Herpes simplex virus, type 1 (HSV-1) produces intermittent lytic, productive infection in many organs, alongside lifelong, latent infection in neurons. HSV-1 infected individuals have greater cognitive dysfunction than uninfected individuals, particularly persons with schizophrenia – even without encephalitis. We investigated whether HSV-1 related cognitive dysfunction is progressive or remediable.
In a prospective naturalistic follow up sample (PNFU), temporal changes in cognitive functions were analyzed in relation to baseline HSV-1 infection in persons with or without schizophrenia (N=226). Separately, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized outpatients with SZ received Valacyclovir (VAL, an antiviral, 1.5 G twice daily for 16 weeks) or placebo (PLA) added to standard antipsychotic treatment, using a stratified randomization design, following placebo run-in (N=67). In both samples, HSV-1 infection (seropositivity) was estimated using serum IgG antibodies. All clinical evaluations were blinded to HSV-1 or treatment. Standardized Z scores for accuracy on eight cognitive domains were analyzed for temporal trajectories using generalized linear models (PNFU) and VAL/PLA differences compared with intent to treat analyses (RCT).
PNFU: At baseline, HSV-1 infected participants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability (p=0.025, 0.029, 0.046, respectively), regardless of SZ diagnosis. They also had a significantly steeper temporal worsening for EMOD (p=0.03). RCT: EMOD improved significantly in VAL-treated patients (p=0.048, Cohen’s d=0.43).
HSV-1 infection is associated with time-related dysfunction in EMOD, which indexes social cognition. Conversely, VAL treatment improves EMOD. A portion of HSV-1 associated cognitive dysfunction is progressive, but remediable.