{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:42:17Z","timestamp":1791380537636,"version":"4.3.3"},"reference-count":16,"publisher":"MedWorks Media","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Psychopharmacol Bull"],"abstract":"<jats:p>In an article published on April 8, 2025 titled \u201cA Case of Clozapine Induced Mania-Like Symptoms in the Treatment of Schizophrenia\u201d,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, D\u00fc\u015f\u00fcnen 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\u20136 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.<\/jats:p>","DOI":"10.64719\/pb.4539","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T11:23:34Z","timestamp":1761045814000},"page":"130-132","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Potential Psychopharmacological Mechanisms Behind the Manicogenic Properties of Clozapine"],"prefix":"10.64719","volume":"55","author":[{"given":"Samuel","family":"Cholette-T\u00e9trault","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrshad","family":"Bakhshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54175","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Sze AH, Pola AS, Smith AG, Vora J, Greenage MP. A case of clozapine induced mania-like symptoms in the treatment of schizophrenia. Psychopharmacol Bull. 2025;55(3):56\u201359.","DOI":"10.64719\/pb.4535"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Millard HY, Wilson BA, Noordsy DL. Low-dose quetiapine induced or worsened mania in the context of possible undertreatment. J Am Board Fam Med. 2015;28(1):154\u2013158. doi: 10.3122\/jabfm.2015.01.140105.","DOI":"10.3122\/jabfm.2015.01.140105"},{"key":"ref3","unstructured":"Yatham LN, Goldstein JM, Vieta E et al. Atypical antipsychotics in bipolar depression: potential mechanisms of action. J Clin Psychiatry. 2005;66(Suppl 5):40\u201348."},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Ashok AH, Marques TR, Jauhar S et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22(5):666\u2013679. doi: 10.1038\/mp.2017.16.","DOI":"10.1038\/mp.2017.16"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Burstein ES, Ma J, Wong S et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2\/D3 partial agonist. J Pharmacol Exp Ther. 2005;315(3):1278\u20131287. doi: 10.1124\/jpet.105.092155.","DOI":"10.1124\/jpet.105.092155"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Maggio R, Novi F, Rossi M, Corsini GU, Millan MJ. Partial agonist actions at dopamine D2L receptors are modified by co-transfection of D3 receptors: potential role of heterodimer formation. Parkinsonism Relat Disord. 2008;14(Suppl 2):S139\u2013S144. doi: 10.1016\/j.parkreldis.2008.04.018.","DOI":"10.1016\/j.parkreldis.2008.04.018"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Becker G, Bolbos R, Costes N, Redout\u00e9 J, Newman-Tancredi A, Zimmer L. Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study. Sci Rep. 2016;6:26633. doi: 10.1038\/srep26633.","DOI":"10.1038\/srep26633"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Cotovio G, Oliveira-Maia AJ. Functional neuroanatomy of mania. Transl Psychiatry. 2022;12(1):29. doi: 10.1038\/s41398-022-01786-4.","DOI":"10.1038\/s41398-022-01786-4"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Brooks JO, Hoblyn JC, Ketter TA. Metabolic evidence of corticolimbic dysregulation in bipolar mania. 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N-desmethylclozapine (NDMC) is an antagonist at the human native muscarinic M(1) receptor. Neuropharmacology. 2010;58(8):1206\u20131214. doi: 10.1016\/j.neuropharm.2010.02.017.","DOI":"10.1016\/j.neuropharm.2010.02.017"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Mao LM, Wang HH, Wang JQ. Antagonism of muscarinic acetylcholine receptors alters synaptic ERK phosphorylation in the rat forebrain. Neurochem Res. 2017;42(4):1202\u20131210. doi: 10.1007\/s11064-016-2157-9.","DOI":"10.1007\/s11064-016-2157-9"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Olianas MC, Dedoni S, Onali P. Coincidence signaling of dopamine D1-like and M1 muscarinic receptors in the regulation of cyclic AMP formation and CREB phosphorylation in mouse prefrontal cortex. Neurosignals. 2013;21(1\u20132):61\u201374. doi: 10.1159\/000335208.","DOI":"10.1159\/000335208"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"St\u0119pnicki P, Kondej M, Kaczor AA. 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