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Schizophrenia What causes schizophrenia? Neuropathology

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Title: Schizophrenia What causes schizophrenia? Neuropathology


1
Schizophrenia
  • What causes schizophrenia?
  • Neuropathology
  • Structural and functional changes
  • Neurochemical alterations
  • Treatments

2
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3
Schizophrenia
  • Emil Kraepelin Dementia Praecox (1896)
  • Blueler Schizophrenia
  • Onset adolescence or young adulthood
  • DSM-IV review
  • Positive symptoms (delusions, hallucinations,
    disorganized speech or behavior)
  • Negative symptoms (catatonia, affective
    flattening, withdrawal, or avolition)
  • Social-occupational disturbance
  • 6 months

4
Associated Features
  • Cognitive Disturbances
  • Memory
  • Sensory filtering
  • Attention
  • Emotion recognition
  • Eye-tracking
  • Interpersonal Dysfunction

5
Subtypes
  • Catatonic
  • Paranoid
  • Disorganized
  • Unlikely to be a related to a single
    physiopathology

6
Neuropathology
  • Neurodevelopmental hypothesis
  • Neurodegenerative hypothesis
  • Dopamine hypothessis
  • Glutamatergic hypothesis
  • These are not exclusive

7
What causes schizophrenia?
  • Heritable (Shastry, 2002)
  • Environmental factors
  • Epidemiological studies
  • Birth complications
  • Maternal stress
  • Seasonality effect
  • Viral epidemics
  • Latitude effect
  • Rh incompatibility

8
NeuropathologyStructural alterations
  • Behavioral symptoms indicative of brain damage
    (unusual rates of blinking, poor control of eye
    movements, unusual facial expressions)
  • Enlarged ventricles (Weinberger Wyatt, 1982
    Andreason)

9
Ventricular enlargement in monozygotic twin with
schizophrenia
Barondes, 1993
10
Hippocampal volume loss and enlarged ventricles
Van Heron et al., 2005
11
NeuropathologyStructural alterations (cont)
  • Alterations in numerous areas, including frontal
    lobes, medial temporal lobes, lateral temporal
    lobes, parietal lobe, basal ganglia, corpus
    callosum, thalamus and even the cerebellum
  • White matter deficits
  • Evidence of disorganized neurons and failures of
    migration
  • Altered density and disorganization of neurons
    found in the white matter below layer VI in the
    cortex
  • Disorganized pyramidal cells in the hippocampus

12
Altered development of hippocampal pyramidal
neurons
13
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14
Neurodevelopmental Hypothesis
  • Home movies from families with schizophrenic
    child displayed abnormal behavior (Walker et al,
    1994 1996)
  • Children who later become schizophrenic exhibit
    poor social adjustment and school performance
  • Developmental delays
  • Premorbid psychopathology (anxiety, depression,
    conduct disorders, ADHD) (Kim-Cohen et al, 2003)
  • Physical abnormalities (Schiffman, et al. 2002)
  • Rates of concordance are higher in monochorionic
    twins compared dichorionic twins (60 vs. 11)
    (Davis, et al, 1995)

15
But why are symptoms not observed until
adolescence?
  • Something must trigger the degenerative process
    at the period of adolescence
  • Loss and disorganization of neurons become
    unmasked with pruning and synaptic
    reorganization

16
Rapid loss of brain volume during adolescence in
schizophrenics
Thompson et al, 2001
17
Thompson et al, 2001
18
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19
Twin studyloss of dlPFC and temporal cortical
tissue
Cannon et al 2002
20
Hypofrontality
  • Reduced activation of the dorsolateral prefrontal
    cortex contributes to negative symptoms and
    cognitive deficits
  • Functional imaging studies report reduced
    activation
  • Evidence of executive functioning deficits

21
Reduced activation of the dorsolateral prefrontal
cortex during a context processing/attention task
in first episode/drug naïve schizophrenics
MacDonald et al., 2005
22
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23
Could altered development be related to
glutamatergic dysfunction?
  • -Underactivation of systems alters migration,
    synaptic organization and cell survival
  • -Overactivation of systems can lead to altered
    synaptic connectivity and cell death

24
Neurodegenerative Hypothesis
25
  • Could the psychotic symptoms themselves be
    producing additional excitotoxicity?

26
Neurochemical Alterations
27
Dopamine Hypothesis
  • Original Formulation
  • Overactivity of subcortical D2 receptors
    contributes to positive symptoms
  • Classical antipsychotics were DA D2 antagonists
  • DA agonists induce psychotogenic effects

28
DOPAMINE PATHWAYS
29
mesolimbic pathway
30
mesolimbic overactivity positive symptoms of
psychosis
31
pure D2 blocker
32
Re-formulation of dopamine hypothesis
  • Imaging studies indicate loss of tissue in the
    frontal lobes as well as reduced activation
  • Deficit in activation of D1 receptors in the
    prefrontal cortex contributes to negative
    symptoms and cognitive deficits

33
meso-cortical pathway
34
Amphetamine-induced dopamine release is enhanced
in schizophrenics
Laruelle et al 2003
35
Amphetamine-induced dopamine release produces
positive symptoms
Laruelle et al, 1996
36
Increased dopamine release in medication-naïve
schizophrenic patients
Hietala, et al. 1995
37
D2 receptors?
  • Mixed data
  • Some find no differences
  • Others find moderate increases (Kestler et al.,
    2001)
  • What about D3 and D4 receptors?

38
What about the mesocortical DA system?
  • One postmortem study indicated a decrease in DA
    innervation of the dorsolateral prefrontal cortex
    (Akil, et al 1999)
  • Two PET studies had mixed findings, but the
    ligands used for D1 receptors were not selective
    (Okubo et al 1997 Karlsson et al 2002)
  • More recently, there is evidence of an
    upregulation of D1 receptors in the DLPFC

39
Increased D1 receptor availability in
schizophrenics suggests underactivation
Abi-Dargham et al, J Neurosci, 2002
40
Increases in D1 receptor availability in the
DLPFC are correlated with working memory deficits
Abi-Dargham et al, J Neurosci, 2002
41
Reduction in dendritic spines in dopaminergic
neurons in the dorsolateral prefrontal cortex
Lewis et al, 2003
42
Glutamate Hypothesis
  • Deficiencies in glutamatergic neurotransmission
  • Dysregulation of DA systems may be secondary to a
    deficit in the function of the glutamatergic NMDA
    receptor

43
Glutamate Hypothesis
  • Noncompetitve NMDA receptor antagonists (like PCP
    and ketamine) induce both positive and negative
    symptoms
  • Unmedicated schizophrenic patients are more
    sensitive to the effects of NMDA receptor
    antagonists
  • Adjunctive treatment with NMDA agonists might
    provide a modest improvement in symptoms

44
Evidence from human studies
  • Alterations in CSF glutamate levels, altered
    glutamate metabolism and altered NMDA receptor
    subunit gene expression (Keshavan, 1999)
  • Direct evidence is still lacking and a coherent
    picture has not yet emerged
  • Lack of adequate radioligands to visualize the
    GLU system in the living brain is a major
    impediment

45
Glutamate-Dopamine Interactions
Laruelle et al, 2003
46
Chronic PCP treatment reduces dorsolateral
prefrontal cortex dopamine and leads to negative
symptoms
  • Human studies
  • Animal studies

47
Jentsch and Roth, 1999
48
Chronic PCP leads to behavioral deficits
consistent with dorsolateral prefrontal cortex
dysfunction
Jentsch et al, Science, 1997
49
Chronic PCP reduces cortical dopamine
Jentsch et al, Science, 1997
50
Effects are reversed with clozapine
Jentsch et al, Science, 1997
51
NMDA receptor antagonism enhances
amphetamine-induced subcortical DA release
Kegelles et al 2000
52
Reduced prefrontal cortex activation in
schizophrenics
Meyer et al., 2002
53
Reduced dlPFC activation was negatively
correlated with striatal dopamine release
Meyer et al., 2002
54
Subcortical Dopamine-Glutamate Interactions
55
GABA alterations
  • Glutamate or GABA?

56
Put it all together
  • Neurodevelopmental brain damage, leads to
    dysfunction in areas like the prefrontal cortex,
    which leads to increased DA in the mesolimbic
    areas

57
What about the temporal lobe damage?
  • Hippocampus and amygdala control a gate that
    influences the effects of the prefrontal cortex
    on n. accumbens neuronal firing
  • This gate modulates reactions of the n. accumbens
    given the context

58
Hippocampus may modulate prefrontal activation of
n. accumbens
Grace, 2000
59
Grace, 2000
60
How does exaggerations of mesolimbic DA activity
lead to positive symptoms?
  • Could altered dopamine in the nucleus accumbens
    alter the salience attributed to internal and
    external stimuli?
  • Kapur reading

61
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62
Treatments
  • Conventional neuroleptics
  • Chlorpromazine
  • Haloperidol
  • Loxapine
  • Pimozide
  • Thieoridazine
  • thirothixene

63
pure D2 blocker
64
Typical antipsychotics are D2 receptor antagonists
65

66
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67
Conventional antipsychotics have other sites of
action
  • Muscarinic cholinergic blockade
  • Side effects of constipation and blurred vision
  • Reduce the likelihood of extrapyramidal symptoms

68
Problems with conventional antipsychotics
  • Because of side effects, many patients
    discontinue treatments, relapse, go back on
    treatment repeatedly
  • Neuroleptic malignant syndrome

69
Atypical antipsychotic drugs
  • Serotonin-dopamine antagonists
  • Clozapine
  • Risperidone
  • Olanzapine
  • Quetiapine
  • Ziprasidone

70
5HT-DA Interactions
71
dopamine neuron
dopamine
Substantia nigra
5HT2A receptor
serotonin
5HT2A receptor
serotonin neuron
Raphe
72
dopamine neuron
dopamine
Substantia nigra
5HT2A receptor
serotonin
5HT2A receptor
serotonin neuron
Raphe
73
dopamine neuron
Substantia nigra
5HT2A receptor
serotonin neuron
Raphe
74
Nigrostriatal pathway
D2 receptor
dopamine
postsynaptic neuron
DA neuron
5HT2A receptor
5HT neuron
75
Nigrostriatal pathway
no dopamine release
serotonin
76
Nigrostriatal pathway
D2 receptor
SDA
77
Nigrostriatal pathway
5HT2A receptor
78
conventional antipsychotic
caudate nucleus
79
serotonin-dopamine antagonist
caudate nucleus
80
mesocortical pathway
primary dopamine deficiency
dopamine release
SDA
serotonin
secondary dopamine deficiency
81
conventional antipsychotic
Cortex
82
serotonin-dopamine antagonist
Cortex
83
  • Fortunately, the serotonin 2A antagonists do not
    block dopamine antagonism in the mesolimbic
    system
  • This suggests that combination drugs may enhance
    DA activity in the prefrontal cortex while
    reducing DA activity in the mesolimbic system

84
  • What about glutamate agonists?

85
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86
Heresco-Levy, et al. 2004
87
Heresco-Levy et al., 2002
88
Summary
  • Schizophrenia is characterized by damage to brain
    areas, including the frontal cortices
    (particularly the DLPFC), temporal lobes,
    parietal cortex
  • Glutamate dysfunction may lead to developmental
    disorganization and cell loss
  • DA dysfunction and/or glutamate dysregulation in
    the prefrontal cortex and limbic system may
    contribute to symptoms of schizophrenia

89
Future directions
  • Neuroprotection
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