Liam Davenport

April 11, 2016

FLORENCE, Italy — Even mild infections significantly increase the risk of later developing schizophrenia and mood disorders, results of a large, population-based registry study indicate.

Regarding the prescribing of anti-infective medications as a proxy for mild infections, the team found that any prior prescription increased the risk for schizophrenia by 37% and the risk for mood disorders by 64%, fitting dose-response and temporal relationships.

Michael E. Benros, MD, PhD, a senior researcher at Mental Health Centre Copenhagen, University of Copenhagen, Denmark, presented the research here at the Schizophrenia International Research Society (SIRS) 2016 Biennial Meeting.

Speaking to Medscape Medical News, Dr Benros said he believes there is likely to be a gene-environment interaction between infections and certain, as yet unidentified, genes that place some individuals at a higher risk.

"We have not found that interaction yet, but we are looking further into that with genetic studies to look at the associations between infections, genes, and mental illness, utilizing the huge iPSYCH cohort in Denmark, with 50,000 cases and 30,000 controls," said Dr Benros.

"I think the whole field is moving towards the idea that there could be a logical basis for immune-related subgroups of schizophrenia and depression," he added.

Dr Michael Benros

He noted that one current theory is that infections can affect the brain directly via inflammation entering the brain or by inducing autoimmunity.

Dose-Response Relationship

Dr Benros began the presentation, which he gave on behalf of lead author Ole Köhler, MD, also at Mental Health Centre Copenhagen, by reflecting that, among other findings, immune alterations have been observed in patients with schizophrenia and mood disorders and that immunosuppressive agents can improve psychiatric symptoms in certain groups.

Moreover, a recent study by Dr Benros and colleagues revealed that infections are a risk factor for the development of schizophrenia in a dose-response relationship, with increasing numbers of hospitalizations for infection increasing the risk for schizophrenia in those with, and without, autoimmune disease.

A similar dose-response relationship was seen in a study by the same team concerning infections as a risk factor for mood disorders in patients with, and without, autoimmune disorders.

To examine whether mild infections also increase the risk for schizophrenia and mood disorders, the team examined data from the nationwide Danish registers to identify all individuals born in Denmark between 1985 and 2002.

These data were matched with data from the hospital registry data on psychiatric and somatic diagnoses to select all people without a hospitalization for infection or a registered mental disorder before 1995.

The national prescription database was used to obtain all redeemed prescriptions of anti-infective agents, including antibiotic and antiviral drugs, since 1995, which were used as a proxy for mild infections.

There were a total of 1,015,447 individuals born in Denmark between 1985 and 2002 who did not have a hospitalization for infection or mental disorder prior to 1995. During the study period, 5759 cases of schizophrenia were diagnosed, along with 13,004 cases of affective disorders.

Taking into account sex, age, calendar year, social factors, hospitalizations, and a family history of mental illness, the team found that any anti-infective prescription was associated with an increased risk for both schizophrenia and affective disorders, at odds ratios of 1.37 and 1.64, respectively.

There was also an additive effect of previous anti-infective prescription and prior hospitalization for infection, at respective odds ratios for later developing schizophrenia and affective disorders of 1.86 and 2.40.

Potential Mechanisms

A temporal association between the last prescription of anti-infective agent and the risk for both schizophrenia and affective disorders was found (P < .001 in all cases).

Interestingly, the risk for schizophrenia and affective disorders remained significantly increased following the prior prescription of anti-infectives for up to 10 years or more, indicating that the associations are not due solely to, for example, detection bias (P < .001 in all cases).

There was also a dose-response association between the number of previous anti-infective prescriptions with the subsequent risk for severe mental disorders, particularly for affective disorders (P < .001).

Analysis by type of anti-infective agent revealed that the greatest associations were with antibiotics, particularly broad-spectrum antibiotics.

The results held after changing the reference group from no prior anti-infective prescriptions to none or one previous prescription, at odds ratios of subsequent schizophrenia and affective disorders following two or more prescriptions of 1.29 and 1.59, respectively.

Dr Benros concluded by saying that the results show that even mild infections increase the risk for schizophrenia and mood disorders. He indicdated that there could be a number of explanations for the association.

The most obvious is that some of the psychiatric symptoms could be caused by infection and inflammation. Other explanations include the possibility that anti-infective treatments could affect the microbiome, or certain genes linked to mental illness may predispose patients toward infections. In addition, the association could be an epiphenomenon resulting from underlying lifestyle factors, medications, or psychological stress.

Inflammation a Likely Culprit

Commenting on the findings, session chair James MacCabe, MD, PhD, reader in the epidemiology of psychosis at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, the United Kingdom, described the research as "very interesting."

Dr James MacCabe

He noted that the most plausible mechanism for the relationship between infectious disease and later psychosis concerns "the inflammatory response of the body to the infection and the effects of that on neurodevelopment...maybe down the line leading to an increased risk of schizophrenia."

Dr MacCabe said that there had been a lot of discussion at the conference about "partitioning out different subtypes of schizophrenia and different pathways to the disorder.

"It may be useful, I think, to look at people who had infections in childhood and developed schizophrenia and compare those who didn't happen to have the infection and see if there are differences in the way that the illness presents itself, the age of onset, and those kinds of things, or any differences in the neurobiology — for example, neuroimaging findings in those patients in adulthood," he said.

Noting that patients who develop schizophrenia, particularly in adulthood, have elevated levels of cytokines and inflammatory markers, Dr MacCabe said: "I would postulate that it's those patients that have had childhood infections who would have those elevated markers in adulthood.

"There are treatments that are designed to target the inflammatory system which are showing some promise in schizophrenia, so it may be that those treatments should be targeted to those particular patients."

This perspective underscores recent opinions that schizophrenia should no longer be considered a single disorder but rather a group of conditions.

"It's in the same way that, years ago, we would have seen arthritis as one disease, and then, as the pathology of different forms of arthritis has come to light, we've then been able to fractionate it into different parts," said Dr MacCabe.

"I think diabetes is another example. The distinction between insulin-dependent and non-insulin-dependent diabetes uncovered two completely different disorders, really, which, beforehand, had been lumped together as one. I do think that that's the way the [schizophrenia] field is going to be moving in the next 20 years or so," he added.

Funding for the study was provided by the Lundbeck Foundation and the Stanley Medical Research Institute and through a European Research Council advanced grant. The investigators and Dr MacCabe report no relevant financial relationships.

Schizophrenia International Research Society (SIRS) 2016 Biennial Meeting: Presented April 5, 2016.

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