Antidepressants for IBS treatment: brain-gut solutions or whole-person care?

By Elizabeth Curley

Nature published an article this month on the “[a]ssociation of pharmacotherapy with all-cause mortality in patients with irritable bowel syndrome” essentially asking, in real-life settings, does medication treatment (antidepressants versus antispasmodics) affect the risk of death in people with IBS? 

In this nationwide study with over 600,000 patients, they found that people with IBS who are treated with antidepressants across every subclass have a higher risk of dying (of any cause) than people treated with antispasmodics. Yet, antispasmodics were not associated with an increased risk of dying. What does that mean and why should we care? 

First, it is important that we all understand what off-label means, because it matters here. Off-label prescribing means that the FDA has not reviewed or approved the drug for that specific purpose, dose, route, duration, or patient population. Antidepressants for IBS are squarely in this category, though estimates suggest that 20-30% of all prescriptions (and up to 75% of antipsychotic use in adults) are off-label. For now, let’s stick to the understanding that off-label prescribing means using an FDA approved drug in an non-FDA approved way, as is the case with our current study of antidepressants for IBS. 

It’s worth stepping back to see how we got here. Gastroenterology guidelines, including those from the American Journal of Gastroenterology, position antidepressants as second-line options for IBS, not first line. They acknowledge the brain-gut connection and high overlap of people with IBS and anxiety, depression, and stress-related symptoms. 

Another report (2021) from the same journal, reports that the antidepressants category were more likely to improve symptoms of abdominal pain than placebo, but that those effects were due to Tricyclic Antidepressants (TCAs), not SSRIs. It should be noted that these benefits are notable when compared to placebo, but in real world settings, patients are often within the context of having access to antispasmodics (on-label) medications. 

Now, the medical doctors will make sure to highlight that there are different profiles of IBS, some with different features of symptoms, for which antispasmodics may not be the best option but still remain a generally effective option for most. 

These gastroenterology guidelines also discuss (and recommend) the use of Gut-Directed Psychotherapies (GDPs) such as Cognitive Behavioral Therapy for IBS and co-occurring psychological symptoms. Non-pharmacological interventions are at least recognized; many psychopharmacology discussions happen in a vacuum separate from therapy, behavioral modification, and other non-medication-based modalities.

However, the clinical guidelines published in 2021 still recommend the usage of GDPs (with other IBS therapies) for people who seem to have cognitive or emotional mechanisms to their IBS symptoms because they are low risk interventions with no reported adverse effects and there may be long-term benefits even when the therapy is discontinued. So, of all of the options, why are SSRIs being used for IBS? 

Additional research has been done to explore practitioners’ and patients’ perspectives of their off-label IBS prescribing experiences. Regarding amitriptyline (a Tricyclic Antidepressant), patients were concerned with the simple fact that they were offered an antidepressant, with specific concerns of the psychotropic effects and the “zombie” effect. Though researcher did note that discussions of the lower dose of the drug in IBS off-label prescribing compared to antidepressant use seemed to “address such concerns” and “facilitate uptake.”

Patient perspectives are much more varied and complex. One study found that although all 15 interviewees reported some improvement in their quality of life since starting antidepressants for IBS, the more focused answers revealed that the balance of benefit and negative effects were contextual for each person, and that there were remaining concerns of dependence and shallow coverage of the surface problem instead of the source. The title of this article, “It doesn’t do any harm, but patients feel better,” lands quite differently after reading the new Nature data.

Perhaps the strongest signal in the Nature article is that mortality is higher in every subclass of antidepressant tested for every demographic subgroup (sex, age group, race/ethnicity, and BMI) and there is a clear dose-response relationship where risk rises with more refills. 

These results also include TCAs, which previously showed the strongest potential in the effectiveness trials for IBS benefit. Antidepressant use was linked to a 35% higher mortality risk overall, with increases of 32% for SSRIs, 27% for TCAs, 32% for SNRIs, and 105% for mirtazapine. 

Additionally, as this study was conducted in real world contexts, we get a vital look into prescribing trends: antidepressants were the most commonly prescribed (52.3%) followed by antispasmodics (22.1%). That gap between guideline recommendations (second-line) and actual practice, makes the mortality finding especially noteworthy.  

Of course, this study has important limits, and the authors are careful to point them out. This article can only discuss associations, not causation. Even with sophisticated statistical matching on 56 variables, confounding is possible: patients who were prescribed antidepressants may have been different in a way they could not capture such as having more severe IBS or psychological symptoms. The paper also only reports all-cause mortality, so we do not know specific causes of death. 

Still, this large real-world study adds a meaningful safety signal. This study supports long-term safety data for several guideline-recommended and FDA-approved options for IBS. However, it also raises questions about the practice of prescribing antidepressants for IBS and the potential for elevated risks, despite common perception. Research and clinical judgment can look like a game of telephone, as our messages are often unclear. With this new study, the conversation continues with an echo: how often are we reaching for antidepressants, assuming the benefits yet consistently dismissing the risks?