{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:12:05Z","timestamp":1789996325834,"version":"4.0.1"},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Xanomeline\u2010trospium chloride (Cobenfy, formerly KarXT) is a first\u2010in\u2010class, oral central M1\/M4 muscarinic receptor agonist approved for the treatment of schizophrenia in adults. Cobenfy represents a paradigm shift by avoiding direct dopamine D2 receptor blockade and thus significantly reduces the burden of metabolic, extrapyramidal, and sedative side effects observed in standard first and second\u2010generation antipsychotics. Trospium chloride is a peripheral muscarinic antagonist with negligible blood\u2013brain barrier penetration. Cobenfy is co\u2010formulated with trospium to minimize peripheral cholinergic effects caused by xanomeline. Under fasting conditions, xanomeline and trospium reach peak plasma concentrations (\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) in 2 and 1\u2009h, and maximum concentrations (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) of 1955 and 5787\u2009pg\/mL, respectively. While food intake does not change xanomeline pharmacokinetics, it reduces trospium\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    by around 70%. Xanomeline has a high volume of distribution (10,800\u2009L) and is metabolized by several cytochrome P450 (CYP) enzymes. Trospium is a P\u2010glycoprotein (P\u2010gp) substrate and is 85% eliminated in feces. In phase III clinical trials (EMERGENT\u20102, EMERGENT\u20103), Cobenfy significantly reduced PANSS total scores (least squares mean difference \u22129.6 and \u22128.4, respectively;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) compared to placebo. Treatment\u2010emergent adverse events were primarily mild to moderate in severity and were mainly transient nausea (19%), constipation (17%), dyspepsia (15%), and vomiting (14%). Discontinuation rates due to adverse events were low (6.2% vs. 5.2% for placebo), and Cobenfy was not associated with weight gain, extrapyramidal symptoms, or cardiometabolic risks seen in conventional antipsychotics.\n                  <\/jats:p>","DOI":"10.1111\/cts.70725","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:41:02Z","timestamp":1789202462000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Xanomeline and Trospium Chloride: Mechanism of Action, Clinical, and Translational Science"],"prefix":"10.1111","volume":"19","author":[{"given":"Samantha","family":"Avila","sequence":"first","affiliation":[{"name":"Department of Psychiatry Kaiser Permanente Oakland Medical Center  Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2950-5069","authenticated-orcid":false,"given":"Ingrid L.","family":"Chen","sequence":"additional","affiliation":[{"name":"The Permanente Medical Group  Oakland Northern California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"e_1_2_13_2_1","volume-title":"VA\/DoD Clinical Practice Guideline for the Management of First\u2010Episode Psychosis and Schizophrenia","author":"Management of First\u2010Episode Psychosis and Schizophrenia Work Group","year":"2023"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214\u2010109X(15)00069\u20108"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/wps.20994"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.20240738"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2024.0785"},{"key":"e_1_2_13_7_1","volume-title":"Multi\u2010Discipline Review: Cobenfy (Xanomeline and Trospium Chloride), Application No. 216158Orig1s000","author":"US Food and Drug Administration","year":"2024"},{"key":"e_1_2_13_8_1","volume-title":"Clinical Pharmacology and Biopharmaceutics Review(s): Sanctura (Trospium Chloride), Application No. 21\u2010595 (Part 1)","author":"US Food and Drug Administration","year":"2004"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0006\u20103223(00)00918\u20105"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010025\u201003023\u2010y"},{"key":"e_1_2_13_11_1","unstructured":"DailyMed\u2014COBENFY\u2014Xanomeline and Trospium Chloride Capsule Coated Pellets COBENFY\u2014Xanomeline and Trospium Chloride Kit accessed February 1 2026 https:\/\/dailymed.nlm.nih.gov\/dailymed\/drugInfo.cfm?setid=8f0e73bf\u20106025\u201044f6\u2010ab64\u20100983322de0df."},{"key":"e_1_2_13_12_1","volume-title":"StatPearls","author":"Kudlak M.","year":"2025"},{"key":"e_1_2_13_13_1","volume-title":"A Phase 3 Multicenter, Randomized, Double\u2010Blind, Placebo\u2010Controlled Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Schizophrenia in Adolescents (13 to 17\u2009Years of Age)","author":"Bristol\u2010Myers Squibb","year":"2026"},{"key":"e_1_2_13_14_1","volume-title":"An Open\u2010Label Study to Evaluate the Efficacy and Tolerability of Xanomeline\/Trospium in First Episode\/Early Phase Schizophrenia Patients","author":"Vanguard Research Group","year":"2025"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0163\u20107258(03)00032\u20109"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2025.12.015"},{"key":"e_1_2_13_17_1","volume-title":"Safety and Tolerability of Xanomeline and Trospium Chloride in Schizophrenia: Pooled Results From the 5\u2010Week, Randomized, Double\u2010Blind, Placebo\u2010Controlled EMERGENT Trials","author":"Marcus I. K. A. C.","year":"2025"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(25)02365\u20107"},{"key":"e_1_2_13_19_1","volume-title":"An Open\u2010Label, Phase 1, Single Ascending Dose\u2010Finding Study to Characterize the Safety, Tolerability, and Pharmacokinetics of a Long Acting Injectable KarXT Formulation in Participants With Schizophrenia","author":"Bristol\u2010Myers Squibb","year":"2025"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(22)01990\u20100"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201041199\u20105"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2026.06.002"},{"key":"e_1_2_13_23_1","volume-title":"A Phase 3, Randomized, Double\u2010Blind, Placebo\u2010Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT + KarX\u2010EC for the Treatment of Agitation Associated With Alzheimer's Disease","author":"Bristol\u2010Myers Squibb","year":"2026"},{"key":"e_1_2_13_24_1","volume-title":"A Phase 3, Randomized, Double\u2010Blind, Placebo\u2010Controlled Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar\u2010I Disorder (BALSAM\u20102)","author":"Bristol\u2010Myers Squibb","year":"2026"},{"key":"e_1_2_13_25_1","volume-title":"A Phase 3, Randomized, Double\u2010Blind, Placebo\u2010Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT + KarX\u2010EC for the Treatment of Agitation Associated With Alzheimer's Disease","author":"Bristol\u2010Myers Squibb","year":"2026"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70725","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70725","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70725","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:44:31Z","timestamp":1789994671000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":24,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/cts.70725"],"URL":"https:\/\/doi.org\/10.1111\/cts.70725","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-05-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70725"}}