Anxiety and depression are prevalent in patients with gastroesophageal reflux disease (GERD), according to a large-scale analysis that also found evidence for a possible underlying causal link between GERD and the common psychiatric conditions.

In a systematic review and meta-analysis, researchers found that anxiety and depressive symptoms were more than twice as likely in patients with GERD than in healthy controls. Among individuals with GERD, up to one-third and one-fourth were affected by anxiety and depressive symptoms, respectively.

Moreover, a Mendelian randomization analysis suggested that a genetic risk for GERD increased the risk of developing depression or anxiety and vice versa.

A genetic predisposition seems to underlie GERD and anxiety or depression, said Nicholas J. Talley, MD, PhD, School of Medicine and Public Health, University of Newcastle, Australia, and corresponding author of the review, published online in the American Journal of Gastroenterology.

Scientifically, the possible underlying link “suggests there are different disease subsets within reflux that probably have a different pathogenesis, and these relationships are an expression of whatever the underlying causal pathways are,” Talley told Medscape Medical News.

Clinically, “if you’ve got a patient with reflux, you should be asking one or two questions about anxiety and particularly depression…because it may impact on how well patients respond to therapy, and how well they do in the longer term,” Talley said.

A Deeper Look

In the review, the authors note that GERD affects about 15% of the general population worldwide and has a negative impact on the health-related quality of life.

The pathogenesis is complex and may be associated with psychological distress alongside the well-known predisposing anatomical factors, aggravated by lifestyle factors such as obesity and smoking.

Individual studies examining the association between GERD and the prevalence of anxiety or depressive symptoms have had mixed results, “perhaps limited by heterogeneous study design, the severity of disease included, and diagnostic criteria for depression and anxiety,” the researchers write.

They therefore set out to perform a systematic review and meta-analysis to assess the issue in greater depth. They looked at three primary outcomes — the prevalence of symptoms of anxiety and depression in individuals with GERD, the epidemiological risk of developing GERD in people with anxiety or depression and vice versa, and the cause-and-effect relationship between anxiety or depression and GERD.

They searched the Embase, PubMed, Scopus, and Web of Science databases, and found 36 eligible studies published between 2003 and 2023.

Of the total, 30 were observational studies that examined the prevalence of anxiety and/or depressive symptoms using validated questionnaires in ≥ 100 individuals aged 18 years or older.

These included 26 studies of anxiety symptoms among 10,378 individuals with GERD, 30 that looked at depressive symptoms among 14,030 subjects with GERD, and four that reported the prevalence of simultaneous anxiety and depressive symptoms in 3878 patients with GERD. Some studies were population based and others were hospital based. The extracted data were combined using a random-effects model.

The overall pooled analyses revealed a prevalence of anxiety symptoms of 34.4% among individuals with GERD, at an adjusted odds ratio versus healthy controls of 4.46 (95% confidence interval [CI], 1.94 – 10.25).

The pooled prevalence of depressive symptoms among those with GERD was 24.2%, at an adjusted odds ratio compared with healthy controls of 2.56 (95% CI, 1.11 – 5.87).

The pooled prevalence of simultaneous anxiety and depression in people with GERD was 22.3% (95% CI, 7.0 – 37.7).

Next, the team added three cohort studies that explored the risk for GERD in individuals with anxiety or depression in the vice versa scenario, as well as three Mendelian randomization studies that assessed the cause-and-effect relationship between anxiety or depression and GERD.

The cohort studies could not be pooled, but individuals with depression had a significantly increased risk for GERD versus those without depression, at an adjusted odds ratio in one study of 2.01 (95% CI, 1.96 – 2.07) and an adjusted hazard ratio in another study of 1.72 (95% CI, 1.60 – 1.85). A similar pattern was seen for anxiety.

The Mendelian randomization studies suggested that a genetic risk for depression was associated with an increased risk of developing GERD, at an odds ratio of 1.36 (95% CI, 1.21 – 1.51), and that a genetic risk for GERD was linked to an increased risk of developing depression, at an odds ratio of 1.30 (95% CI, 1.17 – 1.43).

One study reported a similar effect of a genetic risk for GERD on the risk for anxiety.

“We don’t really know what causes reflux disease. We know the pathophysiology, but we don’t really know what the etiology is, and depression is the same,” Talley noted. “It’s obviously thought to be a brain disease, but sometimes it might be coming from the gut as well, for all we know, and there is certainly evidence for that.”

The “Chicken and Egg” Question

Experts welcomed the findings, saying they supported their observations and validated the idea of looking outside the gut for complicating factors in patients with GERD, but some questioned the clinical relevance of the Mendelian randomization.

Approached for comment, Amir E. Masoud, MD, Medical Codirector, Hartford HealthCare Neurogastroenterology and Motility Center, Fairfield, Connecticut, said the study’s most important contribution is increased recognition of the connection between GERD and anxiety or depression.

“There is a psychological component” to GERD, he said, and it is an “important area for investigation and possible intervention for patients who don’t respond to traditional therapies.”

Masoud singled out the study design. The researchers “tried to tee this up with something we’ve always thought about,” he told Medscape Medical News, referring to the “chicken and egg” question about the relationship between GERD and anxiety or depressive symptoms.

As such, it provides evidence for a common observation in the clinic, he said. “A lot of times, when a therapy that should work does not work for something like GERD, for example, we tend to think of psychological factors that could be playing a role.”

No Longer a Taboo Topic

Rena Yadlapati, MD, medical director, Center for Esophageal Diseases, UC San Diego Health, California, told Medscape Medical News that the study is “validating, in terms of the conversations with patients and some of the non-traditional methods we are trying to explore in their management.”

She noted the bidirectional relationship revealed by the Mendelian randomization, but cautioned that the approach relied on a small number of studies and hasn’t been utilized in gastroenterology as much as in other fields.

“We need to understand that this is hypothesis generating, and there are probably some important limitations,” she added, even if the results “certainly make sense.”

From a clinical perspective, the idea of anxiety or depression being linked to GERD has been a “taboo topic” for a long time, Yadlapati said.

“But if we can effectively communicate that relationship between the brain and gut and this whole cyclical process [to patients], there’s power to gain patient insight and engagement.”

Another key aspect is to consider a psychological referral for patients, as well as engaging them with “simple things like relaxation strategies and diaphragmatic breathing and referring them to people who can do cognitive behavioral therapy.”

Yadlapati emphasized that “it doesn’t necessarily have to be a psychologist. There are a lot of other ways to provide that access to patients.”

Practical Clinical Implications

Philip O. Katz, MD, Director of Motility Laboratories, Division of Gastroenterology, Weill Cornell Medicine, New York City, commented that the study, like many of its kind, reinforces that there are multiple cofactors associated with managing patients with reflux disease.

As for the bidirectional relationship identified through the Mendelian randomization, he was skeptical about its clinical value and pointed out that the odds ratios are “relatively small.”

“It is commonplace for people to look for genetic predispositions to a lot of disease,” Katz told Medscape Medical News, but, “in clinical practice, I don’t believe that it’s particularly meaningful, to be honest.”

However, there is no doubt that GERD symptoms are augmented by times of what is generically called “stress,” he added.

“Regardless of those findings, it doesn’t change the way I view the importance of this article, which is when someone’s not responding to medication to look for reasons other than the original diagnosis,” Katz said.

“There is so much overlap between true GERD and symptoms that sound like GERD” that clinicians need “to be aware that both anxiety and depression are cofactors,” he said.

Am J Gastroenterol. Published online August 21, 2023. Abstract

Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre of Research Excellence in Digestive Health, and he holds an NHMRC Investigator grant. He declares relationships with Norgine, Bristol Myers Squibb, Allakos, Bayer, Planet Innovation, twoXAR, Viscera Labs, Dr Falk Pharma, Sanofi, Glutagen, ISOvive, BluMaiden, Rose Pharma, Intrinsic Medicine, Comvita Manuka Honey, GlaxoSmithKline Australia, and Astra Zeneca; and holds numerous patents. Disclosures for Masoud, Yadlapati, and Katz were not available at time of publication.

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