What receptor does Clozapine (clozapine) act on?

From the Guidelines

Clozapine acts on multiple receptors in the brain, primarily dopamine D2 receptors and serotonin 5-HT2A receptors. Unlike typical antipsychotics that mainly block D2 receptors, clozapine has a unique binding profile with lower affinity for D2 receptors but higher affinity for D1, D4, and 5-HT2A receptors 1. This atypical antipsychotic also interacts with histamine H1, muscarinic M1, and alpha-adrenergic receptors, which contributes to both its therapeutic effects and side effect profile.

Key Receptors Affected by Clozapine

• Dopamine D2 receptors
• Serotonin 5-HT2A receptors
• Dopamine D1 receptors
• Dopamine D4 receptors
• Histamine H1 receptors
• Muscarinic M1 receptors
• Alpha-adrenergic receptors The drug's effectiveness in treatment-resistant schizophrenia is believed to result from this broad receptor activity, particularly its balanced blockade of dopamine and serotonin systems 1. This unique receptor binding profile explains why clozapine can be effective in patients who don't respond to other antipsychotics, though it also accounts for its distinct side effects including agranulocytosis, which requires regular blood monitoring during treatment.

Clinical Implications

• Clozapine is recommended for patients with treatment-resistant schizophrenia 1
• Clozapine is recommended for patients with schizophrenia who are at substantial risk for suicide attempts or suicide 1
• Regular blood monitoring is necessary during clozapine treatment due to the risk of agranulocytosis 1

From the FDA Drug Label

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9. 4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM).

Clozapine acts on several receptors, including:

• Dopamine receptors: D2, D1, D3, D4, D5
• Serotonin receptors: 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7
• Adrenergic receptors: α1A, α2A
• Histamine receptor: H1
• Muscarinic receptor: M1 2

From the Research

Receptor Affinity of Clozapine

• Clozapine has a unique receptor affinity profile, with significant binding to multiple receptor subtypes, including:
  • Dopamine D1 and D2 receptors 3
  • Serotonin 5-HT2A receptors 4, 5, 6
  • Dopamine D4 receptors 6
• The affinity of clozapine for these receptors is thought to contribute to its efficacy in treating schizophrenia, particularly in patients who are refractory to other treatments.

Dopamine Receptor Occupancy

• Clozapine has been shown to have a moderate occupancy of dopamine D2 receptors, with a range of 16-68% occupancy 5
• In contrast, risperidone and olanzapine have been shown to have higher D2 receptor occupancy, with ranges of 63-89% and 43-89%, respectively 5, 7
• Clozapine also has a significant occupancy of dopamine D1 receptors, with a mean striatal D1 occupancy of 55% 3

Serotonin Receptor Occupancy

• Clozapine has a high affinity for serotonin 5-HT2A receptors, with near saturation of these receptors even at low doses 7
• The 5-HT2A receptor antagonism of clozapine is thought to contribute to its reduced side-effect liability and greater efficacy in treating schizophrenia 4, 6