.0%). The link was consistent across antidepressant subclasses and demographic subgroups. Antispasmodic use was not linked to increased mortality (HR, 0.95; 95% CI, 0.89-1.00). For IBS-D, cholestyramine/colestipol, eluxadoline, and rifaximin were not associated with mortality. However, diphenoxylate (HR, 1.89; 95% CI, 1.02-3.51) and loperamide (HR, 2.39; 95% CI, 1.48-3.90) show higher mortality risk. For IBS-C, polyethylene glycol 3350 and secretagogues had no significant link to mortality.

The researchers also observed other effects in patients with IBS using antidepressants: a 21% increase in inpatient visits (P < .0001); a 35% increase in ischemic heart disease or heart failure events; a 43% increase in hypertension; a 70% higher risk for aspiration pneumonia, cerebral infarction, and fall-related incidents; a 60% increase in serotonin syndrome; a 47% increase in gastrointestinal (GI) bleeding; an 80% higher risk for obesity; and a fivefold increase in suicidal ideation.

Population-Level Risk Substantial

While the absolute risk increase (from 1% to 1.6%) may seem small, “this is a nonfatal disease, and if you start a medication that could potentially increase your risk of mortality, that’s something you need to talk about,” Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai in Los Angeles, told Medscape Medical News.

He added that even though the absolute risk is small for individual patients, the population effect size is large when you consider the number of people diagnosed with IBS who start on these medications, often in their twenties and thirties, and remain on them for many decades.

“This 0.6 (absolute risk increase) among 30 million patients in the US alone is substantial, which represents a large health economic issue,” he said.

Findings Should Inform Discussions With Patients

Their findings should help inform discussion between doctors and patients, Rezaie said, but should not be seen as a reason to immediately stop taking them.

“Patients shouldn’t panic if they have a medication that’s working for them, but they also need to know there are other medications they can try that are FDA approved and known to have less side effects. There are also lifestyle modifications that can help.”

GI doctors should think about the potential long-term side effects so patients can help make informed decisions, he said. This study offers a broader look as clinical trials assess the safety of the medications within a limited time, he noted, “and rare side effects and long-term side effects do not pop up in that time.”

Findings ‘Quite Striking’

“I think these results are likely to surprise both patients and GI doctors,” Bryan Curtin, MD, MHSc, director of The Center for Neurogastroenterology and GI Motility at Mercy in Baltimore, told Medscape Medical News.

“We generally think of these agents as relatively benign, so the suggestion that mortality is higher in this group is quite striking” said Curtin, who was not part of the study. “For patients, anything that increases mortality is going to raise all sorts of alarm bells. We saw similar findings with PPIs [proton pump inhibitors] about a decade ago with large population cohorts, and there is still fallout from that even today. It’s really important to emphasize that just because there is an association here doesn’t mean that these agents are causing the mortality.”

As for the size of the mortality risk increase, Curtin said it “is not a tiny signal,” especially in commonly used medications across so many patients.

“It’s interesting that all antidepressants seemed to show elevated risk which suggests it’s not a specific mechanism of the antidepressant but the state of being on an antidepressant that seems to elevate the risk,” Curtin said. “Also, the number of refills seems to directly correlate with an increase in the [HR].”

He said the good news is that other common agents for IBS, including antispasmodics, rifaximin, bile acid sequestrants, eluxadoline, polyethylene glycol, and secretagogues, did not show an association with mortality.

He also urged interpreting the data carefully. “There is clearly huge confounding here. I refer again to my pointing out that the mechanism of the antidepressant didn’t matter, just being on any antidepressant did. There may be many factors that could cause depression that could also increase mortality. It’s really hard to pick out specific actionable information here.”

Rezaie reported consulting for Bausch Health and Ardelyx. In addition, Cedars-Sinai Medical Center reported having a licensing agreement with Gemelli Biotech. Rezaie and a co-author have equity in Gemelli Biotech and Good LFE. Curtin reported being a speaker/consultant for AbbVie and Ardelyx who make IBS medications.

Marcia Frellick is an independent healthcare journalist and a regular contributor to Medscape.