HUF 2-69 Schizophrenia and neuroleptic drugs

Question 1

Symptoms of schizophrenia

Answer 1

Positive Symptoms:

• Delusion (paranoid)
• Hallucination
• Thought disorder (outside agency)
• Abnormal movements (aggressive behaviour)

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 behaviour

Question 2

Dopamine pathways related to schizophrenia

Answer 2

1. Mesocortical pathway dysfunction
   => Negative and cognitive symptoms
2. Mesolimbic pathway overactivity
   => Positive symptoms

Question 3

Neuroleptic drugs or antipsychotics

Answer 3

• Block mesolimbic DA transmission (+ve. symptoms)
• For:
  Schizophrenia
  Manic phase of bipolar disorders
  Acute idiopathic psychotic disorders
  Severe agitation / aggressive behaviours

Typical (1st gen.): bind tightly to D2 receptors
e.g. Chloropromazine, Thiothixene, Haloperidol

Atypical (2nd gen.): bind loosely to D2 receptors but also 5HT-2A

Question 4

Clinical evidence related to therapeutic actions of antipsychotics

Answer 4

1. Affinity towards D2R => clinical efficacy of anti-psychotic effects
   (↑ D2 affinity => ↓ dose needed)
2. ↑ DA receptor density and [DA] in corpus striatum in brains of schizophrenic patients (postmortem examinations)

Question 5

Typical antipsychotics can antagonise multiple receptors with diff. potencies

Answer 5

Preferentially bind to D2, D4 than 5-HT2A
Can also bind to muscarinic, α and H1

• Antagonism to D2R => Treat positive symptoms
• Effective among 70% of patients
• Sedative (CNS depressing)

Question 6

Basic research evidence related to therapeuric actions of antipsychotics

Answer 6

1. Drugs that ↑ central dopaminergic activity => +ve. symptoms
   - Normal people with repeated amphetamine intake
   => Psychosis
   ∵ Amphetamine ↑ release of DA from neurons
2. D2R Antagonists and drugs that block neuronal DA storage => Control +ve. symptoms
   - Prevent amphetamine induced psychotic symptoms
   - e.g. Reserpine: ↓ DA at presynaptic side

Question 7

Major mechanism of antipsychotics actions

Answer 7

Mesolimbic D2R antagonism

• DA theory of schizophrenia: hyperactivity of central DA => psychosis
• +ve. symptoms of schizophrenia related to hyperactivity of mesolimbic DA system

Question 8

High potency typical antipsychotics tend to cause more serious adverse effects

Answer 8

• Exaggeration of -ve. symptoms
• Blockade of nigrostriatal pathway
  => Extrapyramidal symptoms (EPS)
• Blockade of tuberoinfundibular pathway in hypothalamus
  => dysregulate PRL secretion

Question 9

Extrapyramidal symptoms (EPS)

Answer 9

Originated in brainstem; modulated by nigrostriatal pathway

Reversible (Benzatropine: anticholinergic drugs):

• Acute dystonia (days): muscle spasm affecting tongue, face, neck, back
• Akathisia (days to weeks): motor restlessness, continual pacing
• (Pseudo-)Parkinsonism (a few weeks): difficulty in initiating movement

Irreversible:
- Tardive dyskinesia (years): abnormal movements of facial ms, trunk, limbs (upreg. of D2R)

Question 10

Major undesirable endocrine effects of typical antipsychotics

Answer 10

• PRL release from pituitary gland under control of central DA transmission
• D2R blockade of tuberoinfundibular pathway
  => ↓ DA suppression of PRL release
  => Men: gynaecomastia
  Women: galactorrhea

Question 11

Unpredictable life-threatening neurological disorder

Answer 11

Neuroleptic malignant syndrome

• ↑ body temp. > 38°, sweating
• Confused or altered consciousness (agitation , delirium, coma)
• Rigid muscles, muscle cramps, tremors
• Autonomic imbalance e.g. unstable BP
• Typical antipsychotics (haloperidol, chlorpromazine): greatest risk of neuroleptic malignant syndrome

Question 12

Antagonism of other receptors => Undesirable effects of antipsychotics

Answer 12

Block α => postural hypotension
Block H1 => Sedation / Drowsiness
Block M => dry mouth, urinary retention

• Potency of receptor blockade
• High potency drugs tend to have fewer sedative effects and less postural hypotension
  ∵ less dosage needed

Question 13

Atypical (2nd. gen) antipsychotics

Answer 13

• Lower risk of EPS
• Relative lower affinity for D2R (transient D2R occupancy; rapid dissociation from D2R)
• High affinity towards 5-HT2A R
• Better improvement in -ve. symptoms

Question 14

“Atypicality” of atypical antipsychotics

Answer 14

1. 5-HT2A antagonism: high preference toantagonize 5-HT2AR than to D2R (high 5-HT2A/D2 blocking ratio)
   - increase DA transmission in nigrostriatal pathway
   => ↓ risks of EPS
2. Rapid dissociation from D2R (transient binding)
   => ↓ risks of EPS (nigrostriatal pathway)

Question 15

Commonly used atypical antipsychotics

Answer 15

Clozapine
Olanzapine
Risperidone

Question 16

Clozapine

Answer 16

• Weak D2R antagonist; greater antagonist activity at D1, D4 and 5-HT2AR
• Risk of agranulocytosis (fatal in long run)
  ∴ Blood monitoring needed
• Not recommended for 1st-line treatment
• Reserved for patients who DO NOT respond to conventional antipsychotic therapy or who have tardive dyskinesia
• Metabolic changes (glucose metabolism) ; weight gain
  Olanzapine

Question 17

Olanzapine

Answer 17

• Receptor binding profile similar to clozapine
• Higher affinity for 5-HT2AR than D2R
• Less likely yo produce serious undesirable effects e.g. agranulocytosis

Question 18

Risperidone

Answer 18

• Higher affinity for 5-HT2AR than D2R

- Higher daily dose => higher EPS risk

Question 19

Weight gain due to atypical antipsychotics

Answer 19

• Olanzapine, Clozapine

Possible mechanisms:

1. Antagonise H1R => Excessive eating, food craving
2. Antagonise M => ↓ pancreatic insulin release (hyperglycemia)
3. Affect adrenergic system => Hyperglycemia, ↓ lipolysis

Question 20

Other common undesirable side effects of atypical antipsychotics

Answer 20

• Type I hypersensitivity (allergic rxn)
• QT-interval prolongation: block cardiac K+ channels (inward rectifiers) e.g. Clozapine, Risperidone

Block α => postural hypotension
Block H1 => Sedation / Drowsiness
Block M => dry mouth, urinary retention

Question 21

PK profile of antipsychotics

Answer 21

• Highly lipophilic; metabolised in liver
• High binding to plasma proteins
• High first-pass metabolism via oral routes
• Elimination: multiphasic pattern; not strictly first order
  ∴ t1/2 hard to be predicted (8-40 hrs)
• Patients respond differently to individual antipsychotics
  => Be careful when switching between antipsychotics

Question 22

Potential DDI of antipsychotics

Answer 22

1. Interact with Parkinson treatment drugs
   - ↑ synaptic [DA] e.g. Levodopa
   - Direct stimulation of DAR (DA agonist)
2. Potentiate sedative effects of other CNS depressants
   e. g. hypnotics/anxiolytics, 1st gen antihistamines

Question 23

Typical and atypical antipsychotics are equally effective towards +ve. symptoms

Answer 23

• Choice of antipsychotics depends on:
  Tolerance to EPS risk
  Effectiveness of managing -ve. symptoms
  Cost

Notes:
1. Use anticholinergic drugs to block motor side effects of antipsychotics (e.g. benzatropine)
2. Several weeks to see clinical effects of antipsychotics (time lag); undesirable effects, weight gain
∴ Patient education => patient is following treatment regimen