How does clozapine work and how is it different from other medications?

Clozapine is a second generation (atypical) antipsychotic (SGA) medication, yet its mechanism of action is different from the other SGAs. Although clozapine does have some binding affinity for dopamine (D2 receptor antagonist), its affinity for many other receptors is quite higher. This includes mainly histamine (H1), alpha-adrenergic (Alpha-1A, 1B), serotonin (5HT2A, 5HT2B, 5HT7, 5HT2C, 5HT1A), and cholinergic muscarinic (M1). This profile with a ​low D2 affinity (and blocking of 5HT2A receptors) makes clozapine the least likely SGA to cause extrapyramidal symptoms (EPS), actually with no evidence that clozapine does case any EPS.


Saklad, S.R. (2017). Graphic representation of pharmacology: Development of an alternative model. Mental Health Clinician, 7, 201-206. DOI: 10.9740/mhc.2017.09.201

Stahl, S. M. (2017). The prescriber’s guide: Stahl’s essential psychopharmacology (6th ed.). New York: Cambridge University Press.

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