In this Author Insights video for the Primary Care Companion, Warren Cheng, a medical student at Northeast Ohio Medical University and co-author of the article, walks through a cautionary case at the intersection of two antipsychotics. A 42-year-old man with schizoaffective disorder, already taking clozapine, was started on Cobenfy (xanomeline-trospium chloride). Before the cross-taper was complete he abruptly stopped the clozapine while continuing Cobenfy, then developed catatonia that did not fully respond to lorazepam and ultimately required ECT and resumption of clozapine before he substantially improved.
The mechanistic contrast is the crux. Cobenfy is a fundamentally different kind of antipsychotic: xanomeline is a central M1/M4 muscarinic agonist that influences dopaminergic and glutamatergic signaling without directly blocking D2 receptors, and trospium chloride is a peripherally-restricted muscarinic antagonist that blunts xanomeline’s GI and cholinergic side effects. Clozapine, by contrast, is pharmacologically complex, weakly blocking D2 while acting across serotonergic, adrenergic, GABA, glutamate, and, critically here, muscarinic systems with mixed agonist and antagonist activity. The two are not interchangeable even though they touch overlapping circuits.
Cheng’s hypothesis for why the combination may have worsened withdrawal catatonia is rebound cholinergic stimulation: chronic clozapine antagonism at certain muscarinic receptors may upregulate them over time, so abrupt discontinuation leaves them relatively overstimulated, and xanomeline’s direct muscarinic activation then adds to an already sensitized system. He is explicit that this is a hypothesis, catatonia is not fully understood, and no cases of Cobenfy-caused catatonia have been described. The practical message is about transitions: avoid abrupt clozapine discontinuation, taper deliberately, and keep catatonia top of mind as Cobenfy use, and these medication switches, become more common.
