Schizophrenia What causes schizophrenia? Neuropathology

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Schizophrenia

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

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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

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Associated Features

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

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Subtypes

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

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Neuropathology

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

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What causes schizophrenia?

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

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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)

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Ventricular enlargement in monozygotic twin with
schizophrenia
Barondes, 1993
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Hippocampal volume loss and enlarged ventricles
Van Heron et al., 2005
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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

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Altered development of hippocampal pyramidal
neurons
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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)

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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

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Rapid loss of brain volume during adolescence in
schizophrenics
Thompson et al, 2001
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Thompson et al, 2001
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Twin studyloss of dlPFC and temporal cortical
tissue
Cannon et al 2002
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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

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Reduced activation of the dorsolateral prefrontal
cortex during a context processing/attention task
in first episode/drug naïve schizophrenics
MacDonald et al., 2005
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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

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

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Neurochemical Alterations
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Dopamine Hypothesis

• Original Formulation
• Overactivity of subcortical D2 receptors
  contributes to positive symptoms
• Classical antipsychotics were DA D2 antagonists
• DA agonists induce psychotogenic effects

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DOPAMINE PATHWAYS
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mesolimbic pathway
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mesolimbic overactivity positive symptoms of
psychosis
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pure D2 blocker
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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

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meso-cortical pathway
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Amphetamine-induced dopamine release is enhanced
in schizophrenics
Laruelle et al 2003
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Amphetamine-induced dopamine release produces
positive symptoms
Laruelle et al, 1996
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Increased dopamine release in medication-naïve
schizophrenic patients
Hietala, et al. 1995
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D2 receptors?

• Mixed data
• Some find no differences
• Others find moderate increases (Kestler et al.,
  2001)
• What about D3 and D4 receptors?

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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

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Increased D1 receptor availability in
schizophrenics suggests underactivation
Abi-Dargham et al, J Neurosci, 2002
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Increases in D1 receptor availability in the
DLPFC are correlated with working memory deficits
Abi-Dargham et al, J Neurosci, 2002
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Reduction in dendritic spines in dopaminergic
neurons in the dorsolateral prefrontal cortex
Lewis et al, 2003
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Glutamate Hypothesis

• Deficiencies in glutamatergic neurotransmission
• Dysregulation of DA systems may be secondary to a
  deficit in the function of the glutamatergic NMDA
  receptor

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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

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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

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Glutamate-Dopamine Interactions
Laruelle et al, 2003
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Chronic PCP treatment reduces dorsolateral
prefrontal cortex dopamine and leads to negative
symptoms

• Human studies
• Animal studies

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

• Glutamate or GABA?

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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

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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

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Hippocampus may modulate prefrontal activation of
n. accumbens
Grace, 2000
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Grace, 2000
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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

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Treatments

• Conventional neuroleptics
• Chlorpromazine
• Haloperidol
• Loxapine
• Pimozide
• Thieoridazine
• thirothixene

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pure D2 blocker
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Typical antipsychotics are D2 receptor antagonists
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Conventional antipsychotics have other sites of
action

• Muscarinic cholinergic blockade
• Side effects of constipation and blurred vision
• Reduce the likelihood of extrapyramidal symptoms

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Problems with conventional antipsychotics

• Because of side effects, many patients
  discontinue treatments, relapse, go back on
  treatment repeatedly
• Neuroleptic malignant syndrome

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Atypical antipsychotic drugs

• Serotonin-dopamine antagonists
• Clozapine
• Risperidone
• Olanzapine
• Quetiapine
• Ziprasidone

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5HT-DA Interactions
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dopamine neuron
dopamine
Substantia nigra
5HT2A receptor
serotonin
5HT2A receptor
serotonin neuron
Raphe
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dopamine neuron
dopamine
Substantia nigra
5HT2A receptor
serotonin
5HT2A receptor
serotonin neuron
Raphe
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dopamine neuron
Substantia nigra
5HT2A receptor
serotonin neuron
Raphe
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Nigrostriatal pathway
D2 receptor
dopamine
postsynaptic neuron
DA neuron
5HT2A receptor
5HT neuron
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Nigrostriatal pathway
no dopamine release
serotonin
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Nigrostriatal pathway
D2 receptor
SDA
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Nigrostriatal pathway
5HT2A receptor
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conventional antipsychotic
caudate nucleus
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serotonin-dopamine antagonist
caudate nucleus
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mesocortical pathway
primary dopamine deficiency
dopamine release
SDA
serotonin
secondary dopamine deficiency
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conventional antipsychotic
Cortex
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serotonin-dopamine antagonist
Cortex
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• 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

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• What about glutamate agonists?

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Heresco-Levy, et al. 2004
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Heresco-Levy et al., 2002
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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

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Future directions

• Neuroprotection