Michael Eriksen Benros, MD, PhD

National Centre for Register-based Research, Aarhus University; Mental Health Centre Copenhagen, Copenhagen University Hospital, Denmark

First published in Psychiatry Weekly, September 2013, 8(18).


The human body’s inflammatory reaction to infection has for some time been understood as a possible etiological risk factor for the development of some psychiatric disorders. It is not, however, a well-understood risk factor. Animal studies have indicated that inflammation and brain-reactive antibodies can induce neuropsychiatric symptoms. Whether this can be generalized to humans is still debatable, since similar randomized studies in humans are nearly impossible to conduct due to ethical reasons. However, using Danish national health registries, Dr. Michael Eriksen Benros and colleagues recently published the first large scale, population-based study examining the extent to which inflammation and subsequent mood disorders are related.


“We looked at both infection and autoimmune disorders, because animal studies show that inflammation can allow brain-reactive antibodies to permeate the blood-brain barrier and affect the brain, so they might not just be independent risk factors,” explains Dr. Benros. “So if one were to have such antibodies and subsequent inflammation induced by infection, then in theory there would be a higher risk of psychiatric disorders.”


Danish Registry Population

All Danish citizens born between 1945 and 1995, who were alive at 16 years of age or after 1977, comprised the study population (n=3,562,260). The researchers identified those who had received a mood disorder diagnosis between 1977 and 2010 (N=91,637). Then, using hospital records, they identified persons who had hospital contacts for infection (N=29,194) or autoimmune disease (N=4,195) or both (N=2,113) prior to receiving a mood disorder diagnosis.


“Most existing studies of inflammation and mood disorders are cross-sectional, meaning you can only look at people who have a mood disorder and a somatic disease at the same time point,” says Dr. Benros. “Our study, however, was longitudinal, so we could examine the effects of autoimmune disease and infection on the subsequent risk of mood disorders in true time.”



Benros and colleagues calculated the relative risk of mood disorders by way of incidence risk ratios (IRR). Among those who were diagnosed with a mood disorder between 1977 and 2010, a hospital contact for infection increased the risk of a mood disorder diagnosis by 63% (IRR 1.63; 95% CI, 1.61–1.66); autoimmune diseases increased the risk by 45% (IRR 1.45; 95% CI, 1.39–1.52); and if a person was exposed to both infection and an autoimmune disease, the risk more than doubled (IRR 2.35; 95% CI, 2.25–2.46).


“Each number of hospital contacts for infections increased the risk of mood disorders in a dose-response relationship, and we found that having ?5 different types of infections increased the risk of mood disorders by 5 times,” says Dr. Benros.


“We also found a synergistic effect in the interaction between autoimmune diseases and infections,” continues Dr. Benros. “If you have an autoimmune disease and then an infection, for example, then the risk for mood disorder is slightly higher than exposure to either individually.”


Hepatitis, sepsis, and urogenital infections were the types of infections most strongly associated with elevated risk of mood disorders. Among autoimmune disorders, systemic lupus erythematosus, Type 1 diabetes, celiac disease, and autoimmune hepatitis were most commonly associated with an elevated risk of mood disorders.


Infections increased the risk of both unipolar depression and bipolar disorder similarly and more so than autoimmune diseases, whereas autoimmune disease carried a greater risk for unipolar depression than for bipolar disorder (Table).




Risks were higher in the temporal vicinity of the last infection but were elevated for as long as 15 years following the last infection, indicating that the results could not be attributed solely to detection bias. According to Dr. Benros, the temporal vicinity finding strongly suggests that there is a contemporary inflammatory response mechanism in the development of mood disorders, but also that there is a more long term association with mood disorders after severe infections than previously thought.


“Clinicians should be more aware of the associations of some somatic diseases with psychiatric disorders,” says Dr. Benros. “Treating comorbid somatic diseases may improve the symptoms of mood disorders. Even if this association is not causal—and instead an epiphenomenon due to genetics or environmental factors—psychiatric patients with comorbid somatic diseases would most likely still benefit through greater quality of life and improved survival. It’s too early to say that people with infection or autoimmune diseases should be followed for psychiatric disorders, but there are many ongoing studies that will soon augment our understanding of this growing body of research.”


Disclosure: This study was supported by a grant from the Stanley Medical Research Institute. Dr. Eaton’s contribution was supported by the NIMH (MH53188). Dr. Benros reports no affiliations with, or financial interests in, any organization that may pose a conflict of interest.


Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry. 2013;70:812-820.