Two new drugs with novel mechanisms finally break the '5-HT2, D2, me too' mold.
However, while clozapine itself is also strongly anticholinergic, one of its major metabolites is an M1 muscarinic agonist, so it’s possible that clozapine’s superior efficacy could be related to cholinergic stimulation.
More recently, xanomeline has been combined with trospium, a peripheral muscarinic antagonist with minimal activity in the brain, to minimize those cholinergic side effects. A Phase 2 placebo-controlled trial of xanomeline-trospium demonstrated significant positive and negative symptom reduction compared to placebo in schizophrenia.
Years ago, when I was doing clinical research, I witnessed one patient in a clinical trial for a new antipsychotic medication who had never done well on previous medications improve significantly. Unfortunately for him, the study medication was never approved because the overall study results were negative.
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