Herpes simplex virus 1 infection and valacyclovir treatment in schizophrenia: Results from the VISTA study

Alan Breier, Robert W. Buchanan, Deepak D'Souza, Keith Nuechterlein, Stephen Marder, Walter Dunn, Sheldon Preskorn, Matthew Macaluso, Brent Wurfel, Gerald Maguire, Rishi Kakar, Diane Highum, Debra Hoffmeyer, Evagelos Coskinas, Robert Litman, Jenifer L. Vohs, Alexander Radnovich, Michael M. Francis, Emmalee Metzler, Andrew ViscoNicole Mehdiyoun, Ziyi Yang, Ying Zhang, Robert H. Yolken, Faith B. Dickerson

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Background: Several studies have implicated herpes simplex virus-type 1 (HSV-1)in the pathophysiology of schizophrenia. A recent trial demonstrated that the anti-viral medication valacylovir, which prevents replication of activated HSV-1, improved selected cognitive deficits in people with schizophrenia. In this study, we examined demographic and illness related differences between HSV-1 positive versus HSV-1 negative subjects with early phase schizophrenia and attempted to replicate the previous valacyclovir treatment results in this population. Methods: 170 subjects with schizophrenia (HSV-1 positive N = 70; HSV-1 negative N = 96)from 12 US sites participated in the HSV-1 positive versus negative comparisons, and were randomized 1:1 to valacyclovir (1.5 g BID)or placebo for a 16-week, double-blind efficacy trial. The primary endpoints were working and verbal memory. Results: The HSV-1 positive group, as compared to the HSV-1 negative group, were older (p < 0.001)with fewer males (p = 0.003), and had a longer duration of illness (p = 0.008), more positive symptoms (p = 0.013), poorer quality of life (p = 0.034)and more impairment on the letter-number sequencing test, which is a measure of working memory (p = 0.045). Valacyclovir failed to significantly improve any of the cognitive indices, symptom or functioning measures. Conclusions: HSV-1 sero-positivity appears to be a marker of a subgroup with a more severe form of schizophrenia. Valacyclovir was not efficacious in the study, perhaps because the herpes virus was in the dormant, non-activated state and therefore non-responsive to valacyclovir effects. ClinicalTrials.gov Identifier: NCT02008773

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalSchizophrenia Research
StatePublished - Apr 2019
Externally publishedYes


  • Cognition
  • Herpes simplex virus-1
  • Schizophrenia
  • Valacyclovir

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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