SCHIZOPHRENIA

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