1. Schizophrenia:
Past, Present
and Future
Adonis 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 Picture
Upbringing determines the output
Late 19th and early 20th century paradigm

7. Biochemical Paradigm
From 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

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).

11. 21st Century Concept of
Schizophrenia

12. 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

13. 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

14. 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

15. Stages of Schizophrenia as a
Neurodevelopmental Disorder

17. 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

18. 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.

19. Staging of Schizophrenia is
Consistent with fMRI Findings

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

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

23. Early Brain Development is
Affected in Schizophrenia
-neuronal proliferation
-neuronal differentiation
-neuronal migration
-synapse formation
-myelination

25. 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.

26. From Gene to Behavior

27. 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.

28. 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.

29. Sequencing the Human Genome in Fifteen
Minutes
Now
A decade ago

30. 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

31. CNVs Can Explain Non-inherited
Schizophrenia
 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.

33. 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.

34. Connectomics (brain
mapping) in Schizophrenia

35. Mapping The Pathophysiology of
Schizophrenia

36. Schizophrenia : fronto-temporal
dysconnectivity - Graph Analysiss

37. Measuring Dendritic and
Dendritic Spine Density

38. Dendritic Spine Density

39. Automatic Measurement of
Dendritic Spine Density

41. 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

43. 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

44. Neuropsychological Screening
for Prodromal Symptoms

45. 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%

46. Schizophrenia in a Petri Dish

47. Transdifferentiation

48. 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.; Nature
473, 221-225 (12 May 2011) doi:10.1038/nature09915

49. 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

50. Integration of Care and Outcomes
in Schizophrenia.

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

52. Future Biological Treatment
Algorithm
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)

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