schizophrenia
TRANSCRIPT
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.
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 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
Larger ventricles• Subgroup: inverse correlation between
ventricle size and response to drugs
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
Increased loss of gray matter in adolescence
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
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
LSD, mescaline confusion, delirium, disorientation, visual hallucinations.
But schizophrenic hallucinations are mostly auditory
Schizophrenics given LSD say it’s different from their symptoms
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.
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
Problem with DA hypothesis: time course
Phencyclidine (PCP): dissociative anesthetic • Auditory hallucinations• Depersonalization• Delusions• Noncompetitive NMDA antagonist (blocks
Ca2+ channel)
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?????
Seizures!! (also excitotoxicity)
Try mGluR agonists: 8 subtypes of mGluR• Some modulate glutamate release• Others modulate dopamine systems