Schizophrenia Past, Present and Future

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Schizophrenia Past, Present and Future

  1. Schizophrenia:Past, Presentand FutureAdonis Sfera, MD
  2. This year alone 100,000 young people will have a first episode of schizophrenia. 5%of people with schizophrenia will die by suicide.
  3. One Hundred Years of SchizophreniaA century ago we had large public institutions for severe mental illness, tuberculosis and leprosy. Of these three, today only mental illness, especially schizophrenia, remains unchanged in prevalence and disability . Sustained recovery is less than 14% within the first 5 years following a psychotic episode.Thomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552
  4. Schizophrenia: The Past Francisco Goya – The Madhouse 1812
  5. From Kraepelin to Asenapine Premature dementia
  6. The Brain Out of the PictureUpbringing determines the output Late 19th and early 20th century paradigm
  7. Biochemical ParadigmFrom blaming the mother to blamingneurotransmitters Second half of the 20th century Schizophrenia a “dopamine disorder” 1954 discovery of Chlorpromazine Psychopharmacology The biochemical trinity: -dopamine -serotonin - norepinephrine
  8. Computational Paradigm Putting Brains Back in Psychiatry
  9. Computation: Information Processing - Brain is the hardware, mind is the software Information processing - neuronal connections (connectomics).
  10. 21st Century Concept ofSchizophrenia
  11. Events Shaping the NewConcept of Schizophrenia 2003 Human Genome Project results were published. 2009 Human Epigenome Project published results. 2009 Human Connectome Project began.Techniques Novel neuroimaging Techniques Discovery of the Ultramicrotome Cultured Patient Specific Neurons
  12. Computational Paradigm and Its Meaning For Schizophrenia Schizophrenia is a collection of neurodevelopmental disorders that involve alterations in brain circuits during early development. Psychosis is a late occurrence in schizophrenia. Preventive approaches seen as the main intervention. Thomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552
  13. Schizophrenia: A Case forPrevention and Early Detection Birth cohort studies demonstrate that individuals who develop schizophrenia differ from the general population on a range of developmental indices some of which occur as early as the first year of life.Joy Welham,2 Matti Isohanni,3 Peter Jones,4 and John McGrath; The Antecedents of Schizophrenia: AReview of Birth Cohort Studies; Schizophr Bull. 2009 May; 35(3): 603–623, . doi: 10.1093/schbul/sbn084
  14. Stages of Schizophrenia as aNeurodevelopmental Disorder
  15. Learning from Neurodegenerative Disorders Inneurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease changes in the brain precede changes in behavior , sometimes by more than a decade. InParkinson’s disease symptoms only emerge after 80% of dopamine cells have been lost. Thomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552
  16. Learning From MedicinePrevention, Prevention, Prevention Over the past few decades preventive efforts led to: 60%reduction in mortality due to coronary artery disease (1.1 million death averted each year). AIDS was declared a chronic disease.
  17. Staging of Schizophrenia isConsistent with fMRI Findings
  18. Children with Schizophrenia –ExcessiveGray Matter Loss Compared to NormalMaturation
  19. Emerging Biological Markers fMRIand Brain mapping markers Genetic markers Metabolic markers Neuropsychological testing Assessment of Tx efficacy
  20. Early Brain Development isAffected in Schizophrenia -neuronal proliferation -neuronal differentiation -neuronal migration -synapse formation -myelination
  21. More Realistic Perspective on Genes in Schizophrenia There is no gene for schizophrenia, bipolar disorder, depression or anxiety and there will never be one. Genesdo not code for psychiatric illnesses or for behaviors or for symptoms of psychiatric illnesses. Genesoperate at a very basic cellular level. They code for proteins that may lead to subtle molecular abnormalities in cells.
  22. From Gene to Behavior
  23. Genes are Risk Factors for Mental Illness Genes do not respect the boundaries of psychiatric disorders or even the boundaries of medical disciplines. Forinstance most risk genes for schizophrenia are present also in bipolar disorder, schizoaffective disorder, ASD, Alzheimer’s disease and anxiety.
  24. Several Hundred Loci (genes) Can Contribute To the Development of Schizophrenia. There are vulnerability genes as well as resilience genes. The chance that two patients with schizophrenia will have exactly the same combination of mutations is small.
  25. Sequencing the Human Genome in FifteenMinutes Now A decade ago
  26. Copy Number Variation (CNV) Velo-Cardio-Facial Syndrome (VCFS) -33% chance for schizophrenia Genetic Marker 22q11.2 one of the highest risk factors for schizophrenia
  27. CNVs Can Explain Non-inheritedSchizophrenia Spontaneous genetic mutations or “de novo” mutations play a significant role in schizophrenia. Thefunction of the mutated gene and when the gene is expressed are critically important in determining the risk for schizophrenia.
  28. Research Domain Criteria (RDoC) RDoC is an experimental approach to the classification of mental disorders that incorporates multiple dimensions: behavior, thought patterns, neurobiological measures, and genetics. The aim of the project is to develop a more accurate diagnostic system.
  29. Connectomics (brainmapping) in Schizophrenia
  30. Mapping The Pathophysiology ofSchizophrenia
  31. Schizophrenia : fronto-temporaldysconnectivity - Graph Analysiss
  32. Measuring Dendritic andDendritic Spine Density
  33. Dendritic Spine Density
  34. Automatic Measurement ofDendritic Spine Density
  35. Schizophrenia and Metabolism Normally the brain uses glucose as its main energy source, with ketone bodies as an alternative. In schizophrenia brain energy supply is scarce due to mitochondrial dysfunction. The brain shifts its energy supply towards ketone bodies, and fatty acid metabolism. Liver metabolism is shifted towards producing the necessary ketone bodies.J Yang, T Chen, L Sun, Z Zhao, X Qi, K Zhou, Y Cao, X Wang, Y Qiu, M Su, A Zhao, P Wang, P Yang, J Wu, G Feng, L He, W Jia and C Wan
  36. Metabolic Biomarkers inSchizophrenia The following set of metabolic biomarkers have identical sensitivity and specificity as the MSE: Glycerate Eicosenoic acid Beta-hydroxybutirate Pyruvate Cysteine Urine beta hydroxybutiratePotential Metabolite Markers of Schizophrenia; J. Yang et al.; Molecular Psychiatry(213)18, 67-78; doi:10.1038/mp.131
  37. Neuropsychological Screeningfor Prodromal Symptoms
  38. Neuropsychological Screening Tests for the Prodromal Phase of Schizophrenia Severalneuropsychological deficits have been detected in the prodromal phase of schizophrenia. Neuropsychological instruments developed: -Structured Interview for Prodromal Symptoms (SIPS) -Neurocognitive Test Batteries for at Risk Mental states (ARMS) -Cognitive Perceptive Basic Symptoms (COPER)Positive predictive power for conversion to psychosis 75%
  39. Schizophrenia in a Petri Dish
  40. Transdifferentiation
  41. Patient Specific Cultured Neurons Exposed to Loxapine  Cultured neurons from patients with schizophrenia present with decreased neuronal connectivity.  Adding Loxapine resulted in improvement in neuronal connectivityModeling Schizophrenia Using Human Induced Pluripotent Stem Cells;Kristen J. Bernnand et al.; Nature473, 221-225 (12 May 2011) doi:10.1038/nature09915
  42. Integration of Care Currently the care is fragmented into medical care separated from psychiatric care. Both are isolated from psychosocial interventions such as supportive employment, family education. Recovery After Initial Episode of Schizophrenia (RAISE) project is developing a best-practice approach to bundled services.Thomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552
  43. Integration of Care and Outcomesin Schizophrenia.
  44. Redefining Schizophrenia NorthAmerican Prodrome Longitudinal Study (NAPLS) Working on a combination of -neurocognitive testing -neuroimaging -plasma biomarkers
  45. Future Biological TreatmentAlgorithm Dx by MSE Determine the verified by affected Schizophrenia domain of metabolomic schizophrenia panel Staging of the illness (fMRI +connectomics) Choosing best Assessment of therapy Tx efficacy (cultured (dendritic spine patient specific density neurons) measurement)
  46. A vision for schizophrenia over the next decadeThomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552

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