Schizophrenia%20and%20Other%20Human%20Psychiatric%20Diseases%20Challenges%20for%20%2021st%20Century%20Researchers

1
Schizophrenia and Other Human Psychiatric
DiseasesChallenges 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.

2
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

3
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 (gt30) chromosomal regions of linkage
• Genetic polymorphisms of minor effect (OR2)
• No genes of major effect in different populations

4
Microbial Agents and SchizophreniaEpidemiological
Findings

• Specific Infectious Agent
• Perinatal Rubella (Brown et al, 2001 OR3.5)
• Neonatal Enterovirus (Jones et al, 1998 OR4)
• Maternal Herpesvirus (Buka 2001 OR4)
• Possible Infectious Exposure
• Seasonality of Birth (Torrey at al, 1998 OR2)
• Urban Birth (Mortenson et at, 1999, OR2.5)
• Exposures in Pregnancy (Brown et al, 2000 Torrey
  et al, OR3)
• Case Reports
• HIV
• Herpes Simplex Virus
• Borrelia bergdorferii

5
Human Infectious DiseasesKnown Genetic
Associations

• Agent Gene Function
• HIV 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
  

6
Psychiatric DisordersAssociation with Viral
Encephalitis
Caroff et al, Psych Ann 31193, 2001
7
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

8
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
Scz Research 4617-23, 2000
Odds Ratio (95 Conf)
9
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.

10
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

11
Differential Display PCRBrain from Individual
with Schizophrenia (S) and Unaffected Control(U)
S
S
S
U
U
U
M
M
12
HIV
Human Endogenous Retrovirus HERV-W
13
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

14
Endogenous RetrovirusesActivation and
Transcription
DNA
5LTR
Viral Proteins
3LTR
15
Human RetrovirusesActivation by Herpesviruses
16
Endogenous Retroviral PCR CSFsSchizophrenia and
Controls
Scz
DNA
Ctr
Herv-W
HERVw GTTCAGGGATAGCCCCCATCTATTTGGCCAGGCATTAGCCCAAG
ACTTGAGTCAATTCTCATACCTGGACACTCTTGTCCTTCAG
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-
17
Reactivity to RetrovirusesSchizophrenia and
Controls
18
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
  1990s and matched to maternal and cord blood
  serum specimens.

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Schizophrenia in Adult LifeInflammation During
Fetal Development
20
Schizophrenia in Adult LifeInfection During
Fetal Development
6.00
4.80
3.60
Odds Ratio
2.40
1.20
0.00
CMV IgG
CMV IgM
Rub IgG
Rub IgM
Toxo IgG
Toxo IgM
HSV1 IgG
HSV2 IgG
Herv W
21
National Childrens 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

22
Antibody Negative


plt.00001
Infectious Agent (IgG Antibodies)
plt.009
23
Cognitive Functioning in Bipolar DisorderEffect
of HSV-1 Infection
24
Cognitive FunctioningSchizophrenia and Bipolar
Disorder
HSV-1 Infected
HSV-1 Uninfected
100
90
Score
80
70
60
Memory
Total Cognitive
Memory
Total Cognitive
Bipolar Disorder
Schizophrenia
25
Acylovir-Mechanism of Action
26
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

27
Response to ValacyclovirHSV-1 Antibody Status
HSV-1 Seropositive
HSV-1 Seronegative
Positive Symptoms
Total Symptoms
28
Response to Valacyclovir by CMV Status
Plt.006
General Scale
Total Score
20
20
Plt.0005
Plt.02
10
10
Percentage Improvement
0
0
-10
-10
4
8
12
16
2
4
8
12
16
CMV Seropositive
CMV Seronegative
29
Prevalence of CytomegalovirusPopulations with
Schizophrenia
0
10
20
30
40
50
60
70
80
90
Prevalence ()
30
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

31
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.

32
Microbial Agents and Schizophrenia
Acknowledgements

• Harvard University
• Steve Buka
• Ming Tsuang
• University of Heidelberg
• Silke Bachmann
• Johannes Schroeder
• Karolinska Institute
• Håkan Karlsson
• University of Cologne
• F Markus Leweke

• 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