Schizophrenia Past, Present and Future

Schizophrenia:Past, Presentand FutureAdonis Sfera, MD

This year alone 100,000 young people will have a first episode of schizophrenia. 5%of people with schizophrenia will die by suicide.

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

Schizophrenia: The Past Francisco Goya – The Madhouse 1812

From Kraepelin to Asenapine Premature dementia

The Brain Out of the PictureUpbringing determines the output Late 19th and early 20th century paradigm

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

Computational Paradigm Putting Brains Back in Psychiatry

Computation: Information Processing - Brain is the hardware, mind is the software Information processing - neuronal connections (connectomics).

21st Century Concept ofSchizophrenia

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

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

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

Stages of Schizophrenia as aNeurodevelopmental Disorder

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

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.

Staging of Schizophrenia isConsistent with fMRI Findings

Children with Schizophrenia –ExcessiveGray Matter Loss Compared to NormalMaturation

Emerging Biological Markers fMRIand Brain mapping markers Genetic markers Metabolic markers Neuropsychological testing Assessment of Tx efficacy

Early Brain Development isAffected in Schizophrenia -neuronal proliferation -neuronal differentiation -neuronal migration -synapse formation -myelination

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.

From Gene to Behavior

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.

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.

Sequencing the Human Genome in FifteenMinutes Now A decade ago

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

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.

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.

Connectomics (brainmapping) in Schizophrenia

Mapping The Pathophysiology ofSchizophrenia

Schizophrenia : fronto-temporaldysconnectivity - Graph Analysiss

Measuring Dendritic andDendritic Spine Density

Dendritic Spine Density

Automatic Measurement ofDendritic Spine Density

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

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

Neuropsychological Screeningfor Prodromal Symptoms

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%

Schizophrenia in a Petri Dish

Transdifferentiation

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

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

Integration of Care and Outcomesin Schizophrenia.

Redefining Schizophrenia NorthAmerican Prodrome Longitudinal Study (NAPLS) Working on a combination of -neurocognitive testing -neuroimaging -plasma biomarkers

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)

A vision for schizophrenia over the next decadeThomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552

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Schizophrenia Past, Present and Future

by Adonis Sfera, MD on Jan 29, 2013

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