Schizophrenia

Lectures 19/20

Brain areas affected in schizophrenia

Hippocampus: smaller in affected individuals; contains disordered pyramidal cells (disorganized orientation); severity of symptoms correlates with degree of cell disorganization; may be caused by maternal influenza during 2nd trimester

Dopamine pathways involved in schizophrenia

mesolimbic pathway: VTA→ nucleus accumbens and hippocampus; overactivity causes positive symptoms (hallucinations, delusions, disordered thought, bizarre behavior)

mesocortical pathway: VTA→ prefrontal cortex; underactivity produces negative symptoms (social withdrawal, flat affect, anhedonia, reduced motivation, alogia, catatonia)

Positive Symptoms

Added abnormal experiences (hallucinations/delusions); causes by meosolimbic overactivty; occur during psychotic episodes

Negative symptoms

reduced normal function (flat affect, withdrawl, anhedonia); caused by mesocortical underactivity; occur during non-psychotic episodes

Thorazine

Typical, D2 antagonist targeting mesolimbic system; treats positive symptoms; causes motor side effects

Clozapine

Atypical, serotonin receptor blocker with weak DA affinity; treats negative symptoms by increasing DA in prefrontal cortex, fewer motor side effects

Schizophrenic vs. Normal Brain — Ventricles/Sulci

Schizophrenia brains have enlarged lateral and 3rd ventricles and enlarged sulci especially in temporal and frontal lobes

Schizophrenic vs. Normal Brain — Frontal Lobe Blood Flow

Schizophrenics show lower frontal lobe activity at rest and fail to increase activation during tasks, drug treatment can restore frontal activation

Schizophrenic vs. Normal Brain — Grey Matter Loss

Adolescents with schizophrenia lose grey matter at a significantly accelerated rate compared to normal adolescents

Dopamine hypothesis

Positive symptoms result from excess DA or increased postsynaptic DA sensitivity.

Cocaine and amphetamines increase dopamine→ produces positive symptoms (supports hypothesis)

Glutamate hypothesis

Schizophrenia results from underactivation of NMDA glutamate receptors

PCP and ketamine block NMDA receptors→ produce both positive and negative symptoms (supports hypothesis), also explains why atypical antipsychotics improve negative symptoms

Family relatedness

risk increases with genetic closeness

monozygotic twins- 48%

dizygotic twins- 17%

siblings- 9%

general population 1%

strong genetic component but environmental factors necessary

Environmental influences

Preconception (parental age, substance use)

Prenatal (viral infections (rubella/influenza, stress, nutrition)

Perinatal (hypoxia, low birth weight

childhood-adulthood: (abuse, trauma, stress, urban living)

Immune system influence on schizophrenia

C4 complement protein overexpression increases schizophrenia rish-30%

C4 tags synapses for pruning by microglia

overexpression→hyper-elimination of synapses; cytokines from macrophages can also enter the brain→ reduce synaptic plasticity, increase cell death, increase synaptic pruning→ positive, negative, and cognitive symptoms