Exposure to Herpes Simplex Virus Type

1 and Cognitive Impairments in

Individuals with Schizophrenia

Schizophrenia Bulletin (2012) 38(6): 1137-1148 (PMID

22490995)

Konasale Prasad, MDAnnie Watson, BS

Vishwajit Nimgaonkar, MD, PhD

University of PittsburghPittsburgh, PA

Faith Dickerson, PhDSheppard Pratt Health System,

MD

Robert Yolken, MDJohns Hopkins University, MD

Outcome of Schizophrenia Cognitive impairments contribute substantially to poor long

term outcome

Verbal memory, executive functions and vigilance impairments consistently associated with outcome

Antipsychotics (1st & 2nd generation) - small effect on improving cognitive impairments

Need to identify potentially treatable factors associated with cognitive deficits

Infectious agents offer several advantages: Biological discrete Well-characterized pathophysiology and pathology Immune responses are specific, quantifiable, heritable and can

be potential biomarkers Effective treatments may be available

From: Wikipedia

Simplified model of HSV1 Biology: Implications for cognitive impairments

Neuronal Death/Dysfunction

Retrograde axonal transport

Cognitive Impairments

Primary Infection

Latent Infection

Reactivation cycles

Cognitive impairments associated with HSV1 exposure

Study Sample Type Results Comments

Dickerson et al, 2003

Chronic SZ from clinic (n=229)

Cross-sectional

Verbal memoryWorking memory

Medium effect size

Shirts et al, 2008

Chronic SZ from community (n=328)

Cross-sectional

Working memoryExecutive functions

Medium effect size

Schretlen et al, 2010

SZ subjects from clinic (n=40); No controls

Cross-sectional

Working memoryExecutive functions

Medium effect size

Watson et al (2012)

SZ subjects from community (SZ 452, Relatives 808, HS 271)

Cross-sectional

Composite measure of cognitive function (PCH) that included verbal memory &visual memory

Medium effect size

Yolken et al (2011)

SZ subjects from CATIE study (n=1308)

Cross-sectional

Composite measure cognitive function; Verbal memory, Vigilance & Processing speed

Medium effect size

Brown et al, ACNP 2009

SZ subjects from community

Cross-sectional

Prenatal HSV1 exposure associated with verbal memory deficits in adult SZ

Small but well characterized cohort

MRI studies of HSV1 exposure in SZ

Study Sample n Results Comments

Pandurangi et al 1993

SZ 32No controls

Cross-sectional

Frontal “atrophy” and other abnormalities in HSV1 exposed SZ subjects

1T MR images8 mm slices

Prasad et al., 2007

First episode antipsychotic naïve SZ (n=30) & controls (n=44)

Cross-sectional

Prefrontal cortical reduction in HSV1 exposed SZ subjects

1.5 T Scanner1 mm slices Medium to large effect sizes

Schretlen et al., 2010

Medicated SZ subjects (n=40)No controls

Cross-sectional

Prefrontal cortical volume reduction in HSV1 exposed SZ subjects

Working memory & executive function deficits correlated with volume reductions

Prasad et al., 2011

First episode neuroleptic naïve SZ at baseline & controls

Longitudinal

Progressive worsening in executive functions along with progressive grey matter loss in posterior cingulate gyrus (PCG)

Worsening in executive functions correlated with PCG grey matter loss

A Randomized Double-blind Study of Valacyclovir in Early Course Schizophrenia

Systematic Evaluation of Antiviral Medication in Schizophrenia (SEAMS)

Screeningfor HSV1exposure

TestsHSV1 +ve

Baseline 2-week 8-week 16-week12-week4-week Follow-upassessments

Randomization

CNB

6-week 18-week

PANSS

Cognitive domains that showed improvement

Working memorytotal score

Working memory2-back (post hoc)

Verbal memory Visual memory

Moving from association to causation: The Bradford-Hill

Criteria Strength of the Association

Medium to large effect sizes of associations are persuasive

Consistency of the association Similar domains affected in different settings using different

instruments in 6 independent samples

Specificity Common confounds controlled 4 studies examine without psychiatric conditions Bacterial infections, Toxo and possibly CMV not associated with

cognitive impairments

Temporality 2 of the 3 longitudinal studies show progressive decline

Biological gradient One study showing levels of antibody and degree of cognitive

impairments

The Bradford-Hill Criteria - continued

Plausibility Multiple plausible mechanisms, e.g. cytokines, neuronal

death or neuronal dysfunction 3 imaging data showing similar findings

Experiment Valacyclovir treatment resulting in improvement in

selected domains

Analogy One rat experiment concurs with observations on

humans

Coherence Latent infections not adequately modeled in animals for

cognitive impairments

Acknowledgements

Stanley Medical Research Institute

National Institute of Mental Health

National Alliance for Research on Schizophrenia

and Affective Disorders (NARSAD)

American Psychiatric Institute for Psychiatric

Education and Research (APIRE)-Lilly

Clinical & Translational Science Institute (CTSI)