Transcript Infection and Psychiatric Diseases Timing of Disease

Schizophrenia and Other Human
Psychiatric Diseases
Challenges for
21st Century Researchers
Robert H Yolken, MD
Director, Stanley Neurovirology Laboratory
Ted and Vada Stanley Distinguished Professor of Pediatrics, Johns
Hopkins School of Medicine, Baltimore Md.
E Fuller Torrey, MD
Medical Director, Stanley Medical Research Institute, Bethesda Md
Faith Dickerson, PhD
Director of Psychology, Sheppard Pratt Health System, Baltimore Md.
Schizophrenia
Clinical and Epidemiological Features
 Positive Symptoms
 Hallucinations, Delusions, Disordered Thinking
 Negative Symptoms
 Withdrawal, Amotivation, Restricted Expressiveness
 Impairment in Cognitive and Social Functioning
 Structural and Functional Brain Abnormalities
 Lifetime prevalence approximately 1%
 Peak onset of Symptoms in Young Adulthood
 Massive societal Consequences Worldwide
 Currently Available Medications
 Symptomatic improvement
 High rate of side effects
 Do not affect overall disease process
Genetics Of Schizophrenia
• 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 (>30) chromosomal regions of linkage
• Genetic polymorphisms of minor effect (OR~2)
• No genes of major effect in different populations
Microbial Agents and Schizophrenia
Epidemiological 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)
 Exposures in Pregnancy (Brown et al, 2000; Torrey
et al, OR~3)
 Case Reports
 HIV
 Herpes Simplex Virus
 Borrelia bergdorferii
Human Infectious Diseases
Known Genetic Associations
Agent
Gene
Function
HIV
EBV
Hepatitis B
Mycobacteria
Salmonella
H pylori
S mansoni
L donovani
CCR5
XLP
Man BP
Il12; IFN R
Il12; IFN R
HLA-DQ
GMCSF
Cytokines
Co-Receptor
T-Cell Activity
Viral binding
Phagocytosis
Phagocytosis
Immune Response
Phagocytosis
Immune Function
P falciparum
HgS,G6PD
Oxygenation
Psychiatric Disorders
Association with Viral Encephalitis
HSV-1
HIV
Influenza
Measles
EBV
oxsackie
Mumps
Other
Unknown
0
10
20
30
40
Percentage (108 total cases)
Caroff et al, Psych Ann 31:193, 2001
50
Infections and Psychosis
Bacteria and Parasites
Bacteria
Streptococcus
pyogenes
Borrelia burgdorferi
Treponema pallidum
Ehrlichiae
Mycoplasma
pneumoniae
Bartonella henselae
Salmonella typhii
Parasites
Toxoplasma gondii
 Plasmodium falciparum
Babesiae
Taenia solium
Leishmania donovani
Antecedents of Schizophrenia
264 Cases/528 Controls
Fever in Pregnancy
Pregnancy Complications
Delivery Complications
Urban Birth
Developmental Delay
Family Cat
Family Dog
1
Scz Research 46:17-23, 2000
2
3
Odds Ratio (95% Conf)
4
Schizophrenia
Working 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.
 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
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
Differential Display PCR
Library screening
Microarrays
Two-dimensional electrophoresis
Enzyme immunoassays
Samples for Analysis

Brains collected by the Stanley Neuropathology
Consortium
 Cerebrospinal fluid and blood samples from
individuals with recent onset schizophrenia
 Blood samples from mothers of infants who
developed schizophrenia in adult life
Differential Display PCR
Brain from Individual with Schizophrenia (S)
and Unaffected Control(U)
M
S
U
S U S U M
HIV
Human Endogenous
Retrovirus HERV-W
Endogenous Retroviruses
Borderland Between Viruses and Genes II
Dynamic Effects on Gene Function
 Promoter control of adjacent genes- PLA2; Placental Genes
 Functionality of viral proteins-Syncytin; ASCT1 Glutamate
transporter
 Interaction with infectious agents- Herpesviruses; Toxoplasma
 Interaction with soluble mediators-Hormones; Cytokines
Role in Human Disease
 Diabetes- Superantigen activation
 Multiple Sclerosis- Glial cell function
 Autoimmune Arthritis- T cell activity
Endogenous Retroviruses
Activation and Transcription
Microbe
DNA
Hormone Mediator
5’LTR Viral Proteins 3’LTR
Human Retroviruses
Activation by Herpesviruses
Retrovirus
Herpesvirus
Reverse Transcriptase
Activity
Ctr
DNA
Scz
Endogenous Retroviral PCR
CSFs:Schizophrenia and Controls
Herv-W
HERVw
C1
A1
A2
A3
A4
A5
A6
GTTCAGGGATAGCCCCCATCTATTTGGCCAGGCATTAGCCCAAGACTTGAGTCAATTCTCATACCTGGACACTCTTGTCCTTCAG
---------------------------------------------------C--------------------------------------------------------------A---------------------------------------------------TG------------------------------A---------------------------------------------------TG----------------------------------C----------------C--G----------------------------G-----------A----------------------------T----------C--G---------------------------TG-----A------------------------------------------------------------------------------------------T------------CA---TA-------------------C--G---------------------------TG-
0
CSF
Unaff Ctrs
Acute Scz
.
Unaff Ctrs
Neuro Ctrs
Chronic Scz
Acute Scz
Percentage Reactive
Reactivity to Retroviruses
Schizophrenia and Controls
40
p<.001
30
20
10
Blood
Collaborative Perinatal Study
Study Design
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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.
Schizophrenia in Adult Life
Inflammation During Fetal Development
9
8
Odds Ratio
7
6
5
*
*
*
4
3
2
1
0
IgG IgM IgA TNF IL1 IL2 IL6 IL8
*p<01
Schizophrenia in Adult Life
Infection During Fetal Development
6.00
Odds Ratio
4.80
3.60
2.40
1.20
0.00
CMV CMV Rub
IgG IgM IgG
Rub Toxo Toxo HSV1 HSV2 Herv
IgM IgG IgM IgG IgG
W
National Children’s Study
Mandated by congress in 1999
Scheduled to start in 2004
Target enrollment of 100,000 births
Follow-up of offspring for 30 years
Specimen Collection and Storage
Unanswered questions
Target diseases
Number of sites
Consent requirements
System of medical care
Infection and Cognitive Functioning
Individuals with Schizophrenia (N=229)
Antibody Positive
Antibody Negative
Cognitive Score (RBANS Total)
80
**
*
HSV-1
Toxo
75
70
65
60
**p<.00001
*p<.009
CMV
HSV-2
EBV
Infectious Agent (IgG Antibodies)
HHV-6
Cognitive Functioning in Bipolar Disorder
Effect of HSV-1 Infection
HSV- 1 Neg
HSV- 1 Pos
edi at e M emor y
<.01
Del ayed M emor y
Vi sCon
Language
At t ent i on
Tot al
70
75
80
85
RBANS Scor e
90
95
100
Cognitive Functioning
Schizophrenia and Bipolar Disorder
HSV-1 Infected
HSV-1 Uninfected
100
Score
90
80
70
60
Memory Total Cognitive Memory
Bipolar Disorder
Total Cognitive
Schizophrenia
Acylovir-Mechanism of Action
Valacyclovir Clinical Trial
Individuals with Schizophrenia
Enrollment of 66 patients with stable
schizophrenia on standard medication all
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 Valacyclovir
HSV-1 Antibody Status
20
Percen tag e I mp ro vemen t
HSV-1 Seronegative
Percentage Improvement
HSV-1 Seropositive
10
0
- 10
2
4
8
12
16
W e e k o f Va l a c y c l o v i r
Positive Symptoms
20
15
10
5
0
-5
- 10
2
4
8
12
16
Week of Valacyclovir
Total Symptoms
Percentage Improvement
Response to Valacyclovir by CMV Status
20
P<.006
20
10
10
0
0
-10
Percentage Improvement
Negative Scale
Positive Scale
30
2
4
8
12
16
-10
2
4
General Scale
8
16
Total Score
20
20
P<.02
P<.0005
10
10
0
0
-10
12
2
4
8
12
16
CMV Seropositive
-10
2
4
8
12
16
CMV Seronegative
Prevalence of Cytomegalovirus
Populations with Schizophrenia
Cologne-Untreated
Cologne-Recently Treated
Cologne-Control
Heidelberg-Recently Treated
Heidelberg-Control
Baltimore-Chronic
0
10
20
30
40
50
60
Prevalence (%)
70
80
90
New Therapies for Schizophrenia
Ongoing/Proposed Clinical Trials
 Treatment Trials
 Valacyclovir
 Other medications for Cytomegalovirus
 Azithromycin trial for Toxoplasma gondii
 Antimicrobial aspects of Psychiatric Medications
 Epidemiological Studies
 Additional Perinatal Cohorts
 Cohorts of Healthy Young Adults
 Cohorts of High-Risk Adolescents
 Intervention strategies for disease prevention
Infections and Schizophrenia
Conclusions
 Recent onset schizophrenia is associated with:
Increased transcription of HERV-W
Increased levels of antibodies to CMV
 Past infection with HSV-1 and Toxoplasma gondii are
associated with cognitive impairment in individuals with
stable schizophrenia.
 Maternal exposure to infectious agents is associated with an
increased rate of schizophrenia in the adult life of the
offspring.
 The administration of Valacyclovir can reduce symptoms in
some individuals with stable schizophrenia.
Microbial Agents and Schizophrenia
Acknowledgements
 Johns Hopkins University  Harvard University
 Loraine Brando
 Vern Caruthers
 Inna Ruslanova
 Bogdana Krivogorsky
 Stanley Program
 Michael Knable
 John Bartko
 Sheppard Pratt Hospital
 Faith Dickerson
 John Boronow
 Catherine Stallings
 Steve Buka
 Ming Tsuang
 University of Heidelberg
 Silke Bachmann
 Johannes Schroeder
 Karolinska Institute
 Håkan Karlsson
 University of Cologne
 F Markus Leweke