schizophrenia
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SCHIZOPHRENIA. A bit of history. Hideyo Noguchi, 1911: Syphillis (delusions, grandiosity, impulsivity, altered thought structure) is due to bacterium. - PowerPoint PPT PresentationTRANSCRIPT
SCHIZOPHRENIA
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.
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
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
Structural changes in brain
• Larger ventricles– Subgroup: inverse correlation between
ventricle size and response to drugs
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
Structural changes in brain
• Increased loss of gray matter in adolescence
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
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
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
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.
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
Glutamate hypothesis
• Problem with DA hypothesis: time course
• Phencyclidine (PCP): dissociative anesthetic – Auditory hallucinations– Depersonalization– Delusions– Noncompetitive NMDA antagonist (blocks
Ca2+ channel)
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?????
Glutamate hypothesis
• Seizures!! (also excitotoxicity)
• Try mGluR agonists: 8 subtypes of mGluR– Some modulate glutamate release– Others modulate dopamine systems