Schizophrenia Linked With Common Viral Infections

Although genetic factors have been found to explain at least part of the risk for schizophrenia, the etiology of the disease has yet to be fully elucidated. Environmental factors such as maternal preeclampsia, births in the winter and spring, and perinatal infection have also been associated with increased schizophrenia risk.¹ In addition, a growing body of research suggests associations between common viral infections and psychiatric disorders and behavior.

For example, with Toxoplasma gondii (T gondii), the protozoan parasite that causes toxoplasmosis and is primarily transmitted through contaminated food and water or contact with cat litter, and cytomegalovirus (CMV), also known as human herpesvirus 5. Most people who are exposed to either pathogen experience a latent form of disease and remain asymptomatic. However, these infections have been linked to cognitive deficits, psychiatric disorders, traffic accidents, and suicidal behavior.²

“The nature of these associations remains uncertain, but it is plausible that they reflect causality,” wrote the investigators in the results of a new study published in Brain, Behavior, and Immunity.² “The potential role of infections in the etiopathogenesis of schizophrenia is supported by the associations between schizophrenia risk and genes which encode HLA (histocompatability complex A) and other factors which control the immune response to infectious agents,” according to another recent study, published in Schizophrenia Bulletin.¹

Results of both investigations further support the connection between viral infection and psychiatric risk. Brain, Behavior, and Immunity published the results of a serologic case-control study of 11,546 participants from the Danish Blood Donor Study.² Researchers identified T gondii in 25.9% of the sample, which was associated with schizophrenia (odds ratio [OR], 1.47; 95% CI, 1.03-2.09). A stronger association was found when accounting for temporality of exposure (IRR, 2.78; 95% CI, 1.27-6.09).

In addition, 60.8% of participants were shown to be seropositive for CMV, which was associated with the risk for having any psychiatric disorder (OR, 1.17; 95% CI, 1.06-1.29), as well as neurotic, stress-related, and somatoform disorders (OR, 1.27; 95% CI, 1.12-1.44) and suicide attempts or completion (OR, 1.31; 95% CI, 1.10-1.56). When accounting for exposure, CMV was associated with a risk for any psychiatric disorder (IRR, 1.37; 95% CI, 1.08-1.74) and mood disorders (IRR, 1.43; 95% CI, 1.01-2.04).  Investigators did not find a statistically significant association between CMV infection and schizophrenia (OR, 1.25; 95% CI, 0.89-1.77)

“Routinely screening for T gondii and CMV in populations with psychiatric disorders may identify novel stratification groups, which can be used to target treatment, eg, in combination with analysis of genetic risk factors,” the researchers concluded. “Likewise, targeting T gondii or CMV infections can provide novel therapeutic approaches as well as potential biomarkers to identify individuals at increased risk.”

The other study, published in Schizophrenia Bulletin, investigated associations between schizophrenia and the Epstein-Barr virus (herpesvirus 4), the cause of infectious mononucleosis, which has been less commonly studied in this area of research.¹ The sample included 432 individuals with schizophrenia and 311 individuals with no history of psychiatric illness.

The findings demonstrated markedly elevated antibodies to EBV virions in individuals with schizophrenia compared with controls; however, increased reactivity was observed for EBV-viral capsid antibody but not for EBV nuclear antigen-1 or other herpesviruses.

“Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type[s] of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis,” the investigators reported. “Individuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins, indicating an aberrant response to EBV infection. This may contribute to the immunopathology of schizophrenia and related disorders,” they concluded.

Robert H. Yolken, MD, one of the investigators involved in both studies, is the Theodore and Vada Stanley Distinguished Professor of Neurovirology in pediatrics and chair of the Stanley Division of Pediatric Neurovirology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, where he holds a joint appointment in psychiatry and behavioral sciences. Psychiatry Advisor interviewed Dr Yolken for additional insights into the infection-psychosis link and the results of the EBV study.

Psychiatry Advisor: Broadly, what does the research suggest thus far about associations between infectious agents and psychiatric disorders, including schizophrenia?

Dr Yolken: Our group has long been interested in the possible role of infectious pathogens that might affect the brain, probably in connection with some genetic vulnerability. Findings from epidemiologic studies and animal models suggest that certain infections can alter behavior. We are particularly interested in those that can hang around in the brain for a long time, including EBV and T gondii. Most exposed people who have these infections can function normally, but they have been linked to behavior changes.

Psychiatry Advisor: What is the potential explanation for why EBV, but not the other herpes viruses, was linked to schizophrenia?

Dr Yolken: We do not know for sure, but one thing that is different about EBV is that it is typically acquired in early adolescence (though it can also occur in younger children and adults), while many other infections are typically acquired in childhood. So, the link to EBV may have something to do with the timing of infection during this period of rapid brain development.

Psychiatry Advisor: What are the current implications of the EBV findings for clinicians?

Dr Yolken: At this point, the diagnostic tests are not specific enough that we would recommend routine testing, but it is something we are working on. In the long term, we would like to be able to prevent and treat EBV infections.

Psychiatry Advisor: What should be the focus of future research on this topic?

Dr Yolken: Unfortunately, we do not have good medications for EBV and we really need better ones. Ultimately, we would like to have a vaccine as well.

We also need better medications for treating schizophrenia. It would be nice to have one directly related to infectious etiology that could potentially treat these patients with fewer side effects. Based on what I can tell from the literature, there are some agents currently being investigated for this purpose.

References

1. Dickerson F, Jones-Brando L, Ford G, et al. Schizophrenia is associated with an aberrant immune response to Epstein–Barr virus [published online November 20, 2018]. Schizophr Bull. 2018. doi: 10.1093/schbul/sby164
2. Burgdorf KS, Trabjerg BB, Pedersen MG, et al. Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders [published online January 29, 2019]. Brain Behav Immun. doi: 10.1016/j.bbi.201