SCHIZOPHRENIA

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SCHIZOPHRENIA
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A bit of history

• Hideyo Noguchi, 1911 Syphillis (delusions,
  grandiosity, impulsivity, altered thought
  structure) is due to bacterium.
• Emil Kraeplin, 1919 dementia praecox (paranoia,
  grandiose delusions, auditory hallucinations,
  abnormal emotional reg., bizarre thoughts)partly
  genetic
• Eugen Bleuler, 1911 key is dissociative
  thinking also delusions, hallucinations,
  affective disturbance, autism.

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Twin studies

• Why does one twin become schizophrenic and the
  other does not?
• Lower birth weight
• More physiological distress
• More submissive, tearful, sensitive
• Impaired motor coordination

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Genes

• Genes scattered across all but 8 chromosomes have
  been implicated
• Most important
• Neuregulin 1 NMDA, GABA, Ach receptors
• Dysbindin synaptic plasticity
• Catechol-O-methyl transferase DA metabol.
• G72 regulates glutamatergic activity
• Others myelination, glial function
• Paternal age more cell divisions in sperm

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Structural changes in brain

• Larger ventricles
• Subgroup inverse correlation between ventricle
  size and response to drugs

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Structural changes in brain

• Hippocampus, amygdala, parahippocamp.
• Smaller in affected twin (static trait)
• Disordered hippocampal pyramidal cells
• Correlation between cell disorder and severity
• May be due to maternal influenza in 2nd trimester
• Also in entorhinal, cingulate, parahippocampal
  cortex

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Structural changes in brain

• Increased loss of gray matter in adolescence

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Structural changes in brain

• Shrinkage of cerebellar vermis
• Thicker corpus callosum
• Frontal lobes
• Abnormal neuronal migration in one study
• Dendrites have fewer spines
• But no major structural abnormalities
• Measures of frontal function impaired

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Functional changes in brain

• Hypofrontality hypothesis
• Discordant twins low frontal blood flow only in
  affected twin
• Wisconsin card sorting task
• Schizophrenics cant shift attn. to other
  criterion
• Functional imaging frontal lobe activity lower
  at rest, esp. in right hemisphere, does not
  increase during task.
• Drug treatment increased activation of frontal
  lobes

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Neurochemical changes

• LSD, mescaline ? confusion, delirium,
  disorientation, visual hallucinations.
• But schizophrenic hallucinations are mostly
  auditory
• Schizophrenics given LSD say its different from
  their symptoms

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Dopamine hypothesis

• Amphetamine (very high doses) ? paranoia,
  delusions, auditory hallucination
• Also exacerbates symptoms of schiz.
• Effects blocked by DA antagonist chlorpromazine
• Phenothiazines (incl. chlorprom.) all other
  typical neuroleptics block D2 receptors and
  alleviate () symptoms.

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Atypical neuroleptics

• Clozapine blocks 5-HT2A receptors D2
• As effective as typical neuroleptics on ()
  symptoms, more effective on (-) symptoms
• Fewer motor side effects (tardive dyskinesia)
• Actually increase DA release in frontal cortex
• L-DOPA can even be beneficial

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Glutamate hypothesis

• Problem with DA hypothesis time course
• Phencyclidine (PCP) dissociative anesthetic ?
• Auditory hallucinations
• Depersonalization
• Delusions
• Noncompetitive NMDA antagonist (blocks Ca2
  channel)

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Glutamate hypothesis

• 2 weeks PCP in monkeys ? schiz.-like symptoms
• Including poor performance on frontal
  lobe-sensitive task
• Dose- time-sensitive
• Ketamine (NMDA antag)? similar effects
• So, why not give glutamate agonists to treat
  schizophrenia?????

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Glutamate hypothesis

• Seizures!! (also excitotoxicity)
• Try mGluR agonists 8 subtypes of mGluR
• Some modulate glutamate release
• Others modulate dopamine systems

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