Depression appears to be a novel independent risk factor for Clostridium difficile–associated diarrhea in older adults, according to a large national study.
Moreover, the use of certain antidepressants was associated with an increased risk of hospital-onset C. difficile infection in a separate study simultaneously reported by the same researchers. Although the number of such patients was small, adults on the combination of mirtazapine and trazodone at hospital admission had a whopping 33-fold increased risk of subsequently developing hospital-onset C. difficile infection (CDI), according to Mary A.M. Rogers, Ph.D., and her coinvestigators at the University of Michigan, Ann Arbor (BMC Medicine 2013;11:121).
Dr. Mary A.M. Rogers
"While there does appear to be an association between depression and CDI, at this time we cannot completely discern whether it is the pathophysiology of depression itself or the treatment for depression that is the major driver of these findings," Dr. Rogers and her colleagues wrote. "We did not find a class effect for the various antidepressants. Further investigation of the effects of antidepressants on the gut microbiota may be helpful."
One of the two studies was a longitudinal analysis of 16,781 nationally representative older Americans participating in the ongoing National Institute on Aging–sponsored Health and Retirement Study. The rate of subsequent CDI was 282.9 cases/100,000 person-years among study participants with a previous diagnosis of major depressive disorder at any time, compared to 197.1/100,000 person-years in patients without a history of major depression. In a multivariate analysis adjusted for age, sex, race, education, smoking status, body mass index, and comorbid GI or renal disease, the odds of CDI were 36% greater in older subjects with a history of major depressive disorder.
In addition, the risk of CDI was also significantly increased by 54% in subjects who were widowed and by 35% in study participants with a history of any of a broad group of depressive disorders other than major depression. These included diagnoses of brief or prolonged depressive reactions, depressive-type psychosis, bipolar affective disorder with depression, adjustment reaction with anxiety and depression, chronic depressive personality disorder, and depressive disorder not elsewhere classified. Subjects who did not live alone had a 25% lower risk of CDI than those who did.
The mechanism underlying the observed association between depression and CDI in this study is unknown, but a relationship is biologically plausible. It is known that depressed patients have impaired immune responses. In addition, there is evidence that depression and bereavement can alter the gut flora, or microbiome. The brain-gut axis is a hot research area, and the possibility that the relationship is bidirectional has received some research support.
Intrigued by their findings from the longitudinal Health and Retirement Study, Dr. Rogers and her colleagues then conducted a case-control study involving all adults hospitalized during a recent 18-month period in the University of Michigan Health System for any reason other than CDI and who developed diarrhea and other symptoms that prompted stool testing for C. difficile while in-the hospital. A total of 468 patients tested positive and were classified as having hospital-onset CDI, while the remaining 3,579 patients tested negative.
Patients on selected antidepressants at hospital admission had an increased risk of subsequent hospital-onset CDI. The 99 patients on mirtazapine, for example, had an adjusted 2.14-fold increased risk of hospital-onset CDI. And for each dose of mirtazapine they received while in the hospital, their risk increased by 8%. Patients on fluoxetine had nearly a twofold increased risk. So did those on nortriptyline; their risk of hospital-onset CDI climbed by 11% with each dose given. Patients on antidepressant monotherapy with trazodone were not at increased risk.
In a secondary analysis, 17 patients on the combination of trazodone and mirtazapine were at 32.5-fold increased risk.
Other agents in the same antidepressant classes, however, were not associated with hospital-onset CDI.
Interestingly, an identical 57% of patients in the hospital-onset CDI group as well as the C. difficile–negative controls were on a proton pump inhibitor. That observation is noteworthy because it is inconsistent with the Food and Drug Administration’s February 2012 safety warning regarding an association between the use of proton pump inhibitors and CDI in adults.
This project was funded by the National Institute of Allergy and Infectious Diseases. The investigators reported having no conflicts of interest.