Schizophrenia Past, Present and Future

Schizophrenia: Past, Present and 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 blaming neurotransmitters

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 of Schizophrenia

Events Shaping the New Concept 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.


Schizophrenia: A Case for Prevention 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: A Review of Birth Cohort Studies; Schizophr Bull. 2009 May; 35(3): 603–623, . doi: 10.1093/schbul/sbn084

Stages of Schizophrenia as a Neurodevelopmental Disorder

Learning from Neurodegenerative Disorders

In neurodegenerative 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.

In Parkinson’s disease symptoms only emerge after 80% of dopamine cells have been lost.


Learning From Medicine Prevention, 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 is Consistent with fMRI Findings

Children with Schizophrenia –Excessive Gray Matter Loss Compared to Normal Maturation

Emerging Biological Markers

fMRI and Brain mapping markers Genetic markers Metabolic markers Neuropsychological testing Assessment of Tx efficacy

Early Brain Development is Affected 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.

Genes do not code for psychiatric illnesses or for behaviors or for symptoms of psychiatric illnesses.

Genes operate 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.

For instance 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 Fifteen Minutes

A decade ago

Now

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-inherited Schizophrenia

Spontaneous genetic mutations or “de novo” mutations play a significant role in schizophrenia.

The function 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 (brain mapping) in Schizophrenia

Mapping The Pathophysiology of Schizophrenia

Schizophrenia : fronto-temporal dysconnectivity - Graph Analysiss

Measuring Dendritic and Dendritic Spine Density

Dendritic Spine Density

Automatic Measurement of Dendritic 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 in Schizophrenia

The following set of metabolic biomarkers have identical sensitivity and specificity as the MSE:

Glycerate Eicosenoic acid Beta-hydroxybutirate Pyruvate Cysteine Urine beta hydroxybutirate

Potential Metabolite Markers of Schizophrenia; J. Yang et al.; Molecular Psychiatry(213) 18, 67-78; doi:10.1038/mp.131

Neuropsychological Screening for Prodromal Symptoms

Neuropsychological Screening Tests for the Prodromal Phase of Schizophrenia

Several neuropsychological 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

connectivity

Modeling 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.


Integration of Care and Outcomes in Schizophrenia.

Redefining Schizophrenia

North American Prodrome Longitudinal Study (NAPLS)

Working on a combination of -neurocognitive testing -neuroimaging -plasma biomarkers

Future Biological Treatment Algorithm

Dx by MSE verified by Schizophrenia metabolomic panel

Determine the affected domain of schizophrenia

Staging of the illness (fMRI

+connectomics)

Choosing best therapy (cultured patient specific neurons)

Assessment of Tx efficacy (dendritic spine density measurement)

A vision for schizophrenia over the next decade


Health & Medicine

Schizophrenia Past, Present and Future