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

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Hideyo Noguchi, 1911: Syphillis (delusions,
grandiosity, impulsivity, altered thought
structure) is due to bacter...


Why does one twin become
schizophrenic and the other does not?
•
•
•
•

Lower birth weight
More physiological distress
...



Genes scattered across all but 8
chromosomes have been implicated
Most important:
•
•
•
•
•

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Neuregulin 1: NMDA, G...


Larger ventricles
• Subgroup: inverse correlation between ventricle

size and response to drugs


Hippocampus, amygdala,
parahippocamp.
• Smaller in affected twin (static trait)
• Disordered hippocampal pyramidal cell...
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Increased loss of gray matter in
adolescence
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
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Shrinkage of cerebellar vermis
Thicker corpus callosum
Frontal lobes
•
•
•
•

Abnormal neuronal migration in one st...
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Hypofrontality hypothesis
• Discordant twins: low frontal blood flow only in

affected twin
• Wisconsin card sorting ta...
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
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LSD, mescaline  confusion, delirium,
disorientation, visual hallucinations.
But schizophrenic hallucinations are
m...
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



Amphetamine (very high doses) 
paranoia, delusions, auditory
hallucination
Also exacerbates symptoms of schiz.
...
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

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Clozapine blocks 5-HT2A receptors > D2
As effective as typical neuroleptics on (+)
symptoms, more effective on (...



Problem with DA hypothesis: time course
Phencyclidine (PCP): dissociative
anesthetic 
• Auditory hallucinations
• De...


2 weeks PCP in monkeys  schiz.-like
symptoms
• Including poor performance on frontal lobe-

sensitive task
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Dose...


Seizures!! (also excitotoxicity)



Try mGluR agonists: 8 subtypes of mGluR
• Some modulate glutamate release
• Others...
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
Schizophrenia
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Schizophrenia

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Schizophrenia

  1. 1.    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.
  2. 2.  Why does one twin become schizophrenic and the other does not? • • • • Lower birth weight More physiological distress More submissive, tearful, sensitive Impaired motor coordination
  3. 3.   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
  4. 4.  Larger ventricles • Subgroup: inverse correlation between ventricle size and response to drugs
  5. 5.  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
  6. 6.  Increased loss of gray matter in adolescence
  7. 7.    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
  8. 8.  Hypofrontality hypothesis • Discordant twins: low frontal blood flow only in affected twin • Wisconsin card sorting task  Schizophrenics can’t 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
  9. 9.    LSD, mescaline  confusion, delirium, disorientation, visual hallucinations. But schizophrenic hallucinations are mostly auditory Schizophrenics given LSD say it’s different from their symptoms
  10. 10.     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.
  11. 11.     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
  12. 12.   Problem with DA hypothesis: time course Phencyclidine (PCP): dissociative anesthetic  • Auditory hallucinations • Depersonalization • Delusions • Noncompetitive NMDA antagonist (blocks Ca2+ channel)
  13. 13.  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?????
  14. 14.  Seizures!! (also excitotoxicity)  Try mGluR agonists: 8 subtypes of mGluR • Some modulate glutamate release • Others modulate dopamine systems

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