Clozapine has long been the most effective antipsychotic for people whose symptoms do not respond to standard treatments, yet no one has been able to fully explain why. For years, psychiatry has assumed that antipsychotic drugs work mainly by blocking dopamine or serotonin receptors, even though clozapine does not fit comfortably into either explanation. In a recent article, we suggest that the answer may have been hiding in plain sight: clozapine behaves very differently from other antipsychotics in the body’s cholinergic (acetylcholine) system, a difference that turns out to be central rather than incidental (Morrison et al 2025).
This matters because it helps make sense of both clozapine’s unmatched effectiveness and the recent success of a new generation of drugs that do not rely on dopamine blockade. These muscarinic-acting treatments appear to follow the same principle clozapine hinted at decades ago, but with better tolerability. If this approach continues to hold up, it could change how we understand psychosis and mark the beginning of a genuinely new era in antipsychotic treatment (Morrison et al 2025).

