{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:33:44Z","timestamp":1790202824775,"version":"4.1.0"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T00:00:00Z","timestamp":1681084800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T00:00:00Z","timestamp":1681084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Karuna Therapeutics"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Psychopharmacology"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>\n                      The M\n                      <jats:sub>1<\/jats:sub>\n                      \/M\n                      <jats:sub>4<\/jats:sub>\n                      preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer\u2019s disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200933) versus KarXT (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200935). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by\u2009\u2265\u200929%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The\u00a0VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect xanomeline\u2019s PK profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00213-023-06362-2","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T01:02:45Z","timestamp":1681088565000},"page":"1191-1198","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Evidence of trospium\u2019s ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results"],"prefix":"10.1007","volume":"240","author":[{"given":"Alan","family":"Breier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen K.","family":"Brannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-320X","authenticated-orcid":false,"given":"Andrew C.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,10]]},"reference":[{"key":"6362_CR1","unstructured":"Allergan, Inc (2012) Sanctura (trospium chloride). 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Drs. Brannan, Paul, and Miller are employees of and hold equity in Karuna Therapeutics. Dr. Breier is a consultant to Karuna.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}