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