Schizophrenia

Question 1

What is the evidence for the “Glutamate Hypothesis” in SCZ?

Answer 1

• NMDA receptor antagonists (PCP, ketamine) can cause SCZ-like psychotic & cognitive abnormalities
• NMDA receptor agonists (e.g., D-serine, glycine, sarcosine) improve symptoms and have therapeutic benefits.
• Reduced NMDA receptor expression in mouse model displays SCZ-like symptoms.

*Is disrupted inhibition in SCZ linked to NMDA receptor hypo function?

Question 2

What is the evidence for the “Dopamine Hypothesis” in SCZ?

Answer 2

• Mechanism of action of 1st gen antipsychotics is to block D2 dopamine receptors in striatum + potency in treating +ve symptoms strongly correlates with affinity for D2 receptors.

• Administration of Amphetamine (binds & blocks DA re-uptake transporter -> inc extracellular DA) / L-DOPA (DA precursor) can mimic SCZ symptoms (Chen, 2003) + Antipsychotic drugs alleviate some of the symptoms of amphetamine psychosis

• Excess DA release in SCZ patients (Laurelle, 1996)

• Increased DA receptor binding, especially D2 receptors, in brain scans of SCZ patients (Abi-Dargham, 2000)

Question 3

What are the -ve side effects of (1st gen) antipsychotics?

Answer 3

Dose-dependent relationship: more = better, but can lead to movement disorder (similar to PD)
Extrapyramidal side effects include tremor, rigidity, dystonia, tardive dyskinesia - due to impact on nigrostriatal DA system

Question 4

What is the mechanism of action of (1st gen) antipsychotics?

Answer 4

Block D2 DA receptors in striatum

Question 5

What are 3 examples of (1st gen) antipsychotics?

Answer 5

Chlorpromazine
Haperidol
Perphenazine

Question 6

What are the changes in brain structure in SCZ?

Answer 6

Enlargement of lateral & 3rd ventricles

3% reduced brain size & weight - medial temporal lobe (hippocampal formation, subiculum, parrahippocampal gyrus)

Decreased grey matter & cortical volume

Question 7

What is the recent study which further evidences the “Glutamate hypothesis” in SCZ?

Answer 7

Synaptic density marker SV2A reduced (showing decreased glutamatergic synapses) in SCZ patients and unaffected by antipsychotics in rats

Question 8

What are the 3 main modalities of symptoms for SCZ?

Answer 8

+ve
-ve
Cognitive

Question 9

What is the associated social cost of SCZ? (2012)

Answer 9

~11.6 billion in 2012 in England

Question 10

What is the epidemiology of SCZ?

Answer 10

1% prevalence

Mean duration: 15 years

Reduced life expectancy - inc risk of morbidity & mortality (5-10% suicide rate) + inc risk of cardiovascular / metabolic complications in old age due to high incidence of smoking / effects of treatment drugs

Males > females (4:1)

Age of onset: typically late adolescence / early adulthood

Question 11

What is the genetic etiology of SCZ?

Answer 11

More common in those with relatives with SCZ - suggesting genetic component (e.g., Gottesman (1991) - 48% risk for identical twins vs. 1% for general population)

No Mendelian forms of SCZ identified

Common disease variants with very small effect size (e.g., Neuregulin, Cacna1a)

Rare disease variants with very large effect size (e.g., copy number variants, rare point mutations) (e.g., GRIN2A (NMDAR))

Question 12

Cognitive symptoms of SCZ associated with which brain area?

Answer 12

Dysfunction of DORSOLATERAL PRE-FRONTAL CORTEX