Presentation made by Dr. Prasad Konasale on the 13th of November, 2012 at the Schizophrenia Research Forum live webinar (www.schizophreniaforum.org)

1. Schizophrenia Bulletin (2012) 38(6): 1137-1148 (PMID 22490995)
Konasale Prasad, MD Faith Dickerson, PhD
Annie Watson, BS Sheppard Pratt Health System, MD
Vishwajit Nimgaonkar, MD, PhD
Robert Yolken, MD
University of Pittsburgh Johns Hopkins University, MD
Pittsburgh, PA

2. 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

3. Simplified model of HSV1 Biology:
Implications for cognitive impairments
Retrograde
axonal
transport
Neuronal
Death/
Dysfunction
From: Wikipedia
Latent Infection Cognitive
Impairments
Primary Infection Reactivation cycles

4. Cognitive impairments associated with
HSV1 exposure
Study Sample Type Results Comments
Dickerson et al, Chronic SZ from clinic Cross- Verbal memory Medium effect size
2003 (n=229) sectional Working memory
Shirts et al, 2008 Chronic SZ from Cross- Working memory Medium effect size
community (n=328) sectional Executive functions
Schretlen et al, SZ subjects from clinic Cross- Working memory Medium effect size
2010 (n=40); No controls sectional Executive functions
Watson et al SZ subjects from Cross- Composite measure of cognitive Medium effect size
(2012) community (SZ 452, sectional function (PCH) that included verbal
Relatives 808, HS 271) memory &visual memory
Yolken et al SZ subjects from CATIE Cross- Composite measure cognitive Medium effect size
(2011) study (n=1308) sectional function; Verbal memory, Vigilance
& Processing speed
Brown et al, SZ subjects from Cross- Prenatal HSV1 exposure associated Small but well
ACNP 2009 community sectional with verbal memory deficits in characterized
adult SZ cohort

5. MRI studies of HSV1 exposure in SZ
Study Sample n Results Comments
Pandurangi SZ 32 Cross- Frontal “atrophy” and other 1T MR images
et al 1993 No controls sectional abnormalities in HSV1 8 mm slices
exposed SZ subjects
Prasad et First episode Cross- Prefrontal cortical reduction 1.5 T Scanner
al., 2007 antipsychotic naïve SZ sectional in HSV1 exposed SZ 1 mm slices Medium
(n=30) & controls (n=44) subjects to large effect sizes
Schretlen Medicated SZ subjects Cross- Prefrontal cortical volume Working memory &
et al., 2010 (n=40) sectional reduction in HSV1 exposed executive function
No controls SZ subjects deficits correlated
with volume
reductions
Prasad et First episode Longitud Progressive worsening in Worsening in
al., 2011 neuroleptic naïve SZ at inal executive functions along executive functions
baseline & controls with progressive grey correlated with PCG
matter loss in posterior grey matter loss
cingulate gyrus (PCG)

6. Systematic Evaluation of Antiviral Medication
in Schizophrenia (SEAMS)
A Randomized Double-blind Study of
Valacyclovir in Early Course Schizophrenia
PANSS
Randomization
Tests
HSV1 +ve
Screening Baseline 2-week 4-week 8-week 12-week 16-week 18-week Follow-up
6-week
for HSV1 assessments
exposure
CNB

7. Cognitive domains that showed improvement
Working memory Working memory Verbal memory Visual memory
total score 2-back (post hoc)

8. 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

9. 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

10. 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)