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