Apr 1, 2018 - Kehui Chen1, Joel Wood1, Robert H Yolken6. 1University of Pittsburgh ... Michael Francis1, Alexander Radnovich1, Robert Yolken6,. Sheldon ...
Concurrent Symposia S63 underlying neuroanatomical deficits, immune dysregulation, or gene x environmental interactions. The aberrant immune response to EBV may represent underlying immunopathy or exposure to variant viral strains. Other herpesviruses, such as Cytomegalovirus, Herpes Simplex Virus Type 2 and Human Herpesvirus Type 6 have also been associated with schizophrenia risk or with cognitive impairment in some populations. The prevention and treatment of herpesvirus infections might lead to new therapeutic modalities for schizophrenia.
39.3 CAN NEUROVIRAL INFECTIONS WITH HERPES SIMPLEX VIRUS, TYPE 1 (HSV-1) CONTRIBUTE TO RDOC? Vishwajit Nimgaonkar*,1, Smita Deshpande2, Triptish Bhatia3, Konasale Prasad1, Faith Dickerson4, Raquel Gur5, Ruben Gur5, Kehui Chen1, Joel Wood1, Robert H Yolken6 1 University of Pittsburgh; 2Dr. R.M.L. Hospital; 3Indo-US Schizophrenia Study; 4Sheppard Pratt; 5University of Pennsylvania; 6 Johns Hopkins School of Medicine Background: The ‘viral hypothesis of schizophrenia’ is difficult to prove, partly because it is inherently difficult to find causes for chronic conditions. It is also not easy to date and relate the timing of infections or psychiatric diagnoses. Further, many neuroviruses cannot be isolated from infected persons. Progress could be made using RDoC for cognition as outcomes of infection, since those quantifiable variables cross psychiatric diagnostic domains (as do infections); they can also be monitored longitudinally and assessed with regard to treatment. We have tested this paradigm in relation to Herpes simplex virus, type 1 (HSV-1) that infects over 3.4 billion people. Though it can cause encephalitis, it is asymptomatic in the vast majority, only causing lifelong latent infection in neurons. Over 10 cross-sectional studies and longitudinal studies indicate that even in the absence of overt encephalitis, individuals seropositive for HSV-1 perform significantly worse than seronegative individuals in several cognitive domains, particularly those relating to memory. These associations remain significant following adjustment for demographic variables, such as socio-economic status. Even though post-mortem studies have been inconclusive, brain imaging studies also indicate gray matter volume reductions in frontotemporal regions in infected individuals, consistent with the cognitive impairment. Many neuronal models of latency are also available. 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 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). Results: 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). Discussion: 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. Viral infections could be used to investigate and validate RDoC criteria.
39.4 A DOUBLE-BLIND TRIAL OF VALACYCLOVIR TO IMPROVE COGNITION IN EARLY PHASE SCHIZOPHRENIA: RESULTS FROM THE VISTA STUDY Alan Breier*,1, Faith Dickerson2, Robert Buchanan3, Stephen Marder4, Keith Neuchterlein4, Deepak D’Souza5, Michael Francis1, Alexander Radnovich1, Robert Yolken6, Sheldon Preskorn7, Matthew Macaluso7, Ziyi Yang1, Nicole Mehdyoun1, Rishi Kakar8, Walter Dunn4, Debra Hoffmeyer9, Gerald Maguire10 1 Indiana University School of Medicine; 2Sheppard Pratt; 3 Maryland Psychiatric Research Center; 4University of California, Los Angeles; 5Yale University School of Medicine, VA Connecticut Healthcare System; 6Johns Hopkins University School of Medicine; 7 Kansas University Medical Center; 8Segal Trials; 9CI Trials; 10 University of California, Riverside Background: Several lines of evidence suggest that Herpes Simplex Virus type 1 (HSV-1) may contribute to cognitive impairment in schizophrenia. Herpes viruses are enveloped, double stranded DNA viruses that are capable of infecting human CNS resulting in life-long infection with over 40% of the population seropositive for this virus. Valacyclovir is an effective treatment for the suppression of herpes virus infections. A previous small clinical trial (N=24) assessed the efficacy of valacyclovir for cognitive impairment in patients with early phase schizophrenia who were seropositive for HSV-1 (Prasad et al 2013). Results indicate that adjunctive valacyclovir, as compared to placebo, showed improvement in working and visual memory. The current study was undertaken to confirm and extend these findings and determine if HSV-1 seropositive, as compared to those who were HSV-1 seronegative, derived cognitive improvement from adjunctive valacyclovir. We hypothesized that individuals who were HSV-1 positive, but not HSV-1 negative, would demonstrate significant valacyclovir efficacy for cognitive impairment. Methods: An early psychosis network comprised of 12 US sites was established for the valacyclovir trial. Subjects had early phase schizophrenia (within 8 years since psychosis onset) and were randomized 1:1 to a 16-week trial of adjunctive valacyclovir (3 grams/day) or placebo. Assessments included cognitive domains (MATRICS), role functioning (UPSA-B, Q-LES-Q-SF, PSP), psychiatric symptoms (PANSS, NSA16) and a range of inflammatory markers. The primary outcome was change in working (composite score of Spatial Span and Letter Number span) and visual (Brief Visuospatial Memory Test) as measured by the MATRICS. Results: 170 subjects with early phase schizophrenia were stratified by HSV-1 status and randomized 1:1 to adjunctive valacyclovir or adjunctive placebo. Of those randomized, 74 were HSV-1 seropositive and 96 were seronegative. The valacyclovir vs. placebo groups, respectively, were well matched: age (28.4 vs. 27.5 years), gender (males: 69% vs. 77.9 %), race (white-caucasian: 28.6% vs. 33.7%) and duration of psychosis (3.7 vs. 4.0, years). Baseline working memory scores (Letter-Number Span) were significantly lower in HSV1 positive vs. negative subjects (mean/SD: vs. 35.1/9.0 vs 38.3/11.0, p=0.046). Treatment outcome analyses have only recently commenced and are ongoing. Full results of the cognitive, functioning, symptom and safety measures will be presented at the meeting. Discussion: The current study included 170 patients with early phase schizophrenia randomized to valacyclovir or placebo and stratified by HSV1 sero-status. Baseline working memory scores (Letter-Number Span) were significantly lower in HSV1 positive compared to HSV1 negative subjects. As analyses of treatment effects are ongoing, detailed results of valacyclovir’s effects on cognitive domains, symptoms, functioning and safety will be presented at the meeting. Additional research is needed to determine the full therapeutic potential of valacyclovir and other medications targeting herpes viruses in the treatment of schizophrenia.
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