Triptish Bhatia1, Joel Wood2, Satish Iyengar3, Sreelatha S Narayanan4, Ram Pratap Beniwal5, Konasale M Prasad6, Kehui Chen7, Robert H Yolken8, Faith Dickerson9, Ruben C Gur10, Raquel E Gur11, Smita N Deshpande5, Vishwajit L Nimgaonkar12. 1. Indo-US Projects, Dept. of Psychiatry, Centre of Excellence in Mental Health, PGIMER-Dr. Ram Manohar Lohia Hospital, Park Street, New Delhi 110001, India. 2. Department of Psychiatry, WPIC, University of Pittsburgh, Pittsburgh 15213, USA. Electronic address: woodja@upmc.edu. 3. Department of Psychiatry, WPIC, University of Pittsburgh, Pittsburgh 15213, USA; Department of Statistics, University of Pittsburgh, Pittsburgh 15260, USA. Electronic address: ssi@pitt.edu. 4. GRIP-NIH Project, Dept. of Psychiatry, Centre of Excellence in Mental Health, PGIMER-Dr. Ram Manohar Lohia Hospital, Park Street, New Delhi 110001, India. 5. Dept. of Psychiatry, Centre of Excellence in Mental Health PGIMER-Dr. Ram Manohar Lohia Hospital, Park Street, New Delhi 110001, India. 6. Department of Psychiatry, WPIC, University of Pittsburgh, Pittsburgh 15213, USA. Electronic address: prasadkm@upmc.edu. 7. Department of Psychiatry, WPIC, University of Pittsburgh, Pittsburgh 15213, USA; Department of Statistics, University of Pittsburgh, Pittsburgh 15260, USA. Electronic address: khchen@pitt.edu. 8. Stanley Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 9. Sheppard Pratt IRB, Sheppard Pratt, 6501 North Charles St., Baltimore, MD 21204, USA. Electronic address: fdickerson@sheppardpratt.org. 10. Perelman School of Medicine, Department of Psychiatry, University of Pennsylvania, Philadelphia, USA. Electronic address: gur@mail.med.upenn.edu. 11. Perelman School of Medicine, Department of Psychiatry, University of Pennsylvania, Philadelphia, USA. Electronic address: raquel@mail.med.upenn.edu. 12. Department of Psychiatry, WPIC, University of Pittsburgh, Pittsburgh 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh 15261, USA. Electronic address: nimga@pitt.edu.
Abstract
BACKGROUND:Herpes simplex virus, type 1 (HSV-1) infects over 3.4 billion people, world-wide. Though it can cause encephalitis, in the vast majority it is asymptomatic, with 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. METHODS: 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/without schizophrenia (N=226). Independently, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized SZ outpatients received Valacyclovir (VAL, an HSV-1 specific antiviral, 1.5G twice daily for 16weeks) 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. Clinical evaluations were blinded to HSV-1 or treatment status. 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). RESULTS:PNFU: At baseline, HSV-1 infected participants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability, regardless of SZ diagnosis (p=0.025, 0.029, 0.046, respectively). They also had significantly steeper temporal worsening for EMOD (p=0.03). RCT: EMOD improved in VAL-treated patients (p=0.048, Cohen's d=0.43). CONCLUSIONS: A proportion of age related decline in EMOD is attributable to HSV-1 infection.
RCT Entities:
BACKGROUND:Herpes simplex virus, type 1 (HSV-1) infects over 3.4 billion people, world-wide. Though it can cause encephalitis, in the vast majority it is asymptomatic, with 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. METHODS: 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/without schizophrenia (N=226). Independently, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized SZ outpatients received Valacyclovir (VAL, an HSV-1 specific antiviral, 1.5G twice daily for 16weeks) 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. Clinical evaluations were blinded to HSV-1 or treatment status. 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). RESULTS: PNFU: At baseline, HSV-1 infectedparticipants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability, regardless of SZ diagnosis (p=0.025, 0.029, 0.046, respectively). They also had significantly steeper temporal worsening for EMOD (p=0.03). RCT: EMOD improved in VAL-treated patients (p=0.048, Cohen's d=0.43). CONCLUSIONS: A proportion of age related decline in EMOD is attributable to HSV-1 infection.
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