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.
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 2 nd trimester –Also in entorhinal, cingulate, parahippocampal cortex
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