8 Schizophrenia and neuroleptic drugs

Question 1

Symptoms of Schizophrenia

Answer 1

Positive symptoms:

• Delusion
• Hallucination
• Thought disorder
• Abnormal movement ( sometimes aggressive)

Negative symptoms:

• Social withdrawal
• Flattening of emotions

Cognitive symptoms:

• Unable to make sense of everyday world
• Unable to link thoughts with outside events
• Cannot understand other people’s normal behaviours

Question 2

Antipsychotic drugs therapeutic uses

Answer 2

1) Schizophrenia
2) Manic phase of bipolar disorder
3) Schizoaffective
4) Acute idiopathic psychotic disorder
5) Depression with psychotic manifestation

Question 3

Dopamine theory

Answer 3

Positive symptoms due to overactivity of mesolimbic dopaminergic pathway activating D2 receptors

Negative symptoms due to decreased activity of mesocortical dopaminergic pathway where D1 receptors predominate.

Question 4

Serotonin theory

Answer 4

• Atypical drugs act as 5-HT2A receptor antagonists
• 5HT2A receptor is Gi protein coupled receptor that reduces dopamine release
• LSD (5-HT2A agonist) –> hallucination

Question 5

Glutamate theory ( seems that no drug deals with this)

Answer 5

• NMDA receptor hypofunction causing:
  1) reduced GABAergic inhibition on dopaminergic neurons in VTA–> positive symptoms
  2) reduce activity of mesocortical dopaminergic neurons–> negative symptoms
  3) affect GABAergic interneuron and cortical processing–> cognitive impairment

Question 6

Classification of antipsychotic drugs

Answer 6

Typical antipsychotics: D2 & D4&raquo_space; 5-HT2A + M1, alpha1, H1 antagonist

Atypical antipsychotics: 5-HT2A&raquo_space; D4 > D2 + M1, alpha1, H1 antagonist

Question 7

Typical antipsychotics examples and mechanism of action

Answer 7

Chlorpromazine
Flupentixol
Haloperidol
Trifluoperazine
Zuclopenthixol

Mechanism:
Block D2 receptors
1) In mesolimbic –> reduce positive symptoms
2) In mesocortical–> may cause negative symptoms (but fortunately D1 predominates)
3) In nigrostriatal–> causing EPS side effects
4) In tuberoinfundibular pathway–> increase prolactin secretion

Question 8

Atypical antipsychotics examples and mechanism of action

Answer 8

Clozapine
Olanzapine
Sulpiride
Risperidone

Mechanism:
Blocking D2 receptors
In mesolimbic–> reduce positive symptoms

Blocking 5HT2A receptors

1) In mesolimbic–> reduce positive symptoms
2) In mesocortical–> increase dopamine and glutamate–> improve negative symptoms
3) In nigrostriatal–> reduce EPS

Block M receptor
In striatum–> reduce EPS ( Ach DA balance hypothesis)

Question 9

Typical antipsychotics side effects:

Answer 9

1) Extrapyramidal symptoms (can be blocked by anticholinergic agents e.g. benztropine)
- Acute dystonia
- Akathisia
- Parkinsonism
- Tardive dyskinesia
2) Gynaecomastia (men) & galactorrhoea (women)
3) Neuroleptic malignant syndrome
- -> hyperthermia, autonomic instability, muscle rigidity, sweat shock, confusion/ altered consciousness
4) Postural hypotension (alpha 1 receptor)
5) Sedation/ drowsiness (H1 receptor)
6) Dry mouth, urinary retention (M1 receptor)
7) Increased QT interval ( haloperidol ONLY)

Question 10

Atypical antipsychotics side effects:

Answer 10

1) No EPS (except risperidone)
2) Hypersensitivity
3) Weight gain ( clozapine and olanzapine)
4) Increase QT interval ( clozapine and risperidone)
5) Postural hypotension ( alpha 1)
6) Dry mouth, urinary retention (M1)
7) Sedation/Drowsiness (H1)
8) Agranulocytosis ( clozapine)

Question 11

Pharmacokinetics

Answer 11

Oral, I.V, or intramuscular depot

Eliminated by liver

Potentiate sedative effects of other CNS depressants

Take several weeks to change dopaminergic pathway

Variable half life: 8-40 hrs