Antiherpes Virus-Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

To test our hypothesis that valacyclovir, an antiherpes virus-specific
medication, added to antipsychotics (APs) would improve cognitive performance and
psychopathology among schizophrenia subjects exposed to neurotropic herpes
simplex virus, type 1 (HSV1).Methods:Using a double-blind placebo-controlled
design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive
either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to
stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily
orally. At each visit, subjects were evaluated for severity of psychopathology
and side effects using standardized scales and a study-specific semistructured
checklist. A computerized neurocognitive battery validated on both schizophrenia
and healthy subjects was administered at baseline and follow-up. Intent-to-treat
analysis, using linear regression models that included all randomized subjects,
were used to examine differential changes in cognition and psychopathology scores
over 18 weeks between valacyclovir and placebo, accounting for placebo
response.Results:Valacyclovir group improved in verbal memory, working memory,
and visual object learning compared with placebo group. The effect sizes (Cohen's
d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for
the visual object learning. Psychotic symptom severity did not
improve.Conclusions:Supplemental valacyclovir may alleviate impairments in
cognitive domains that are often observed in schizophrenia but not psychotic
symptoms in those exposed to HSV1. If replicated, this approach could provide a
novel strategy to treat cognitive impairments in a subgroup of schizophrenia
subjects who can be reliably identified using a blood test.