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NEW SCIENCE AND THERAPIES FOR PATIENTS WITH MENTAL ILLNESS Now is the most promising time in the past two decades for mental health research WHY? PAST INVESTMENTS IN BASIC RESEARCH Basic neuroscience • Mental illness is a biological brain disease • Medicines in development based on basic neuroscience research Human genetics • A new era has dawned for understanding complex human genetic diseases • Fostering new approaches to treatment and diagnosis Example from autism spectrum disorder How can we come to understand the underlying molecular causes of schizophrenia and bipolar illness? The single largest risk is the sequence of a patient’s genes Twin studies support a strong genetic component Dizygotic twins Schizophrenia Monozygotic twins 2 DZ twins MZ twins Bipolar disorder 1 00 20 20 40 40 60 60 80 80 100 100 Concordance rate Gottesman 1991 Families are at an increased risk Parents parents Bipolar disorder Siblings siblings Schizophrenia Children children Half-siblings half sibs BP Grandchildren grandchildren SCZ Nephews/Nieces nephew s/nieces Aunts/Uncles aunts/uncles GeneralGeneral population population 0 0 55 10 10 15 15 20 20 Lambda Tsuang and Faraone 1990 GENETIC MAPPING Mendelian genetic diseases: rare variants 1. Determinative mutations; strong effects 2. High penetrance: % of people with the gene that get the illness is high Dad 3. >2000 discovered in humans Mom 4. Tracing gene transmission in families B b BB Bb Bb bb B b DNA-based frequency variants and disease susceptibility Penetrance of disease High Mendelian disease Intermediate Modest Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 Map of Orlando — state level DNA-based frequency variants and disease susceptibility Penetrance of disease High Mendelian disease Complex genetic disease Intermediate Low-frequency variants with intermediate penetrance Modest Hard to identify genetically Variants identifiable by whole-genome association studies Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 COMPLEX GENETIC DISEASES Multiple genes • Common variants, small effects each gene; rare gene variants, stronger effects • Additive effects lead to risk of illness Need large patient samples • Using most sophisticated methods available in human genetics How many samples are needed? 30,000 each from patients with: • Schizophrenia • Bipolar disorder • Controls Power to detect in a psychiatric genetics study Number of Cases and Controls in the Study Rare 15% increased risk Common 1,000 5,000 10,000 30,000 0 0 0 3 0 0 1 52 0 1 14 98 0 30 93 100 0 0 0 21 0 0 10 96 0 8 61 100 0 83 100 100 0 0 7 92 0 13 75 100 0 68 100 100 10 98 100 100 Rare 20% increased risk Common Rare 30% increased risk Common Good Power No Power Large, collaborative whole-genome studies ~70% of data or ~6 billion genotypes produced at the Stanley Center/Broad Institute Bipolar disorder Schizophrenia 3 studies combined ~4,400 cases, ~6,200 controls 7 sites combined ~3,500 cases, ~3,500 controls Wellcome Trust Case Control Consortium DNA-based frequency variants and disease susceptibility Penetrance of disease High Intermediate Variants identifiable by whole-genome association studies Modest Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 Map of Orlando — city level WHAT MAKES THIS POSSIBLE? • Sequence of human genome • Dense map of markers or signposts across the genome — like signs along the highway • Methods for measuring signs or markers that allow for measurement of 1–2 million markers at once in an individual human sample of DNA • Computer programs allow interpretation of results • Methods only 2+ years old METHOD FOR STUDYING COMPLEX GENETICS Association study • Search for markers in populations, not families Association studies Where effects are probabilistic, must compare frequencies in cases and controls Affecteds Controls Whole-genome study of 4400 bipolar cases Statistical assessment of gene findings Cases 4434 Controls 6214 Probability assessment 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chromosome Manuel Ferreira, Yan Meng ANK3: Ankyrin G Bennett et al. (2008) • Coordinates large protein complexes at specific membrane sites • Neuronal sodium channels • Potassium channels • Lamotrigine used to treat bipolar disorder CACNA1C: L-type, voltagegated calcium channel, alpha1c subunit • Calcium channel blockers have been used to treat bipolar disorder Bidaud et al. (2006) Biological implications of genetic findings “ The cardinal feature of heritable ion channel disease is a periodic disturbance of rhythmic function in a constitutionally hyperexcitable tissue. ” Gargus, Biological Psychiatry 2006 FINDINGS THUS FAR IN SCHIZOPHRENIA Association findings Novel gene deletions Whole-genome study of 3400 schizophrenia cases Statistical assessment of gene findings Cases 3414 Controls 3625 Probability assessment 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Chromosome Jennifer Stone Deletions of genes in schizophrenia An excess of DNA deletions in genes in samples of patients vs. controls • Per patient very small increase • Biological implications being evaluated will be clues to underlying causal pathways DNA-based frequency variants and disease susceptibility Penetrance of disease High Intermediate Variants identifiable by whole-genome association studies Modest Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 DNA-based frequency variants and disease susceptibility Penetrance of disease High New methods rapidly developing Intermediate Low-frequency variants with intermediate penetrance Modest Hard to identify genetically Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 Map of Orlando — street level NEW TECHNOLOGIES FOR GENETICS • High-throughput DNA sequencing: ability to sequence all genes in 1000 patient samples and 1000 controls • More detailed map of the human genome • Next 2–5 years WILL see this technology DNA-based frequency variants and disease susceptibility Penetrance of disease High Mendelian disease Intermediate Low-frequency variants with intermediate penetrance Modest Hard to identify genetically Variants identifiable by whole-genome association studies Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 IMPORTANT REALIZATION • Science’s ability to unravel the underlying causes of severe mental illness is upon us • Technologies are rapidly progressing • What is limiting? Not the intellectual approach • For the first time in the history of the field there is a way forward that can lead to significant improvements in diagnosis and therapy Largest treatment studies Study Disorder Outcomes CATIE 1 Schizophrenia 74% discontinued study medication by 18 months; little difference in efficacy among antipsychotics STAR*D 2 Depression 28% achieved remission by 14 weeks of treatment with SSRI STEP-BD 3 Bipolar disorder 49% of patients who achieved recovery had recurrence within 2 year follow-up Antipsychotic metanalysis 4 Schizophrenia Small effects vs. placebo; durability issue 1 Lieberman 2 et al., N Engl J Med, 2005; 353:1209–1223. Trivedi et al., Am J Psychiatry, 2006; 163 :28–40. 3 Perlis et al., Am J Psychiatry, 2006; 163: 217–224. 4 Leucht et al., Mol Psychiatry, 2008; 1–19. GENETIC DISCOVERY TO TREATMENT • Many examples of discovering genetic predispositions to disease and translating the discoveries into important, new treatments • As technology for discovering genes for disease have evolved, technologies for translating the discoveries into treatments have also evolved Impact of genetics on biomedicine Discovery of drug targets: • Statins and HMG Coa reductase • Proscar and benign prostatic hyperplasia (5-alpha reductase) • Gleevec and CML (aberrant kinase) • Herceptin antibody to Her2 for breast cancer • New approaches to Alzheimer’s Approaches to therapy: other illnesses Fragile X syndrome: • a disease of abnormal brain development • molecular defect known • animal models created based on human defect • abnormal physiology clarified • new treatments discovered based on abnormal physiology • good results in animal model with human defect • in early development for humans • mGluR5 antagonists Paradigm for new treatments for autism, bipolar disorder, and schizophrenia Identify risk genes Develop cellbased assays Develop mouse model with a quantifiable phenotype; a consequence of variant gene Identify chemicals that reverse cell-based and animal-based phenotype Human trials in genetically defined variant Test in broader group of patients with the illness Possible new drugs in development • Glu 2,3 agonist • D-cycloserine • Desmethyl clozaril • M1 allosteric agonists • Gaba alpha 2,3 agonists • PDE-10 inhibitors • Alpha-7 nicotinic agonists New approaches to therapy Drug mechanism Stage of research mGlur2,3 agonist Expanded human trials Desmethyl clozaril Human trials Alpha-7 nicotinic receptor agonist Human trials Gaba alpha 2,3 agonist Early human trials New approaches to therapy Drug mechanism Stage of research D-cycloserine: novel regimen, use with psychotherapy Proven in acrophobia, anxiety Phosphodiesterase 10 inhibitors Animal research, excellent results SUMMARY OF WHERE WE ARE • Significant progress on new therapies is possible, even in genetically determined disease where development of the brain is awry • Significant progress toward identifying underlying causes of schizophrenia, bipolar disorder, and autism, with genetic technologies evolving rapidly • The coming 5–10 years will lead to a much greater understanding of molecular basis for these and other related disorders What will this mean for patients? • Much better diagnostic tools, clearer categories of diagnosis, and more personalized therapy • Many new targets for new medicines DNA-based frequency variants and disease susceptibility Penetrance of disease High Mendelian disease Complex genetic disease Intermediate Low-frequency variants with intermediate penetrance Modest Hard to identify genetically Variants identifiable by whole-genome association studies Low Very rare Rare Uncommon Common Frequency of DNA variation in population McCarthy et al., Nat Genet Rev 2008 IMPORTANT REALIZATION • Science’s ability to unravel the underlying causes of severe mental illness is upon us • Technologies are rapidly progressing • What is limiting? Not the intellectual approach • For the first time in the history of the field there is a way forward that can lead to significant improvements in diagnosis and therapy