Is Epstein-Barr Virus to Blame for Cognition in Schizophrenia?

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Although cognitive difficulties may not be the primary symptom addressed in patients with schizophrenia, these impairments are a central feature that can contribute to social and functional disability.¹ Cognitive dysfunction in schizophrenia affects not only attention, verbal memory, reasoning, and processing speed, but also social cognition and interactions.² Thus, the topic has received increased attention. (For more information, see the Psychiatric Times^TM Cognition Special Report in the December 2020 issue—Ed.)

A growing body of research results indicates viruses may play a role in both schizophrenia and cognitive difficulties. One in particular, Epstein-Barr virus (EBV), has received notable attention in the possible pathophysiology of schizophrenia as well as of associated cognitive dysfunction, although findings have been inconsistent. For instance, in a previous study of 229 patients with schizophrenia, the data did not indicate an association between EBV seropositivity and cognitive performance.³ Importantly, previous studies have generally measured exposure by reactivity to a single EBV protein, rather than to a panel of proteins or EBV virions. EBV, also known as human herpesvirus 4, is a lymphotropic virus that can produce acute and latent infections.

The Study

Using the MATRICS Consensus Cognitive Battery (MCCB), Dickerson and colleagues⁴ tested their hypothesis that antibodies to various EBV proteins may be associated with different levels and domains of cognitive functioning in patients with schizophrenia.⁵ Patients with schizophrenia or schizoaffective disorder were enrolled at the Stanley Research Program at Sheppard Pratt in Baltimore, Maryland, in 1 of 3 trials of adjunctive medications for adults with schizophrenia that were conducted between 2014 and 2019.

Inclusion and Exclusion Criteria Across 3 Trials

Across the 3 trials, inclusion criteria were: receiving outpatient (vs inpatient) treatment; aged > 18 years; diagnosis of schizophrenia/schizoaffective disorder confirmed by structured clinical interview; and current stable antipsychotic treatment. Patients were excluded from the study if they had clinically significant or unstable medical disorders; were pregnant or breastfeeding; had current or recent substance use disorder; or were found to have an intellectual disability or IQ below 70 (Table 1).⁴ In addition to the MCCB, the psychopathology of each patient was assessed using the Positive and Negative Syndrome Scale (PANSS). The total sample size was 84 (Table 2).

Patient Characteristics

Blood was assayed for immunoglobulin G antibodies to EBV antigens derived from intact virions using enzyme immunoassay. Assay values for patients were compared with a standard score based on the reactivity of controls without psychiatric disorders. Reactivity to herpes simplex virus type 1 (HSV-1) was also measured by immunoassay. In all studies, blood samples and cognitive testing were completed before the administration of any study medication. Linear regression models were used to determine whether EBV antibodies (to the whole virion and to specific proteins) were associated with MCCB composite and domain scores (Table 3), controlling for age, sex, race, education, smoking, and HSV-1 serology.⁵

Results and Conclusions

Cognitive Domains in Schizophrenia Assessed by the MCCB

The authors found a significant association between the lower MCCB overall percentile composite score (ie, worse cognition) and higher levels of antibodies to the whole EBV virion, to the EBV nuclear antigen-1 (EBNA-1), and to the EBV viral capsid antigen (VCA). There was also a significant association between lower MCCB social cognition and higher level of EBV virion, EBNA-1, and VCA antibodies. Lower MCCB processing speed was associated with higher EBV virion antibodies at a trend level. Lower MCCB working memory was also associated with higher EBNA-1 antibodies at a trend level.

The authors concluded that worse cognitive functioning in schizophrenia was associated with specific patterns of reactivity to EBV, including global and social cognition. Dickerson and colleagues acknowledged both strengths and limitations of their study. For instance, the present study includes the comprehensive cognitive battery (MCCB) and the measurement of EBV reactivity to specific EBV proteins. The investigators noted that the biological basis for the association between cognitive functioning and immune response to EBV is unknown. However, this study included a relatively small sample size, so the results may not be generalizable to other samples of patients with schizophrenia. Similarly, there may be possible residual confounding effects (eg, diet, genetics).

The Bottom Line

Exposure to EBV may contribute to cognitive impairments in patients with schizophrenia, which may have clinical implications. In particular, certain antiviral medications may be relevant to the prevention and treatment of EBV-associated cognitive impairment.

Regardless of these findings, it is important for clinicians to remain vigilant in the identification and assessment of cognitive impairment in schizophrenia, given its impact on social and functional disability. Although there are not any approved medications, clinicians can potentially improve cognitive outcomes by optimizing antipsychotic dosing based on symptoms and adverse effects, treating underlying depression, facilitating treatment of medical comorbidities (eg, hypertension, diabetes), and utilizing other therapies (eg, cognitive remediation) as available and appropriate.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior of Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times^TM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

References

1. Dickerson F, Boronow JJ, Ringel N, Parente F. Neurocognitive deficits and social functioning in outpatients with schizophrenia. Schizophr Res. 1996;21(2):75-83.

2. Green MF, Horan WP, Lee J. Social cognition in schizophrenia. Nat Rev Neurosci. 2015;16(10):620-631.

3. Dickerson FB, Boronow JJ, Stallings C, et al. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60(5):466-472.

4. Dickerson F, Katsafanas E, Origoni A, et al. Exposure to Epstein Barr virus and cognitive functioning in individuals with schizophrenia. Schizophr Res. 2021;228:193-197.

5. MCCB [MATRICS Consensus Cognitive Battery] Neuropsychological Assessment. MATRICS Assessment Inc. Accessed February 4, 2021. https://www.matricsinc.org/mccb ❒