What is the mechanism of action of clozapine?

Mechanism of Action of Clozapine

Clozapine's therapeutic efficacy is mediated through antagonism of dopamine D2 and serotonin 5-HT2A receptors, though its exact mechanism remains incompletely understood. 1

Primary Receptor Targets

The FDA states that clozapine's antipsychotic effects are proposed to occur through combined D2 and 5-HT2A receptor antagonism, distinguishing it from typical antipsychotics. 1 This dual mechanism is critical to understanding why clozapine works differently than conventional agents.

• Clozapine exhibits weak D2 receptor antagonism (Ki 160 nM), which is notably weaker than typical antipsychotics and explains its low propensity for extrapyramidal symptoms. 1
• The drug demonstrates potent 5-HT2A receptor antagonism (Ki 5.4 nM), with this high 5-HT2/D2 receptor affinity ratio being the hallmark that distinguishes atypical from typical antipsychotics. 1, 2
• According to the American Academy of Child and Adolescent Psychiatry, this unique receptor binding profile—weak D2 antagonism combined with potent 5-HT2 inhibition—likely accounts for clozapine's efficacy against both positive and negative symptoms of schizophrenia. 2

Broad Multi-Receptor Profile

Clozapine acts on numerous neurotransmitter systems beyond dopamine and serotonin, which contributes to both its therapeutic effects and side effect profile. 1

The FDA documents clozapine's binding affinity hierarchy (from strongest to weakest):

• Histamine H1 (Ki 1.1 nM) - strongest binding
• 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)
• Additional weaker binding to α2A, 5-HT3, 5-HT1A, D2, D1, D5, and D3 receptors 1

Clinical Implications of Mechanism

• The weak D2 antagonism explains why clozapine causes little or no prolactin elevation, unlike typical antipsychotics that strongly block D2 receptors in the tuberoinfundibular pathway. 1
• The American Academy of Child and Adolescent Psychiatry notes that this receptor profile produces fewer extrapyramidal symptoms compared to typical antipsychotics. 2
• The drug's ability to treat both positive and negative symptoms likely relates to its balanced effects on multiple neurotransmitter systems rather than selective D2 blockade alone. 2

Metabolic and Cardiometabolic Effects

• Clozapine's actions on histaminergic, serotonergic, and other receptor systems contribute to its poor cardiometabolic profile, including significant effects on weight, glucose metabolism, and lipids. 2
• The potent H1 antagonism (Ki 1.1 nM) is particularly relevant to weight gain and metabolic disturbances. 1

Neurophysiological Effects

• EEG studies demonstrate that clozapine increases delta and theta activity, slows dominant alpha frequencies, and may produce sharp wave activity and spike-wave complexes. 1
• The drug increases REM sleep to 85% of total sleep time, with REM onset occurring almost immediately after falling asleep, and patients report intensified dream activity. 1