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Question
Question: Does autoimmune disease or severe infection increase the risk of a mood disorder?
People: 3.56 million people identified through the Danish Civil Registration System who were born between January 1945 and December 1996. Participants who had hospital contact because of infections or autoimmune disease up to the age of 65 years were followed up for hospital contacts for mood disorders from their 16th birthday up until 31 December 2010.
Setting: Denmark, January 1977–December 2010.
Risk factors: Autoimmune diseases or severe infections as coded in the Danish National Hospital Registry (ICD-10 and ICD-8). Infections included sepsis, hepatitis, gastrointestinal infections, skin infections, pregnancy-related infections, respiratory infections, urogenital infections and central nervous system infections (HIV or AIDS were excluded). A person was classified as having an autoimmune disease if they had one or more of 30 listed conditions, which were further subdivided into those with and without suspected presence of brain-reactive antibodies. Initial onset of autoimmune disease or infection was defined as the first inpatient or outpatient hospital contact that led to recording of the diagnosis in the register. Participants with multiple autoimmune diseases or infections were included, but only the first eight identified infections were used for analysis.
Outcomes: Mood disorders as coded in the Danish Psychiatric Central Research Register (ICD-8 and ICD-10). Mood disorders were classified into bipolar affective disorder, psychotic depression, unipolar depression and other mood disorders. The date of onset was defined as the first day of hospital contact (inpatient, outpatient or emergency department) that led to one of these diagnoses.
Methods
Design: Prospective cohort study.
Follow-up period: 77 506 581 person-years.
Main results
The cohort comprised 3 562 260 people. Mood disorders were diagnosed in 91 637 people (2.6%). In people with mood disorders, prior infections were diagnosed in 29 194 people (31.9%); autoimmune disorders were diagnosed in 4195 people (4.6%); autoimmune disease and infection were diagnosed in 2113 people (2.3%). Infection history increased risk of mood disorder compared with no infection (incidence rate ratio (IRR) 1.63, 95% CI 1.16 to 1.66). A prior autoimmune disorder without infection increased risk of mood disorder as compared with neither diagnosis (IRR 1.45, 95% CI 1.39 to 1.52). In people with an autoimmune disorder, hospital contact for an infection increased risk of mood disorders as compared with neither diagnosis (IRR 2.35, 95% CI 2.25 to 2.46). Analyses revealed that in people with autoimmune disease and infection risk of mood disorders was greater than what would be expected if individual effects were combined (synergy index 1.27, 95% CI 1.15 to 1.39). Of people with autoimmune disorders, those with suspected brain-reactive antibodies had the highest risk of mood disorders (see online table 1). Eight or more infections increased risk of mood disorders compared with fewer infections in an apparent dose–response relationship (see online table 1).
Conclusions
Autoimmune diseases and infections are associated with the increased risk of mood disorders.
Abstracted from
Commentary
Mood disorders are common comorbidities in medical illnesses, and human and animal studies have provided links between inflammation, autoimmunity and risk of mood disorder development.1 No large-scale human studies have examined the connection between inflammation and subsequent mood disorders over time. In this study, Benros et al make a substantial addition to the literature by using the Danish Registry to examine a large patient cohort over multiple decades in attempting to understand how autoimmune disease and severe infection impact risk of mood disorder development. The authors conclude that autoimmune disease and severe infection can play a significant aetiological role in mood disorder development in a subset of patients. Remarkably, 12% of all mood disorders diagnosed in the population in this study might be accounted for by risk associated with severe infection. Because this research focused on patients with hospital contacts leading to diagnosis, it is unclear how the data can be generalised to less severe disease states. Moreover, as the authors point out, the association between inflammation and mood changes may in fact be bidirectional: mood disorders (or unknown factors that predispose to mood disorders) might trigger autoimmune changes or increase likelihood of infection, as opposed to infection/autoimmunity leading to mood changes.2 The study does not indicate inflammation as causal, as stress itself might increase the risk of all factors examined: infection, autoimmune response and mood. Future work will need to address whether less severe (and more common) infections similarly increase risk of mood disorders and examine whether/how inflammation directly leads to psychiatric symptoms. In sum, this work is consistent with the hypothesis that abnormal immunological responses are linked to mood disorders in some patients, and is particularly convincing in showing a relationship between hospital-based diagnosis of infection and mood disorders.
Footnotes
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Sources of funding: Stanley Medical Research Institute and National Institute of Mental Health (NIH grant 2T32HL007713-21).
Footnotes
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Competing interests None.