1	Infectious Agents and Schizophrenia Dr. E Fuller Torrey, MD Stanley Medical Research Institute Dr. Robert Yolken, MD Johns Hopkins School of Medicine www.Stanleyresearch.org www.Stanleylab.org
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4	Genetics Of Schizophrenia Increased Risk in Biological First Degree Relatives (7-9 fold) Most individuals with schizophrenia do not have a first degree relative with this disease. Genetic factors have a large relative risk but a small population risk in the overall population (5%) Intensive search for genes using molecular methods: Multiple (>30) chromosomal regions of linkage Many genetic polymorphisms (>200) of minor effect (OR~2) No genes of major effect in different populations Shared genes for schizophrenia and bipolar disorder Several genes associated with endophenotypes such as cognitive impairment
5	Sites of Genetic Linkage for Schizophrenia
6	Human Brain Diseases Gene-Environmental Interactions
7	Gene-Infection Interactions in Psychiatric Diseases: Potential Mechanisms and Targets Immune Response T cell determinants B cell activity Macrophage/Glia function Mediators of Inflammation Cytokines (tnf-alpha, il-6) Brain derived neurotrophic factor (BDNF) Pathogen use of CNS Receptors ASCT1/2 Glutamine Transporter (Retroviruses) 5HT2a Serotonin Receptor (Polyoma Viruses) Microbial alteration of Neurotransmitters COMT (Herpesviruses) D2 (Toxoplasma)
8	Complex Human Diseases Beyond Koch and Mendel
9	Complex Human Diseases Beyond 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?
10	Schizophrenia and Bipolar Disorder Lifelong studies of etiology and prevention
11	Differential Display PCR Brain from Individual with Schizophrenia (S) and Unaffected Control(U)
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13	Endogenous Retroviruses Borderland 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
14	Endogenous Retroviruses Borderland 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
15	Endogenous Retroviruses Activation and Transcription
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17	Herv-W and Amino Acid Transporters Lavillette et al, J Virol Jul;76(13):6442-52.
18	ASCT-1 Retrovirus Receptor Cingulate Gyrus of Cases and Controls
19	Human Endogenous Retroviruses Activation by HSV-1Perron et al J Gen Virol. 1993 Jan;74 ( Pt 1):65-72.
20	Schizophrenia and Bipolar Disorder Lifelong studies of etiology and prevention
21	Brain Derived Neurotrophic Factor Relevance to Schizophrenia Biological Properties Central role in neuronal development Controls calcium channel activity Modulates excitotoxicity of glutamate Protects CNS from effects of infection Functional val/met polymorphism Role in Disease Abnormal level of expression in brain Variable results of genetic linkage studies
22	BDNF, CMV and Risk of Schizophrenia Individuals with Established Disease
23	Viruses and Brain Receptors
24	Schizophrenia and Bipolar Disorder Lifelong studies of etiology and prevention
25	Lima Study: Risk of Schizophrenia by Antibody Status (N=120 cases, 120 controls)
26	Lima Study: Additive Effect of Antibodies to Multiple Agents CMV, HSV-1, HSV-2
27	HSV1 seropositive patients with recent onset schizophrenia (Pittsburgh) Prefrontal gray matter reduction
28	Schizophrenia and Bipolar Disorder Lifelong studies of etiology and prevention
29	Military New Onset Psychiatric Disease Study Design Identification of individuals discharged from the armed forces with a diagnosis of schizophrenia or bipolar disorder. Obtaining of sera (0.5ml) from repository On recruitment 1-2 months prior to onset of symptoms 4-6 months after onset of symptoms Testing of samples Antibodies to infectious agents Markers of Inflammation DNA polymorphisms Proteomics Other tests after protocol modification
30	Military New Onset Psychiatric Disease Status (6/15/05) Bipolar Disorder 1864 samples tested 200 cases and 600 controls selected Average 2.3 samples per individual Ongoing analysis and clinical confirmation Approved for 800 cases and 1800 controls Schizophrenia 1777 samples tested 200 cases and 600 controls, 2.2 samples/individual
31	Toxoplasma Infection and Risk of Schizophrenia-Cohort Study
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37	Toxoplasma serum and CSF antibody First-episode cases and controls
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41	Inhibition of Toxoplasma Valproate and Trimethoprim
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47	Acylovir-Mechanism of Action
48	Valacyclovir Clinical Trial Individuals 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
49	Response to Valacyclovir HSV-1 Antibody Status
50	Response to Valacyclovir by CMV Status
51	Inhibition of Toxoplasma Valproate and Trimethoprim
52	New Therapies for Schizophrenia Ongoing/Proposed Clinical Trials Herpesviruses Placebo-Control study of Valacyclovir in stable patients Placebo-Control study of Valacyclovir in new-onset patients ? Other medications for HSV ?Other medications for CMV Allopurinol Toxoplasma gondii Azithromycin Trimethoprim Trimethoprim-Sulfoxasole Prevention Early intervention Vaccination/Immune Prophylaxis
53	Microbial Agents and Schizophrenia Collaborators Johns Hopkins University Loraine Brando Shuojia Li Yang Inna Ruslanova Bogdana Krivogorsky Stanley Medical Research Institute Michael Knable Maree Webster Serge Weiss Sheppard Pratt Hospital Faith Dickerson John Boronow Walter Reed Army Research Institute Amy Millikan David Cowen David Neibuhr Y Li University of Heidelberg, Germany Silke Bachmann Johannes Schroeder Karolinska Institute, Sweden Håkan Karlsson University of Cologne, Germany F Markus Leweke University of Lima, Peru Carla Gallo Guido Mazzotti University of Aarhus, Denmark Preban Mortensen