Infections and Psychiatric DiseasesLecture Outline
Clinical and Epidemiologic Features of Schizophrenia and Bipolar Disorder
Biology of Endogenous Retroviruses Role of Herpesviruses in Retroviral
Transcription Clinical Epidemiology of Herpesvirus
Infections and Psychiatric Diseases Clinical Trials of Antimicrobial Agents
Schizophrenia and the Clinical LaboratoryOpportunities and Challenges
OpportunitiesCommon Disease (1% of American Population)Availability of more easily tolerated medications
ChallengesRudimentary knowledge of disease pathogenesisNo relevant animal models or cell linesNo laboratory testsMinimal prediction of response to medication
Schizophrenia and Bipolar DisorderClinical Features
Schizophrenia Positive Symptoms
Hallucinations, Delusions, Disordered Thinking Negative Symptoms
Withdrawal, Amotivation, Restricted Expressiveness Impairment in Cognitive and Social Functioning Lifetime prevalence ~ 1% worldwide
Bipolar Disorder Mania Depression Variable degree of positive and negative symptoms Variable degree of cognitive impairment Lifetime prevalence ~0.5% worldwide
A Beautiful MindHollywood or Reality
A Beautiful MindHollywood vs Reality?
Reality Onset of schizophrenia without clear cause Attractiveness of delusions Role of medication Disease “burn out” at later age
Hollywood Delusions coinciding with creativity Shock therapy used at “high class” hospital Family support
Schizophrenia and Bipolar DisorderBiological and Epidemiological Features
Lifelong illness with peak onset in early adulthood. Range of structural and functional brain abnormalities
visible on fMRI and PET scans. Abnormal expression of brain receptors
Dopamine Glutamate
Massive social and economic consequences Available medications
Control symptoms in many patients Have a high rate of side effects Do not appreciably alter the course of disease
Microbial Agents and SchizophreniaEpidemiological Findings
Specific Infectious Agent Perinatal Rubella (Brown et al, 2001; OR~3.5) Neonatal Enterovirus (Jones et al, 1998 OR~4) Maternal Herpesvirus (Buka 2001; OR~4)
Possible Infectious Exposure Seasonality of Birth (Torrey at al, 1998; OR~2) Urban Birth (Mortenson et at, 1999, OR~2.5) Fever in Pregnancy (Torrey et al 2000, OR~3) Pre-eclampsia ( Dalman et al, 1999, OR~2.5)
Case Reports HIV Herpes Simplex Virus 1/2 Toxoplasma gondii
Genetics Of Schizophrenia and Bipolar Disorder
• Increased Incidence in Biological First Degree Relatives • General Population 1%• First Degree Relatives 7-9%• Monozygotic Twins 30%
• Most individuals with schizophrenia do not have a first degree relative with this disease.
• Genetic factors have a large relative risk but a small risk in the overall population (5%)
• Intensive search for genes using molecular methods• Multiple chromosomal regions of linkage• Single nucleotide polymorphisms of minor effect in selected
populations (OR~2) • No genes of major effect in different populations
Complex Human DiseasesBeyond Koch and Mendel
Mendel-Human traits are determined by individual
genes which function independently of other genes and of environmental
influences
Koch-Many human diseases are caused by microbes which exert
their effect independently of other microbes, environmental factors and
genes
Microbial Agents and Human Disease Koch’s Postulates
Principles Specific infectious agents cause clearly delineated
disease states The diseases cannot exist without the specific agent Etiologic agents cause disease in animal models
Limitations Shared pathways of response to infection Genetic determinants of response Individual variation in response to infection Limited animal models of complex human diseases
Complex Human DiseasesBeyond Koch’s Postulates
Most common human diseases are caused by the interaction of environmental insults and susceptibility genes.
Many of the susceptibility genes are diverse determinants of human response to environmental factors to infection.
Informative laboratory methods for complex disorders have to address both genetic and environmental factors.
Prevention or treatment of the infections may result in the effective treatment of complex disorders: Helicobacter-Peptic Ulcer HPV-Genital Cancer Chlamydia-Cardiac Disease?
Etiology of Complex Human DiseasesRelative vs. Attributable Risk
Relative Risk-Chance of an individual with an exposure acquiring a disease relative to the general population
Population Attributable Risk-Percentage of the population with a disease which can be attributed to a specific factor
Diseases of single or limited etiologies-High relative and attributable risks CFTR gene-Cystic Fibrosis HIV-Acquired Immunodeficiency Syndrome
Complex Human Diseases Factors with high relative risk may have low attributable risks if exposures are rare Apoliprotein genes-Alzheimer’s Disease Maternal alcohol-Fetal malformations M tuberculosis-Lung Disease
Epidemiology of SchizophreniaRelative vs. Attributable Risk
Factor Relative Risk
Affected Father 7.2
Affected Mother 9.3
Affected Sibling 7.0
Urban Birth 2.4
Winter Birth 1.1
No Factor 1.0
Mortenson et al, NEJM 340:603, 1999
Epidemiology of SchizophreniaRelative vs. Attributable Risk
Factor Relative Risk % Cases In Population
Affected Father 7.2 1.2%
Affected Mother 9.3 2.4%
(No affected parent) 88.8%
Affected Sibling 7.0 2.2%
(No affected sibling) 97.8%
Urban Birth 2.4 32.9%
Winter Birth 1.1 25%
Mortenson et al, NEJM 340:603, 1999
Epidemiology of SchizophreniaRelative vs. Attributable Risk
Risk Factor Population Attributable Risk
Affected Parent 3.8%
Affected Sibling 1.9%
Affected Parent or Sibling 5.5%
Place of Birth 34.6%
Season of Birth 10.5%
Place and Season of Birth 41.4%
All Variables 46.6%
Mortenson et al, NEJM 340:603, 1999
SchizophreniaWorking Hypotheses
Most cases of schizophrenia are the result of infections and other environmental insults occurring in genetically susceptible individuals before the onset of clinically apparent symptoms.
Distinct gene-environmental interactions may be operant in different populations.
Interactions do not follow Koch’s postulates. The role of specific infectious agents can be defined
by clinical trials of anti-microbial chemotherapy.
Identification of Infections in Schizophrenia Methods-Old and New
Analytic Methods Differential Display PCR Library screening Microarrays Two-dimensional electrophoresis Enzyme immunoassays
Samples for Analysis Brains collected by the Stanley Neuropathology
Consortium Cerebrospinal fluids (CSF’s) from individuals with recent
onset schizophrenia Blood samples from mothers of infants who developed
schizophrenia in adult life.
Differential Display PCRBrain from Individual with Schizophrenia (S)
and Unaffected Control(U)
S S SU U UM M
Human Endogenous Retrovirus HERV-W
HIV
Endogenous RetrovirusesBorderland Between Viruses and Genes
Integrated Genomic Elements with Homology to Retroviruses Arising from Germ Line Integration of infectious viruses during evolution All Primates Old World Monkeys Apes Humans Individuals
Endogenous RetrovirusesBorderland Between Viruses and Genes II
Dynamic Effects on Gene Function Promoter control of adjacent genes- PLA2; Placental Genes Interaction with infectious agents- Herpesviruses, Toxoplasma Interaction with soluble mediators-Hormones; Cytokines
Functionality of viral proteins-Syncytin; amino acid transporters Role in Human Disease
Diabetes- Superantigen activation Multiple Sclerosis- Glial cell function Autoimmune Arthritis- T cell activity Pre-Eclampsia- Aberrant Fusion of Trophoblasts
Endogenous RetrovirusesActivation and Transcription
DNA 5’LTR Viral Proteins 3’LTR
Microbe Hormone Mediator
Endogenous RetrovirusesBorderland Between Viruses and Genes
Integrated Genomic Elements with Homology to Retroviruses Arising from Germ Line Integration of infectious viruses during evolution All Primates Old World Monkeys Apes Humans Individuals
Herv-W
K113
Scz Ctr
DN
A
Endogenous Retroviral PCRCSFs:Schizophrenia and Controls
HERVw GTTCAGGGATAGCCCCCATCTATTTGGCCAGGCATTAGCCCAAGACTTGAGTCAATTCTCATACCTGGACACTCTTGTCCTTCAG C1 ---------------------------------------------------C--------------------------------- A1 ------------------------------A---------------------------------------------------TG- A2 ------------------------------A---------------------------------------------------TG- A3 ----------------------------------C----------------C--G----------------------------G- A4 -----------A----------------------------T----------C--G---------------------------TG- A5 -----A------------------------------------------------------------------------------- A6 ------------T------------CA---TA-------------------C--G---------------------------TG-
Herv-W
Herv-W EnvelopeChromosomal Distribution
Herv-W and Amino Acid TransportersLavillette et al, J Virol Jul;76(13):6442-52.
ASCT1 HERV-W ReceptorBrains of Cases and Controls
Neuron Inter-Neuron White Matter0
1
2
3
4
5
Con
ten
trati
on
of
AS
CT1 R
ece
pto
r
Schizophrenia Bipolar Disorder Control
Cingulate Gyrus
P<.005
P<.009
P<.02
Human Endogenous RetrovirusesActivation by HSV-1Perron et al J Gen Virol. 1993 Jan;74 ( Pt 1):65-72.
HSV-1Retrovirus Reverse Transcriptase Activity
HSV-1 Toxo CMV HSV-2 EBV HHV-660
65
70
75
80
Cog
nit
ive S
core
(R
BA
NS
Tota
l)
Cognitive Functioning and Antibodies to Infectious AgentsIndividuals with Schizophrenia (N=229)
Antibody Positive Antibody Negative
***
**p<.00001
*p<.009 Infectious Agent (IgG Antibodies)
Cognitive Deficits In Individuals with SchizophreniaRelationship with Antibodies to HSV-1
Immediate Memory
Concentration
Language
Attention
Delayed Memory
RBANS Total
50 55 60 65 70 75 80 85 90
Score(Mean+/-95% Confidence)
HSV-1 Pos
N=101
HSV-1 Neg
N=128
******
******
****
**
**
*** p<.0001*** p<.0001**p<.001**p<.001* p<.009* p<.009
Cognitive FunctioningAssociation with HSV-1 Serostatus
Schizophrenia Bipolar Disorder Control60
65
70
75
80
85
90
95
100
RB
AN
S T
ota
l S
core
HSV-1 Seropositive HSV-1 Seronegative
N=229Pr=44.1%
N=117Pr=41.9%
N=67Pr=41.8%
Cognitive Function in Schizophrenia and Bipolar DisorderHSV-1 Antibodies and Quintile of Total Score
<20th 20-40 40-60 60-80 >80th
Percentile- Total Cognitive Score
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
Pro
port
ion
HS
V-1
Sero
reacti
ve Schizophrenia
N=229
Bipolar Disorder
N=117
Collaborative Perinatal StudyStudy Design
65,000 healthy mothers enrolled from 1957-1964 from 11 geographically diverse sites.
Mothers followed closely during pregnancy. Neurocognitive and developmental testing during first
7 years of life. Primary outcomes cerebral palsy and mental retardation.
Serum samples obtained from mothers during pregnancy and infants at birth (cord).
Offspring identified with psychiatric diseases in 1990’s and matched to maternal and cord blood serum specimens.
Unselected offspring evaluated for abnormalities of pregnancy, birth, and child development.
Schizophrenia in Adult LifeInfection During Fetal Development
CMVIgG
CMVIgM
RubIgG
RubIgM
ToxoIgG
ToxoIgM
HSV1IgG
HSV2IgG
HervW
0.00
1.20
2.40
3.60
4.80
6.00
Od
ds R
ati
o
Effect of HERV-K and HSV-1 on Eclampsia and Mental Illness
Herv-K HSV-1HERV-K/HSV-1 . Herv-K HSV-1HERV-K/HSV-10
1
2
3
4
5
6
7
8
9
10
Od
ds R
ati
o
Unadjusted Adjusted for
Race, SES
Eclampsia Mental Illness
Effect of Maternal HSV-2 on Pregnancy and Child Development
Age 7-8 Perinatal
Abnormal Speech
Low IQ Abnormal Vision
AnyComplication
Fetal Deaths0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
Od
ds R
ati
o
Unadjusted Adjusted for
Race, SES
Valacyclovir Clinical TrialIndividuals with Schizophrenia
Enrollment of 66 patients with stable schizophrenia on standard medication given Valacyclovir 2 gm/day for 16 weeks
Evaluation by the positive and negative symptom score (PANSS)
Change in score correlated with viral antibody status at start of study HSV1/2 CMV Other herpesviruses
Response to ValacyclovirHSV-1 Antibody Status
2 4 8 12 16
Week of Valacyclovir
-10
0
10
20
Perc
en
tag
e I
mp
rovem
en
t
2 4 8 12 16
Week of Valacyclovir
-10
-5
0
5
10
15
20
Perc
en
tag
e I
mp
rovem
en
t
Positive Symptoms Total Symptoms
HSV-1 Seropositive HSV-1 Seronegative
Response to Valacyclovir by CMV Status
2 4 8 12 16-10
0
10
20
30
Per
cen
tag
e Im
pro
vem
ent
Positive Scale
2 4 8 12 16-10
0
10
20Negative Scale
2 4 8 12 16-10
0
10
20
Per
cen
tag
e Im
pro
vem
ent
General Scale
2 4 8 12 16-10
0
10
20Total Score
P<.0005P<.02
P<.006
CMV Seropositive CMV Seronegative
Prevalence of CytomegalovirusPopulations with Schizophrenia
0 10 20 30 40 50 60 70 80
Prevalence (%)
Cologne-Untreated
Cologne-Recent Onset- Treated
Cologne-Control
Heidelberg-Recent Onset- Treated
Heidelberg-Control
Baltimore-Stable Treated
Baltimore-Control
Effect of Valacyclovir on SchizophreniaPossible Explanations
Statistical artifact ? p<.0005 with covariance for multiple factors
Placebo effect? Improvement only in CMV seropositive subjects Improvement persists throughout treatment
Non-viral effect of valacyclovir/acyclovir? Effect only in CMV seropositive individuals
The replication of CMV contributes to the symptoms of schizophrenia in some individuals Possible role of an antigenically related herpesvirus?
Valacyclovir Treatment of Schizophrenia-Planned Trials
Placebo-control trials using encapsulated valacyclovir and placebo Stable patients with schizophrenia Recent onset patients with schizophrenia Patients with bipolar disorder High-risk individuals with prodromal symptoms
Study supported by the Stanley Medical Research Institute, without support from the pharmaceutical industry.
Infections and SchizophreniaConclusions
Recent onset schizophrenia is associated with: Increased transcription of HERV-W Increased levels of antibodies to CMV
Past infection with HSV-1 is associated with cognitive impairment in individuals with stable schizophrenia and bipolar disorder, but not in unaffected controls.
Maternal exposure to infectious agents is associated with an increased rate of schizophrenia in the offspring.
The administration of valacyclovir can reduce symptoms in some individuals with stable schizophrenia.
The continued evaluation of the role of the prevention and treatment of infection in the management of psychiatric diseases remains a high priority.
Microbial Agents and Schizophrenia Acknowledgements
Johns Hopkins University Loraine Brando Frances Yee Vern Caruthers Inna Ruslanova Bogdana Krivogorsky
Stanley Medical Research Institute Michael Knable Maree Webster
Sheppard Pratt Hospital John Boronow Catherine Stallings
Harvard University Steve Buka Ming Tsuang
University of Heidelberg Silke Bachmann Johannes Schroeder
Karolinska Institute Håkan Karlsson
University of Cologne F Markus Leweke
