Abstract
We report the case of an 83-year-old male with Parkinsonism and severe psychosis characterized by persistent daytime and nighttime hallucinations associated with marked fear and distress. His psychosis failed to respond to therapeutic trials of quetiapine, brexpiprazole, and pimavanserin. He was referred specifically for a trial of clozapine therapy, which the patient and caregiver declined due to its risk profile. Treatment with xanomeline-trospium was initiated at 50/20 mg twice daily and resulted in substantial improvement, including resolution of nighttime hallucinations within two weeks. He further achieved a near complete resolution of psychotic symptoms within three weeks of a dose escalation to 100/20 mg twice daily. To our knowledge, this is the first published case of Parkinson's disease psychosis successfully treated with xanomeline-trospium, a novel M1/M4 muscarinic receptor agonist-based therapy. The patient's psychosis proved refractory to three pharmacologically distinct therapies-quetiapine, a low-affinity, rapidly dissociating dopamine D2 receptor antagonist; brexpiprazole, a dopamine D2 partial agonist; and pimavanserin, a selective 5-HT2A receptor inverse agonist-before improving with xanomeline-trospium, whose antipsychotic effects are mediated through central M1/M4 muscarinic receptor agonism. This case supports the further investigation of muscarinic receptor agonism as a therapeutic strategy for Parkinson's disease psychosis.