Chapter 16

Schizophrenia

http://www.npr.org/programs/atc/features/2002/aug/schizophrenia/

18.2 Treatment of the mentally ill

• Schizophrenia

– A serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and mood disturbance.

Schizophrenia

• Positive Symptoms– Delusions– Hallucinations– Disorganized behavior

• Negative Symptoms– Social withdrawal– Mood disturbance– Reduced motivation

John Nash

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• Schizophrenia–Positive symptoms

–Dopamine hypothesis:• Overactivity of dopamine in

mesolimbic pathway (VTA to nucleus accumbens and amygdala)

• Schizophrenia– How are positive symptoms related to

dopamine?

– Hypothesis:• Mesolimbic system important for reinforcement of

behavior• We all have irrational thoughts, but usually brush

them aside• But if mesolimbic system was active when the

thought occurred, we might take it more seriously, leading to delusions

– Hypothesis cont.:• Confirming piece of evidence:

schizophrenics often report euphoria at onset of positive symptoms

• Disordered thinking?– System so active that it does not discriminate

between thoughts, making it hard to follow a logical sequence

• Terrifying element of delusions?– Strong dopaminergic projection to amygdala

Dopamine HypothesisEvidence for excessive dopamine

• Dopamine agonists (cocaine, amphetamine, PCP) produce symptoms of psychosis.

• Dopamine antagonists reduce psychotic behavior.

• Patients may have abnormalities involving dopamine autoreceptors.

SchizophreniaPositive Symptoms

• Schizophrenia– Positive Symptoms

– Chlorpromazine:• A “typical neuroleptic”

• A dopamine receptor blocker for D2 receptors

– Clozapine:• An “atypical neuroleptic”

• An antipsychotic drug that blocks D4 receptors in the nucleus accumbens

• Tardive dyskinesia involves tremors and involuntary movements.

• Supersensitivity: increased sensitivity of neurotransmitter receptors (D2) to dopamine

• Due to side effects, about 50% now use atypical neuroleptics like clozapine.

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SchizophreniaSide Effects of Typical Antipsychotics

SchizophreniaSide Effects of Typical Antipsychotics

Dopamine HypothesisEvidence for increase in D3 receptors

Failure of Prepulse Inhibition in Schizophrenia

Restoring Prepulse Inhibition in Schizophrenia

Problems With a Excessive Dopamine Hypothesis• 25% of patients do not respond to dopamine

antagonists.

• Atypical antipsychotic medications (clozapine) act primarily on neurotransmitters other than dopamine.

• Drugs change dopamine activity immediately, but patient may not improve for weeks.

• PCP produces symptoms similar to schizophrenia by blocking the NMDA glutamate receptor.

• Schizophrenia–Negative symptoms

–Brain damage:• Many of the negative symptoms are

also seen in people with frontal lobe damage

Lifetime risks of developing schizophrenia

Search for Brain AbnormalitiesEvidence for changes in ventricular size

Courtesy D.R. Weinberger, NIMH, St. Elizabeth’s Hospital, Washington, D.C.

Disorganization of cells in the hippocampus

Search for Brain AbnormalitiesLoss of gray matter with age

Search for Brain AbnormalitiesLoss of gray matter with age

Cause of delay of onset??

• Lower frontal lobe activity may account for the negative symptoms of schizophrenia.

• During rest (top) and an effortful cognitive test (bottom), patients with schizophrenia show less frontal lobe activity.

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Hypofrontality in schizophrenia

Hypofrontality in schizophreniaWisconsin Card Sorting Task

Possible Causes of the Brain Abnormalities

– Seasonal effect– Latitude effect– Maternal exposure to viruses– Nutritional deficiency

• Hunger Winter study– Thiamine deficiency– Vitamin D deficiency (latitude effect?)

– Father’s age– Rh Incompatibility

How are positive & negative symptoms related?

VTA

PrefrontalCortex

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DopamineHypoactivity(too little DA)

GABA neurons

Dopamine hyperactivity(too much DA)

18.17 Schematic representation of the neurodevelopmental model of schizophrenia

18.16 A modified representation of the vulnerability–stress model