Schizophrenia Bulletin (2012) 38(6): 1137-1148 (PMID 22490995)     Konasale Prasad, MD            Faith Dickerson, PhD    ...
Outcome of Schizophrenia Cognitive impairments contribute substantially to poor long term  outcome Verbal memory, execut...
Simplified model of HSV1 Biology:     Implications for cognitive impairments                    Retrograde                ...
Cognitive impairments associated with                           HSV1 exposureStudy                Sample                  ...
MRI studies of HSV1 exposure in SZStudy           Sample                     n          Results                       Comm...
Systematic Evaluation of Antiviral Medication          in Schizophrenia (SEAMS)           A Randomized Double-blind Study ...
Cognitive domains that showed improvementWorking memory   Working memory      Verbal memory   Visual memorytotal score    ...
Moving from association to causation:        The Bradford-Hill Criteria Strength of the Association    Medium to large e...
The Bradford-Hill Criteria - continued Plausibility    Multiple plausible mechanisms, e.g. cytokines, neuronal death or ...
Acknowledgements          Stanley Medical Research Institute          National Institute of Mental Health National Allianc...
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Prasad konasale

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

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Prasad konasale

  1. 1. Schizophrenia Bulletin (2012) 38(6): 1137-1148 (PMID 22490995) Konasale Prasad, MD Faith Dickerson, PhD Annie Watson, BS Sheppard Pratt Health System, MDVishwajit Nimgaonkar, MD, PhD Robert Yolken, MD University of Pittsburgh Johns Hopkins University, MD Pittsburgh, PA
  2. 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. 3. Simplified model of HSV1 Biology: Implications for cognitive impairments Retrograde axonal transport Neuronal Death/ Dysfunction From: Wikipedia Latent Infection Cognitive ImpairmentsPrimary Infection Reactivation cycles
  4. 4. Cognitive impairments associated with HSV1 exposureStudy Sample Type Results CommentsDickerson et al, Chronic SZ from clinic Cross- Verbal memory Medium effect size2003 (n=229) sectional Working memoryShirts et al, 2008 Chronic SZ from Cross- Working memory Medium effect size community (n=328) sectional Executive functionsSchretlen et al, SZ subjects from clinic Cross- Working memory Medium effect size2010 (n=40); No controls sectional Executive functionsWatson 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 memoryYolken et al SZ subjects from CATIE Cross- Composite measure cognitive Medium effect size(2011) study (n=1308) sectional function; Verbal memory, Vigilance & Processing speedBrown et al, SZ subjects from Cross- Prenatal HSV1 exposure associated Small but wellACNP 2009 community sectional with verbal memory deficits in characterized adult SZ cohort
  5. 5. MRI studies of HSV1 exposure in SZStudy Sample n Results CommentsPandurangi SZ 32 Cross- Frontal “atrophy” and other 1T MR imageset al 1993 No controls sectional abnormalities in HSV1 8 mm slices exposed SZ subjectsPrasad et First episode Cross- Prefrontal cortical reduction 1.5 T Scanneral., 2007 antipsychotic naïve SZ sectional in HSV1 exposed SZ 1 mm slices Medium (n=30) & controls (n=44) subjects to large effect sizesSchretlen 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 reductionsPrasad et First episode Longitud Progressive worsening in Worsening inal., 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. 6. Systematic Evaluation of Antiviral Medication in Schizophrenia (SEAMS) A Randomized Double-blind Study of Valacyclovir in Early Course Schizophrenia PANSS RandomizationTestsHSV1 +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. 7. Cognitive domains that showed improvementWorking memory Working memory Verbal memory Visual memorytotal score 2-back (post hoc)
  8. 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. 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. 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)

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