The unique efficacy of clozapine is attributable to muscarinic receptor agonism

Clozapine is superior to all other antipsychotic drugs for treatment-resistant schizophrenia, but the molecular underpinnings for this have remained elusive for decades. Recently, we proposed a cholinergic mechanism, based on the distinct pharmacology of clozapine in the parasympathetic branch of the autonomic nervous system, a hypothesis strengthened by the translation of a new cholinergic-based antipsychotic drug into clinical practice. A recent article has challenged the cholinergic hypothesis and instead proposed a mechanism involving the action of clozapine at noradrenaline receptors of the α₂ class. We consider that this hypothesis is implausible for two reasons. Firstly, numerous antipsychotics that are inferior to clozapine act at α₂ noradrenergic receptors, in an identical manner to clozapine. Moreover, there is no evidence that α₂ noradrenergic antagonists have any antipsychotic effects in the clinic. A clear difference between clozapine and the other, less efficacious antipsychotics is its ability to behave as an agonist at acetylcholine receptors of the muscarinic class. In the striatum, acetylcholine and dopamine are vital signals for salience and neuroplasticity. Dopamine (D₂) antagonism and acetylcholine (muscarinic M₁/M₄) agonism carry an antipsychotic signature. Clozapine may have the ideal properties of low-potency dopamine D₂ binding, allied with partial agonism at muscarinic M₁ and M₄ receptors.