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Schizophrenia and Other Human Psychiatric Diseases
Challenges for 21st Century Researchers
Robert H Yolken, MDDirector, Stanley Neurovirology Laboratory
Ted and Vada Stanley Distinguished Professor of Pediatrics, Johns Hopkins School of Medicine, Baltimore Md.
E Fuller Torrey, MDMedical Director, Stanley Medical Research Institute, Bethesda Md
Faith Dickerson, PhD
Director of Psychology, Sheppard Pratt Health System, Baltimore Md.
SchizophreniaClinical 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 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) Exposures in Pregnancy (Brown et al, 2000; Torrey et al,
OR~3) Case Reports
HIV Herpes Simplex Virus Borrelia bergdorferii
Human Infectious DiseasesKnown Genetic Associations
Agent Gene FunctionHIV CCR5 Co-Receptor
EBV XLP T-Cell Activity
Hepatitis B Man BP Viral binding
Mycobacteria Il12; IFN R Phagocytosis
Salmonella Il12; IFN R Phagocytosis
H pylori HLA-DQ Immune Response
S mansoni GMCSF Phagocytosis
L donovani Cytokines Immune Function
P falciparum HgS,G6PD Oxygenation
Psychiatric DisordersAssociation with Viral Encephalitis
HSV-1
HIV
Influenza
Measles
EBV
Coxsackie
Mumps
Other
Unknown
0 10 20 30 40 50
Percentage (108 total cases)
Caroff et al, Psych Ann 31:193, 2001
Infections and PsychosisBacteria 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 Schizophrenia264 Cases/528 Controls
Fever in Pregnancy
Pregnancy Complications
Delivery Complications
Urban Birth
Developmental Delay
Family Cat
Family Dog
1 2 3 4
Odds Ratio (95% Conf)Scz Research 46:17-23, 2000
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.
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 fluid and blood samples 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
Endogenous RetrovirusesBorderland 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 RetrovirusesActivation and Transcription
DNA 5’LTR Viral Proteins 3’LTR
Microbe Hormone Mediator
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
Reactivity to RetrovirusesSchizophrenia and Controls
Acu
te S
cz
Ch
ron
ic S
cz
Neu
ro C
trs
Un
aff
Ctr
s
.
Acu
te S
cz
Un
aff
Ctr
s
0
10
20
30
40
Perc
en
tag
e R
eacti
ve
CSF Blood
p<.001
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.
Schizophrenia in Adult LifeInflammation During Fetal Development
IgG IgM IgA TNF IL1 IL2 IL6 IL80
1
2
3
4
5
6
7
8
9
Odds R
ati
o
*p<01
**
*
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
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
HSV-1 Toxo CMV HSV-2 EBV HHV-660
65
70
75
80
Cog
nit
ive S
core
(R
BA
NS
Tota
l)
Infection and Cognitive FunctioningIndividuals with Schizophrenia (N=229)
Antibody Positive Antibody Negative
***
**p<.00001
*p<.009 Infectious Agent (IgG Antibodies)
Cognitive Functioning in Bipolar DisorderEffect of HSV-1 Infection
Immediate Memory
Delayed Memory
VisCon
Language
Attention
Total
70 75 80 85 90 95 100
RBANS Score
HSV-1 Neg HSV-1 Pos
<.01
Cognitive FunctioningSchizophrenia and Bipolar Disorder
MemoryTotal CognitiveMemoryTotal Cognitive60
70
80
90
100
Score
HSV-1 Infected HSV-1 Uninfected
Bipolar Disorder Schizophrenia
Valacyclovir Clinical TrialIndividuals 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 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 90
Prevalence (%)
Cologne-Untreated
Cologne-Recently Treated
Cologne-Control
Heidelberg-Recently Treated
Heidelberg-Control
Baltimore-Chronic
New Therapies for SchizophreniaOngoing/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 SchizophreniaConclusions
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 Loraine Brando Vern Caruthers Inna Ruslanova Bogdana Krivogorsky
Stanley Program Michael Knable John Bartko
Sheppard Pratt Hospital Faith Dickerson 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