Antidepressants may do more than help inflammatory bowel disease (IBD) patients cope with psychological comorbidities, according to Danish researchers.
The results of their review of a nationwide Danish registry showed that use of antidepressants also significantly lowered relapse rates, particularly in Crohn’s disease (CD), reported Marie Skov Kristensen, MSc, RN, of the University of Southern Denmark in Copenhagen, and colleagues.
Writing online in Inflammatory Bowel Diseases, the team noted that the positive effect on disease activity was especially pronounced in patients with no exposure to antidepressants before IBD onset and held regardless of whether the antidepressants were taken as monotherapy or as part of combination therapy.
When the researchers adjusted for various confounders, the results showed a lower incidence of disease activity in antidepressant users versus non-users in both CD and UC patients, with an incidence rate ratio (IRR) of 0.75 for CD (95% confidence interval 0.68-0.82) and 0.90 for UC (95% CI 0.84-0.95).
Kristensen and co-authors identified patients with an incident diagnosis of CD or ulcerative colitis (UC) during 2000 to 2017 in the Danish National Patient Register. A total of 42,890 patients were included in the analysis, of whom 29,804 (69.5%) had UC and 13,086 (30.5%) had CD. Women accounted for 52.5% of UC patients and 54.9% of CD patients. The median age of onset of the two diseases was 42 years for UC and 34 years for CD.
About 5% of patients in both groups had anxiety or depression and about 80% in both groups had started antidepressant therapy before developing IBD, with about 20% having their first antidepressant prescription after developing IBD. Approximately 28% of the cohort filled at least one prescription for an antidepressant.
Across the measures of disease activity, antidepressant users in both IBD groups had a significantly lower risk of initiating step-up medication with corticosteroids and anti-tumor necrosis factor (TNF) agents, as well as a lower risk of IBD-related hospitalization.
Antidepressants included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and mirtazapine, used either alone or in combination. Stratified by antidepressant type, the IRRs for disease activity in CD patients with post-IBD antidepressant use only versus no exposure ever were 0.23 for SSRIs, 0.28 for mirtazapine, and 0.60 for mixed use. For other agents, the numbers were too small to allow IRR calculation, the researchers said.
In UC, the corresponding IRRs were 023, 0.13, and 0.72, and for mixed use, 0.80.
‘Clear Mind-to-Gut Link in IBD’
Asked to comment on the findings, Miguel Regueiro, MD, of the Cleveland Clinic, who was not involved in the research, said: “In my own practice, patients in whom we address depression also seem to improve their physical IBD symptoms – there is a clear mind-to-gut link in IBD, and as healthcare providers treating IBD, we need to take this into account.”
Many IBD patients have psychological conditions that are exacerbated by the stress of having IBD, and anxiety and depression in turn adversely affect their disease, he told MedPage Today. “The main question that has not been answered is causality — meaning, do psychological conditions trigger or cause IBD, or does IBD trigger or cause psychological disease?”
Last year, a systematic review by Macer and colleagues also suggested that antidepressants may favorably impact the course of IBD. And earlier this year, a study by Frolkis and associates suggested that antidepressants may lower the risk of developing IBD.
Kristensen and colleagues noted that in terms of potential pathways, antidepressants affect levels of pro-inflammatory cytokines such as interleukin and TNF, known to be involved in the pathogenesis of IBD. “Hence, decreased levels of pro-inflammatory cytokines may explain the observed favorable influence on the course of IBD,” the team wrote, adding that antidepressants also positively affect brain-gut interaction.
The investigators also found markedly lower rates of disease activity for both conditions in patients unexposed to antidepressants before IBD onset: IRR for CD 0.51 (95% CI 0.43-0.62); and IRR for UC 0.67 (95% CI 0.59-0.75).
The team hypothesized that patients treated pre-IBD for psychiatric comorbidity may not see further benefit from the potential anti-inflammatory effect of the drugs when treated after IBD onset. In addition, patients receiving antidepressants pre-IBD may be more vulnerable during the disease course because of psychological challenges unrelated to IBD that increase relapse risk. Despite the high prevalence of anxiety and depression in IBD, however, many patients do not receive appropriate psychiatric treatment,” the researchers stated.
“Antidepressants have the potential to be an adjuvant treatment to the conventional therapy for IBD, similar to treatment for irritable bowel syndrome,” the authors wrote, adding that the time has come for randomized controlled trials.
Rugueiro said that the study highlights the importance of screening for behavioral health in IBD patients. “Those who have depression and anxiety should be treated,” he said. “This is a very important part in the overall management of Crohn’s disease and ulcerative colitis and has been understated until recent studies such as this Danish study.”
Kristensen and co-authors noted several limitations to the register-based analysis. For example, proxy measures of IBD activity were solely identified by chart-based register data, whereas specific clinical data on IBD symptoms and objective biomarkers of inflammation would have strengthened the validity of the outcome measures.
Moreover, filled prescriptions may not fully reflect actual intake, and specification of antidepressant doses was not possible. Furthermore, when stratifying analyses by antidepressant subtype, several categories had such small numbers that it was difficult to fully interpret the findings. In addition, the register offered no information on smoking, adherence to medications, or non-pharmacological treatment for presumed depression or anxiety, making it impossible to rule out potential confounding from non-pharmacological treatment, the team said.
In addition, the results may not be generalizable to patients with mild disease activity as the cohort had signs of moderate-to-severe activity. Also, the researchers said, confounding by indication could not be ruled out, and antidepressant users may be different from nonusers according to unmeasured confounding.
Kristensen and co-authors note that their article is based on data obtained for a separate study conducted by Applied Economics and Health Research (ApEHR) and funded by Merck Sharp & Dohme Corp.
A co-author, Anders Green, is a partner and scientific director of ApEHR; the other co-authors reported having no conflicts of interest.
Regueiro noted having financial relationships with several pharmaceutical companies but no competing interests related to his comments.