3.1 Psychosis: Basic Sciences

Question 1

What brain morphology is associated with poorer outcomes in schizophrenia?

Answer 1

• Reduced frontal lobe volume and frontal lobe grey matter
• Enlarged lateral ventricle volume
• Reduced temporal cortex volume- superior temporal gyrus
• Reduced temporal cortex and median temporal lobe volumes

Question 2

What is the dopamine hypothesis of schizophrenia?

Answer 2

• Dopamine releasing drugs (amphetamines) or D2 receptor agonists produce psychotic state
• dopamine receptor antagonists treat symptoms of schizophrenia
• schizophrenia due to overactivity of dopamine pathways

Question 3

What do the dopamine receptor subtypes do in the brain?

Answer 3

D1/F5: stimulate cAMP

D2/3/4: inhibit adenylyl cyclase, inhibit voltage activated Ca2+ channels and open K+ channels (makes cell more -)

Question 4

What is the distribution of D1 receptors? D2 receptors?

Answer 4

D1: neostriatum, cerebral cortex, olfactory tubercle, nucleus accumbens
D2: neostriatum, olfactory tubercle, nucleus accumbens

Question 5

What is an agonist and antagonist of dopamine D2 receptor?

Answer 5

Agonist: bromocriptine (can tx parkinsons, pit tumour, hyperprolactinemia)
Antagonist: raclopride, haloperidol

Question 6

What receptor does clozapine block?

Answer 6

Clozapine is a D4 antagonist

Question 7

What is the reformulated Dopamine hypothesis?

Answer 7

Psychosis: due to subcortical dopamine hyperactivity
Negative/cognitive symptoms: due to mesocortical dopamine hypoactivity.

Failure to activate ventral striatum during rewarding cues associated with stronger negative symptoms

Question 8

What is the glutamatergic hypothesis of schizophrenia?

Answer 8

Due to altered NMDA receptor subunit expression

Evidence: ketamine can cause psychotic symptoms

Question 9

What is the Serotonergic hypothesis of schizophrenia?

Answer 9

Due to abnormal serotonin NA binding potential in frontal cortex
Evidence: this binding potential is smaller in pts with schizophrenia

Question 10

What genes are implicated in schizophrenia brain pathology?

Answer 10

neuregulin- role in growth and development of organs
dysbindin- essential for neural plasticity
DISC-1- neurite outgrowth and cortical development role

Question 11

Name some typical antipsychotics, and the definition

Answer 11

drugs without atypical properties

• chlorpormazine
• thioridazine
• fluphenazine
• haloperidol
• zuclopentixol

Question 12

What is the definition of atypical antipsychotic? What are some examples?

Answer 12

1. Less likely to cause extrapyramidal side effects
2. High 5HT-2A to D2 blockade ratio
3. Better efficacy vs. negative symptoms
4. Effective in pts not responsive to typical drugs
   - olanzapine
   - risperidone
   - quetiapine
   - clozapine
   - aripiprazole
   - amisulpride

Question 13

What do extrapyramidal effects mean?

Answer 13

Akathesia
Acute dystonia
Parkinsonism
(Tardive dyskinesia- the presentation of these effects after several months)

Do not occur with clozapine
Less prominent with atypical antipsychotics
-Result from D2 blockade in the nigrostriatal pathways

Question 14

What is the principle SE of 5HT-2 blockade in antipsychotics?

Answer 14

Metabolic syndrome
-related to antagonism/inverse agonist activity at 5HT2C receptors

• weight gain
• hypertension
• hyperglycaemia
• hypercholesterolaemia

Question 15

What is the principle SE of histamine blockade in antipsychotics?

Answer 15

Sedation

Increased appetite

Question 16

What is the principle SE of alpha-1 adrenergic blockade in antipsychotics?

Answer 16

Postural hypotension
Problems ejaculating
Nasal stuffiness

Due to lack of sympathetic stimulation that should cause increased HR and BP.

Question 17

What are the principle SE of muscarinic blockade in antipsychotics?

Answer 17

Dry eyes/mouth
Constipation 
Blurred vision
Increased ocular pressure
Trouble micturating

CNS muscarinic blockade may also cause confusion

Question 18

Which is the best drug for treatment resistant psychosis/schizphrenia? What is it’s major side effect?

Answer 18

Clozapine

• Drowsiness (high H1, M1 and 5HT blocking effect, low S2 effect)
• agranulocytosis - do FBC q1/52 x 6/12, then q2/52 x 6/12, then q1/12 x duration of therapy + 1/12
• myocarditis