Cognitive impairments are a central feature in schizophrenia 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.2
Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a lymphotropic virus that can produce acute and latent infections. The association between EBV exposure and cognitive function has been studied previously with inconsistent findings. One previous study in 229 patients with schizophrenia did not find 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 a panel of proteins or EBV virions.
Dickerson and colleagues4 hypothesized that antibodies to different EBV proteins may be associated with different levels and domains of cognitive functioning in schizophrenia using the MATRICSTM Consensus Cognitive Battery (MCCBTM).5 Study authors enrolled patients with schizophrenia or schizoaffective disorder enrolled at the Stanley Research Program at Sheppard Pratt, Baltimore, Maryland, in 1 of 3 trials of adjunctive medications for adults with schizophrenia conducted between 2014 and 2019.
Inclusion criteria across the 3 trials were outpatients aged >18 years, a diagnosis of schizophrenia/ schizoaffective disorder confirmed by structured clinical interview, and current stable antipsychotic treatment. Exclusion criteria were clinically significant or unstable medical disorders, pregnancy or breastfeeding, current or recent substance use disorder, or intellectual disability or IQ below 70 (Table 1). All patients were assessed with the MCCB. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS).
Blood was assayed for immunoglobulin G (IgG) 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 specific proteins) were associated with MCCB composite and domain scores (Table 2), controlling for age, sex, race, education, smoking, and HSV-1 serology.
The total sample consisted of 84 participants: 50% schizophrenia and 50% schizoaffective disorder. The mean age was 36 years; 77% were male; 45% were Caucasian and 50% African American; and mean PANSS total score 76. A quarter (27%) of patients had reactivity to HSV-1. At the time of the assessment, of the 84 patients, 87% were receiving atypical antipsychotics; 27% valproate; 41% anticholinergics; and 44% antidepressants.
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, the EBV nuclear antigen-1 (EBNA-1), and 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 worse cognitive functioning in schizophrenia was associated with specific patterns of reactivity to EBV, including global and social cognition. Strengths of the present study includes the comprehensive cognitive battery (MCCB), and the measurement of EBV reactivity to specific EBV proteins. They note that the biological basis for the association between cognitive functioning and immune response to EBV is unknown. Limitations of the present study include the relatively small sample size, results may not be generalizable to other samples of patients with schizophrenia, and possible residual confounding (eg, diet, genetics).
The Bottom Line
Exposure to EBV may contribute to cognitive impairments in schizophrenia, which may have clinical implications. In particular, certain antiviral medications may be relevant to the prevention and treatment of EBV-associated cognitive impairment. 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 for cognitive impairment in schizophrenia, clinicians can potentially improve cognitive outcomes by optimizing antipsychotic dosing based on symptoms and side 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 professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. 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.
1. Dickerson F, Boronow JJ, Ringel N, et al. Neurocognitive deficits and social functioning in outpatients with schizophrenia. Schizophr Res. 1996;21:75–83.
2. Green MF, Horan WP, Lee J. Social cognition in schizophrenia. Nat Rev Neurosci. 2015;16:620–631.
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: 466–472.
4. Dickerson F, Katsafanas Em, Origoni A, et al. Exposure to Epstein Barr virus and cognitive functioning in individuals with schizophrenia. Schizophr Res. 2021;228:193-197.
5. MATRICSTM Consensus Cognitive Battery (MCCBTM). Accessed February 4, 2021. http://www.matricsinc.org/mccb