Treating Depression May Mitigate IBD Risk, Study Shows

Diana  Phillips

October 26, 2018

Patients with depression are at increased risk of developing inflammatory bowel disease (IBD), but the risk is reduced among those taking antidepressant medication, new data show.

Although the link between mood disorders and both forms of IBD — ulcerative colitis (UC) and Crohn's disease (CD) — has previously been established, this is the first study to consider the temporal association between depression and subsequent IBD diagnosis, and it is also the first to look at the influence of antidepressant therapy on this risk, Alexandra D. Frolkis, PhD, Department of Medicine, University of Calgary, Alberta, Canada, and colleagues report in an article published online October 18 in Gut.

Given the findings, clinicians should screen and counsel patients with IBD and/or depression. "Specifically, our findings indicate that selective serotonin reuptake inhibitor (SSRI) use is associated with a reduced risk of developing both CD and UC," Frolkis and colleagues write. In addition, a "recent systematic review identified that antidepressant therapy may indeed be beneficial in IBD, improving prognosis through both somatic symptom control and anti-inflammatory effects."

To evaluate these relationships, the researchers conducted a retrospective cohort study using data from The Health Improvement Network (THIN), a nationally representative database of UK primary care electronic medical records. They identified 5,727,655 eligible patients, aged 10 to 90 years, and compared those who had an incident diagnosis of depression (n = 403,665) between 1996 and 2012 with those who did not (n = 5,323,986). The primary outcome was a diagnosis of CD or UC.

During a median follow-up of 6.7 years, 203 (0.05%) patients with depression and 1589 (0.03%) patients in the control group developed CD, and 539 (0.13%) patients with depression and 4675 (0.09%) in the control group developed UC.

After adjusting for age, sex, socioeconomic status, comorbidities, obesity, smoking status, anxiety, and antidepressant medications, the risk of developing CD among patients with depression was more than two-times higher than in those without depression (hazard ratio [HR], 2.11; 95% CI, 1.65 - 2.70). The adjusted analysis demonstrates a similarly increased risk for developing UC among patients with versus without depression (HR, 2.22; 95% CI, 1.92 - 2.60).

The underlying mechanism linking depression and IBD has yet to be established, but the connection may result in part from the interaction of high levels of stress hormones associated with depression and serum markers of chronic inflammation associated with IBD, the authors hypothesize.

"The link between IBD and depression is not surprising at all. More and more research has confirmed the significant role the gut–brain axis plays not just in irritable bowel syndrome and motility disorders but also in inflammatory bowel diseases," said Alyssa M. Parian, MD, assistant professor of Medicine in the Division of Gastroenterology at Johns Hopkins Hospital in Baltimore, Maryland, who was not involved in this study.

"The hormones released just during acute stress reactions have a major role in flare-ups of IBD. Therefore depression, anxiety, and other long-standing mental health illnesses must definitely have long-term effects on the [gastrointestinal] tract due to hormone and cytokine release," she said in an interview with Medscape Medical News.

The study authors further assessed the proportion of patients in the depression cohort who developed CD or UC who did and did not take antidepressants and compared this with the proportion of patients in the general population. They determined that use of SSRIs and tricyclic antidepressants (TCAs) were protective against both CD and UC. Additionally, mirtazapine, serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin modulators offered protection against UC.

Specifically, the HR for developing CD was 0.63 (95% CI, 0.50 - 0.78) among those who took SSRIs and 0.77 (95% CI, 0.61 - 0.97) among those who took TCAs.

For UC, the respective HRs among those who took SSRIs, TCAs, mirtazapine, SNRIs, and serotonin modulators were 0.48 (95% CI, 0.42 - 0.55), 0.59 (95% CI, 0.51 - 0.68), 0.34 (95% CI, 0.15 - 0.77), 0.46 (95% CI, 0.25 - 0.83), and 0.46 (95% CI, 0.23 - 0.92).

In sensitivity analyses examining the relationships between antidepressant use and CD or UC development, the risk of CD among the depression cohort was lowest in patients treated with antidepressants, at 0.05%, compared with 0.07% in patients who did not take antidepressants. In contrast, in the general population cohort, the risk of CD was slightly higher, at 0.04%, among those treated with antidepressants (for indications other than depression) than those who weren't, at 0.03%. The risk of UC in the depression cohort was also lower among those treated with antidepressants, at 0.12%, than those who weren't, at 0.20%, while no difference in risk associated with antidepressant use was observed in the general population (0.09% in both), the authors report.

The differential effect of SNRIs, serotonin modulators, and mirtazapine in UC versus CD "suggests that neurotransmitter-related immune modulatory responses in these two diseases differ," the authors write. Although the underlying mechanism for this difference remains unexplained, disease-related differences in mucosal immunity and barrier homeostasis between the two conditions likely play an important role, they note. 

Parian cautions that more information is needed to determine the true protective effect of antidepressants in this population. "My one critique of this excellent study is that we cannot be certain when the IBD actually started," she explained. "Typically, IBD patients have symptoms for months or years prior to actual diagnosis. More studies are needed looking at antidepressants as a risk-attenuator, but they could be an interesting intervention in patients who are at high risk for IBD."

Although the absolute risk of an IBD diagnosis in individuals with depression is low, "based on our findings, we recommend increasing the index of suspicion for a diagnosis of IBD in patients with depression and gastrointestinal symptoms, and considering introduction of antidepressants," the study authors write. They also advocate for additional research to evaluate whether treating depression can reduce the incidence of IBD.

The study findings — which reflect an association versus causality — add to a growing body of literature elucidating the association between depression and IBD and point to important clinical considerations, according to Bharati Kochar, MD, of the Division of Gastroenterology and Hepatology at the University of North Carolina Chapel Hill School of Medicine, who was not involved in the study.

"In our own work, we have shown that, for patients with IBD, depression can affect disease outcomes over time," she said, referring to a recent prospective observational cohort study in which she and her colleagues demonstrated a strong link between baseline depression and a risk for aggressive IBD. The current study adds yet another layer to the association by linking depression with the development of IBD, she said.

Given the association between depression and both the development of IBD and worsening disease activity over time, "the authors' conclusion that GI symptoms in patients who are depressed should be taken more seriously is certainly a reasonable one," said Kochar. "The reverse, that mood symptoms should be taken seriously in IBD patients, has been well established in the literature to date."

The study was funded by a grant from the Canadian Institutes of Health Research. Co-author Kaplan has disclosed financial relationships with Janssen, AbbVie, GlaxoSmithKline, and Shire. Co-authors Shaheen, Swain, and Kaplan have disclosed a limited partnership related to a shared patent. Kochar has reported no relevant financial relationships.

Gut. Published online October 18, 2018. Abstract

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