- Schizophrenia was originally described as having distinct subtypes with different symptoms, but all involve dissociative thinking. Genes on multiple chromosomes have been implicated in schizophrenia risk. Environmental factors like lower birth weight, stress in pregnancy, and advanced paternal age may also play a role. - Brain abnormalities in schizophrenia include enlarged ventricles, reduced hippocampal and prefrontal cortex volume, and abnormal prefrontal function. The hypofrontality hypothesis suggests dysfunction in prefrontal regions, supported by brain imaging studies. Psychedelic drugs can induce schizophrenia-like symptoms, and NMDA receptor antagonists like PCP and ketamine also produce similar effects in animals. Current drug treatments target dopamine and serotonin receptors.

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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.

5. 
Why does one twin become
schizophrenic and the other does not?
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Lower birth weight
More physiological distress
More submissive, tearful, sensitive
Impaired motor coordination

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

8. 
Larger ventricles
• Subgroup: inverse correlation between ventricle
size and response to drugs

12. 
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

16. 
Increased loss of gray matter in
adolescence

18. 
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Shrinkage of cerebellar vermis
Thicker corpus callosum
Frontal lobes
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Abnormal neuronal migration in one study
Dendrites have fewer spines
But no major structural abnormalities
Measures of frontal function impaired

19. 
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

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LSD, mescaline  confusion, delirium,
disorientation, visual hallucinations.
But schizophrenic hallucinations are
mostly auditory
Schizophrenics given LSD say it’s
different from their symptoms

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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.

24. 
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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

26. 
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Problem with DA hypothesis: time course
Phencyclidine (PCP): dissociative
anesthetic 
• Auditory hallucinations
• Depersonalization
• Delusions
• Noncompetitive NMDA antagonist (blocks Ca2+
channel)

29. 
2 weeks PCP in monkeys  schiz.-like
symptoms
• Including poor performance on frontal lobe-
sensitive task
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Dose- & time-sensitive
Ketamine (NMDA antag) similar effects
So, why not give glutamate agonists to
treat schizophrenia?????

30. 
Seizures!! (also excitotoxicity)
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Try mGluR agonists: 8 subtypes of mGluR
• Some modulate glutamate release
• Others modulate dopamine systems