Clozapine has a unique clinical pharmacology. Yet the usual explanations for its superiority have not stood the test of time.
It is not blockade of serotonin receptors, nor weak blockade of dopamine D2 receptors. Nor is it an action at other dopamine receptors or at noradrenaline receptors.
The real clue all along was acetylcholine.
Clozapine is sticky at muscarinic acetylcholine receptors. Some of its most common side-effects are at muscarinic receptors in the body… and are highly atypical of an antipsychotic drug. For instance, stimulation of saliva resulting in hypersalivation. Or stimulation of the bladder resulting in nocturnal enuresis.
This suggests that clozapine is not simply blocking muscarinic receptors. In some tissues, it actually appears to stimulate them.
How do we test that idea?
Well, the cleanest approach is to express cloned human muscarinic receptors in a cell line and to examine the drug-receptor interaction directly.
In such assays, clozapine does indeed stimulate muscarinic receptors. It behaves as a partial agonist, stickier for the receptor than acetylcholine itself…but weaker once it gets there.
In stark contrast other antipsychotics either block muscarinic receptors or leave them alone. Clozapine is unique in being a partial agonist at muscarinic receptors.
Confirmation
The crucial test of that hypothesis is fairly intuitive. Does a drug which stimulates muscarinic receptors, but which leaves dopamine receptors untouched, have antipsychotic properties?
This is challengining because stimulation of muscarinic receptors in the body produces major autonomic side-effects. Drugs just weren’t available until recently… But three years ago, Cobenfy solved that problem.
Cobenfy is composed of a partial muscarinic agonist called xanomeline alongside a molecule which protects muscarinic receptors in the rest of the body.
And as you might know, it works. And that changed everything. For the first time, we have a muscarinic-based antipsychotic. Or is that true?
Surely Clozapine was the first member of this class all along. Clozapine was the prototype of this new muscarinic class.
The next phase
Going forward, a major question for psychiatry is whether Xanomeline reproduces the full benefits of clozapine…. without the baggage. If it does, that is a major advance.
If it doesn’t, then perhaps the ideal treatment for psychosis is combining what we now know to be two distinct antipsychotic mechanisms.
Weak stimulation of muscarinic receptors… AND… weak blockade of dopamine D2 receptors.
Fairly easy to test. Say, Xanomeline plus low dose amisulpride (or quetiapine). Put the two together and you may have recreated clozapine. And a safe clozapine at that.
