Lecture 26: Neuropharmacology of antipsychotic drugs

Which dopamine pathways are affected by psychosis?

Mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways

What is dopamine’s role in the brain and what are the different types?

It’s a key neurotransmitter involved in mood, reward, and motor control

D1-like = D1, D5

D2-like = D2, D3, D4

Which dopamine receptor type do most antipsychotics primarily target?

D2 receptors

How do antipsychotics alleviate positive symptoms of schizophrenia?

By blocking D2 receptors in the mesolimbic pathway

What effect does D2 blockade in the mesocortical pathway have?

It can worsen negative symptoms (cognition, motivation, emotional regulation)

Why can D2 blockade in the nigrostriatal pathway cause EPS?

Because this pathway is involved in movement control

What characteristics would the ideal antipsychotic have?

Decrease dopamine in mesolimbic, increase in mesocortical, and avoid side effects from nigrostriatal and tuberoinfundibular pathways

What receptors do atypical (2nd gen) antipsychotics primarily act on?

Serotonin (5-HT) and dopamine (D2) receptors

What is the ‘fast-off-D2’ theory?

Atypical antipsychotics bind less tightly to D2 receptors, reducing side effects while maintaining efficacy

What does inverse agonism at 5-HT2A receptors do?

Reduces receptor baseline activity, enhancing dopamine release and improving mood, cognition, and negative symptoms while reducing EPS

What are common side effects of atypical antipsychotics?

Weight gain, metabolic syndrome, sedation, and increased diabetes risk

What is tardive dyskinesia (TD)?

Involuntary, repetitive movements (e.g., lip smacking, grimacing, tongue movements) caused by long-term antipsychotic use

Reversible if the medication is stopped

Name common first-generation (typical) antipsychotics

Chlorpromazine, haloperidol, pimozide, and trifluoperazine

Name common second-generation (atypical) antipsychotics

Olanzapine, quetiapine, risperidone, and clozapine

Why are atypical antipsychotics generally preferred?

Lower risk of EPSs, though they require monitoring for metabolic side effects

What conditions is risperidone used to treat?

Schizophrenia and acute manic episodes in bipolar disorder

Which receptors does risperidone block and how is this balance beneficial?

5-HT (5-HT2A and 5-HT7) and D2 receptors

Reduces psychotic symptoms while minimising side effects (effective in both positive and negative effects)

What is paliperidone?

It is the major active metabolite of risperidone

When is clozapine prescribed?

For treatment-resistant schizophrenia

What symptoms does clozapine effectively reduce and what receptors does it block most strongly?

Both positive and negative symptoms, and it helps prevent relapse

5-HT2A, 5-HT2C, and D4 (more than D2)

What is the major risk associated with clozapine and how is this monitored?

Agranulocytosis — a dangerous drop in white blood cell count

Monitored using a traffic light system:

• Green: safe, continue treatment

• Amber: borderline, monitor closely

• Red: dangerous, stop immediately

What are clozapine’s common side effects?

Sedation, hypersalivation, and metabolic changes

What conditions is olanzapine used to treat?

Schizophrenia and bipolar disorder

Which receptors does olanzapine have high affinity for and what receptor action explains olanzapine’s sedation and weight gain?

5-HT2A and D2 receptors

Strong antagonism at H1 receptors - sedation/weight gain

What additional receptors can olanzapine act on, causing dry mouth or constipation?

M3 and adrenergic receptors

What disorders is quetiapine approved to treat and which receptors are blocked?

Acute and chronic psychotic disorders

5-HT2A and D2 receptors

What other receptors does quetiapine affect, contributing to sedation and hypotension?

H1 and adrenergic receptors

When might quetiapine’s sedative effects be considered beneficial?

In agitated patients or those with disturbed sleep