Abstract
In an article published on April 8, 2025 titled “A Case of Clozapine Induced Mania-Like Symptoms in the Treatment of Schizophrenia”,1 we recognized a clinical scenario similar to one we encountered in a 23-year-old African American male with no history of mania or hypomania who also appeared to have suffered mania-like symptoms from Clozapine initiation. At the time, Düşünen Adam was the only scientific journal presenting a case report and offering a possible mechanistic explanation via 5-HT2C, D4, and D1 receptor activation. It appears that the new publication in your journal agrees with their proposition as a probable explanation. In this present letter, we aim to propose further mechanisms to explain the suspected manicogenic properties of Clozapine. In addition to the mechanisms described in the published paper, we further hypothesize that, as shown with other atypical antipsychotics, selective blockade of 5-HT2A increasing dopamine in the mesolimbic pathway as well as the partial agonism of D2 and D3 by Norclozapine might contribute to the manic shift.2–6 Review of the literature and the mechanism of action of Clozapine and Norclozapine demonstrate action on many other targets in the brain, notably 5-HT1A agonism and muscarinic M1 antagonism.
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