Schizophrenia

Question 1

How do antipsychotics work?

Receptor occupancy?

Answer 1

Dopamine receptors, D2 reversible antagonists in associative striatum

60-75% occupancy to see effect/avoid side effects

Question 2

Other effects of APS action?

Answer 2

• EPSE in nigrostriatal pathways
• Antiemetic effect from chemotactic zone
• Constipation from enteric nervous system
• Hyperprolactinaemia from tuberoinfundibulnar pathway
• Neuroleptic Malignant Syndrome from hypothalamic region

Question 3

Non-dopamine receptor actions of APS?

Answer 3

5HT2C - Hunger/obesity
5HT1A, H1, alpha 1 - Sedation, low arousal, postural hypotension
M1 - Urinary retention, dry mouth, blurred vision
Membranes - Fits, cardiac arrhythmias

Question 4

When would clozapine be used?

Answer 4

2 previous antipsychotics haven’t worked or intolerable at maximum dose

Question 5

How effective is clozapine if used within first 3 years of diagnosis?

Answer 5

Can see effects in up to 75-80% of patients, usually around 30-50% of patients

Question 6

What are the side effects of clozapine?

Answer 6

Hunger
Hypersalivation
Diabetes
Agranulocytosis
Sedation

Question 7

Chance of relapse if on maintenance therapy?

Answer 7

Down to 27% over 11 months of treatment

Question 8

Relapse rate with rapid discontinuation?

Answer 8

46%

Question 9

Relapse rate with intermittent prescription?

Answer 9

50%

Question 10

What did the MESIFOS trial show?

Answer 10

Relapse rate doubled (20 to 42%) when antipsychotics discontinued vs maintenance

Question 11

What did MESIFOS and OPUS find regarding first episode treatment?

Answer 11

25% got off APS treatment within 5-10 years

Question 12

Advantages of depot?

Answer 12

Less relapse risk
Reduces non compliance
20-30% readmission/relapse

Question 13

Second APS as adjunct therapy?

Answer 13

Not unless a clean D3/D4 antagonist

Question 14

When is there a high risk of stopping antipsychotics?

Answer 14

After first admission

Question 15

Causes of poor adherence? (6)

Answer 15

1) Attitudes
2) Cognitive impairment
3) Circumstances
4) Support
5) Knowledge and engagement
6) Formulation

Question 16

What could be considered short term interventions? (3)

Answer 16

1) Counselling
2) Written info
3) Phone calls

Question 17

What could be considered long term interventions? (4)

Answer 17

1) Reminders/diaries
2) Therapy
3) Crisis intervention
4) Supervision

Question 18

Describe the PCP model for cognitive deficits in schizophrenia

Answer 18

Sub-Chronic dosing with phencyclidine - 2mg/kg BD for 7/7
Induces pathology
7 day washout to remove active drug
Cognitive tests - NOR, should see control spend longer on novel object in retention phase whereas subject spends equal time on existing object and novel object (deficit)
Drug can then be administered to test acute, chronic and discontinuation effects

Question 19

Novel target in schizophrenia?

Why?

Answer 19

Kv3 channels on parvalbumin-containing GABA neurones

Lower cell density of these neurones in schizophrenics, the Kv3 channels are involved in making neurones ready to fire, quicker firing to bridge loss in neurones

Question 20

Example novel drug for cognitive deficit?

Tests?

Answer 20

AUT6

Acute testing after one dose - improvement in NOR and reversal learning
Chronic testing every week for 21 days - improvement in NOR
Washout period - cognitive deficit returned

Question 21

Physiology with treatment?

Answer 21

With chronic treatment, neurone cell density increased but depleted once stopped

Question 22

Novel drug + APS?

Answer 22

Showed efficacy and safety