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SCHIZOPHRENIA

SCHIZOPHRENIA. A bit of history. Hideyo Noguchi, 1911: Syphillis (delusions, grandiosity, impulsivity, altered thought structure) is due to bacterium.

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SCHIZOPHRENIA

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  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.

  3. 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

  4. 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

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

  6. 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

  7. Structural changes in brain • Increased loss of gray matter in adolescence

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

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

  14. 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?????

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

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