How do antipsychotics work?

Mechanism of Action of Antipsychotics

Antipsychotics primarily work by blocking dopamine D2 receptors in the mesolimbic pathway to reduce positive psychotic symptoms, while newer atypical antipsychotics also target serotonin 5-HT2A receptors, which may help address negative symptoms and reduce extrapyramidal side effects. 1, 2

Primary Mechanisms

Dopamine Receptor Blockade

• Conventional (typical) antipsychotics:
  • Act primarily by blocking dopamine D2 receptors throughout the central nervous system 2
  • Effective for positive symptoms (hallucinations, delusions, thought disorder) by reducing excessive dopamine neurotransmission in the mesolimbic pathway 2
  • Limited effect on negative symptoms (blunted affect, anhedonia, asociality) 2

Serotonin-Dopamine Antagonism

• Atypical antipsychotics:
  • Block both dopamine D2 receptors and serotonin 5-HT2A receptors 3
  • The 5-HT2A antagonism helps modulate dopamine release in different brain regions:
    • Increases dopamine release in the prefrontal cortex (potentially improving negative symptoms)
    • Reduces dopamine release in the nigrostriatal pathway (reducing extrapyramidal side effects) 3

Receptor Targets of Different Antipsychotics

Typical Antipsychotics

• High affinity for D2 receptors with relatively indiscriminate blockade across brain regions 2
• Examples include haloperidol, with maximum doses of 4-6 mg recommended for first-episode psychosis 4

Atypical Antipsychotics

• Preferred due to better efficacy for both positive and negative symptoms 5
• Examples include:
  • Risperidone (recommended initial target dose: 2 mg/day) 4
  • Olanzapine (recommended initial target dose: 7.5-10.0 mg/day) 4
  • Clozapine (reserved for treatment-resistant cases due to risk of agranulocytosis) 4, 5

Additional Neurotransmitter Systems Affected

Beyond dopamine and serotonin, many antipsychotics also interact with:

1. Histaminergic receptors (H1) - contributing to sedation and weight gain 1
2. Muscarinic cholinergic receptors - causing anticholinergic side effects 1
3. Alpha-adrenergic receptors - leading to orthostatic hypotension 1

Neurobiological Basis of Antipsychotic Action

The therapeutic effect of antipsychotics is based on the dopamine hypothesis of schizophrenia:

• Positive symptoms result from excessive dopamine activity in the mesolimbic pathway 2
• Negative symptoms may be related to reduced dopamine activity in the mesocortical pathway 2
• Current evidence shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies positive symptoms 1

Therapeutic Window and Side Effects

• A therapeutic window exists for D2 receptor blockade:

  • Too little: insufficient antipsychotic effect
  • Too much: increased risk of extrapyramidal symptoms and hyperprolactinemia 1
  • Long-term administration can upregulate D2 receptors, potentially leading to supersensitivity psychosis 6

• Common side effects based on receptor blockade:

  • D2 blockade: extrapyramidal symptoms, hyperprolactinemia
  • H1 blockade: sedation, weight gain
  • Muscarinic blockade: dry mouth, constipation, blurred vision
  • Alpha-1 blockade: orthostatic hypotension 1, 7

Newer Approaches to Antipsychotic Action

Recent research is exploring alternative mechanisms:

• Partial D2/D3 receptor agonists (e.g., aripiprazole) that stabilize dopamine signaling rather than simply blocking it 1
• Targeting dopamine synthesis and storage 1
• Modulating dopamine through other systems (cannabinoid, muscarinic, GABAergic, glutamatergic) 1

Understanding these mechanisms has led to more targeted treatment approaches with fewer side effects, though the fundamental dopamine-blocking action remains central to antipsychotic efficacy.