1. SCHIZOPHRENIA

2. 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.

5. 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

7. 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

8. Structural changes in brain
Larger ventricles
Subgroup: inverse correlation between ventricle size and response to drugs

12. 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

16. Structural changes in brain
Increased loss of gray matter in adolescence

18. 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

19. Functional changes in brain
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

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

22. 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.

24. 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

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

29. 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?????

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