Understanding Schizophrenia

1
Understanding Schizophrenia

• J. Daniel Ragland PhD
• Associate Professor of Psychiatry

2
Clinical Features

• Brain disorder - impairs ability to perceive,
  understand and interpret the environment. 1
  worldwide.
• Impaired function - social and motivational
• Behavioral syndrome - positive and negative
  symptoms
• Onset in late teens to early 20s
• Unremitting course with later onset better
  outcome for women
• Genetically complex - like heart disease
• Genetic environmental factors
• Multiple genes with variable penetrance

3
Symptoms

• At least 4 weeks of 2 of the following
• Hallucinations
• Delusions
• Negative symptoms
• Disorganization
• Minimum duration of 6 months of continuous signs
  of illness
• Functional decline!

4
Clinical Course
First
Relapses
episode
Residual
Prepsychotic
phase
phase
Premorbid
phase

10
15
20 25

Age
Prodrome
First
onset
Early
development
treatment
Untreated illness
Adolescence
Keshavan
5
Heterogeneity of Schizophrenia

• Symptom diversity
• DSM subtypes paranoid, undifferentiated,
  disorganized, catatonic
• Other typologies type I and type II (Crow),
  deficit and non deficit (Carpenter)
• People have increasingly tried to understand
  symptoms rather than the disorder itself

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Epidemiology

• 1 of population world wide
• Males and females equally affected but females
  have later onset and better functional outcome
• Onset in late adolescence, early adulthood
• Loss of function, inability to achieve expected
  function
• 10 SSI/SSDI, 2 GNP in direct care costs and
  lost productivity

7
Genetics

• Highly heritable
• Risk increases with relationship e.g. 10 for
  first degree relative or fraternal twin, 50
  concordance for monozygotic twin
• Environmental factors certain but poorly
  characterized (intrauterine malnutrition, viral
  illnesses, perinatal insults, drug exposure)

8
Genetic Risk
9
Genetic Association
10
(Endo)Phenotypes
Affectation status reflects an underlying
quantitative trait liability, susceptibility,
risk of developing disease.
Discrete
Continuous
(disease)
(liability)
0
1
t
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Causes of Schizophrenia

• Risk gene/environment interactions
• Altered neurodevelopment leading to symptoms in
  early adolescence/young adulthood
• Gross structural changes in the brain
• Specific functional changes in the brain
• Alterations in local circuit architecture
• Alterations in dopamine neurotransmission

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Gross Pathology
n63 Age 78.3 (SD9.7, Range 67 - 99) Brain
Weight 1192 g (SD143, Range 932 - 1520) PMI
12.6 hrs (SD4.9, Range 932 - 1520) Diagnoses
Normal brain 45 Alzheimers disease 5
Lewy body variant AD 1 Parkinsons
disease 2 Cerebrovascular lesions 6
Meningioma 2 Metastatic adenocarcinoma
(lung) 1 Adult polyglucosan body disease 1
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Neurodegenerative Lesions
PHFtau NFTs
Ab SPs
Arnold et al., 1998
14
Neuron Density and Size
Arnold et al., 1995
15
Entorhinal Cytoarchitecture
1.4 1.0 0.6
N S
Dispersion Index
40 20 0
N S
Arnold et al., 1997
Effective Radius
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Molecular Components of Structural Plasticity
Axons Terminals Dendrites Spines
LTP
Synapsin-1 Synaptophysin SNAP25
VGluT-1 VGaT GAP43
NCAM Dysbindin
b-Dystrobrevin
Homer pGluR pNMDAR1
N-cadherin pCamKII Rim 1
Homer MAP2 NFM/H-P-
Synaptopodin F-actin Drebrin EphA4
17
(No Transcript)
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Specific functional changes in the brain
Right BA 9
Left BA 10/46
Dis. Sx in Patients r-.55, plt.005
Dis. Sx in Patients r-.40, plt.05
Neg. Sx in Patients r-.46, plt.01

• FE Schiz
• FE Other Psych

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Alterations in dopamine neurotransmission

• The classical dopamine hypothesis (too much
  dopamine in schizophrenia) rested on the
  observation that DA releasing drugs can cause
  psychosis, and the discovery that antipsychotics
  were dopamine antagonists.

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Alterations in dopamine neurotransmission

• C11 Racolpride displacement reflects DA release

21
Increased subcortical DA related to psychosis
22
Alterations in dopamine neurotransmission

• Decreased prefrontal activity may lead to
  subcortical DA dysregulation and psychosis

Decreased PFC function
Increased DA
VTA

23
Progressive Neuro- developmental Model
Keshavan
24
Management of Schizophrenia

• Early intervention important for improving
  functional outcome
• Medication treatments
• Psychosocial Treatments

25
Future Directions in the Treatment of
Schizophrenia

• More optimistic view of outcome
• Much stronger focus on early intervention and
  prevention e.g. early psychosis clinics and
  prodromal studies
• Specific treatments for cognition in
  schizophrenia
• As molecular pathways associated with neural
  phenotypes become understood new, non dopamine
  based therapies
• Renewed emphasis on rehabilitation, supported
  employment etc.