{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T01:46:11Z","timestamp":1782438371928,"version":"3.54.5"},"reference-count":84,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Schizophrenia remains a debilitating global health challenge where pharmacologic treatment has been stagnant for over seventy years, relying almost exclusively on the blockade of dopamine receptors. While this mechanism controls positive psychosis, it frequently fails to address negative symptoms or cognitive impairment and carries a significant burden of metabolic and motor adverse effects. This review evaluates the scientific and clinical validation of xanomeline\u2013trospium (Cobenfy\u00ae; investigational name KarXT), the first approved antipsychotic with a completely non-dopaminergic mechanism of action. We synthesize data ranging from the unique structural biology of the bitopic M1\/M4 muscarinic receptor agonist xanomeline to the pharmacokinetic innovation of using the peripheral antagonist trospium chloride to mitigate systemic toxicity. Comprehensive analyses of the EMERGENT clinical trial program demonstrate that this combination significantly reduces heterogeneous schizophrenia symptoms with a safety profile distinct from current standards of care, specifically avoiding weight gain and extrapyramidal movement disorders. Furthermore, we contrast this success with the recent failures of other novel mechanisms and explore the potential for precision medicine through the identification of muscarinic receptor deficit biotypes. We conclude that M1\/M4 muscarinic receptor agonism represents an important advance toward circuit-based therapeutics that may help overcome some of the limitations inherent to dopamine-centered pharmacotherapy.<\/jats:p>","DOI":"10.3390\/ijms27135734","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:49:23Z","timestamp":1782434963000},"page":"5734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Xanomeline\u2013Trospium Validates Muscarinic Agonism as an Effective Non-Dopaminergic Treatment for Schizophrenia"],"prefix":"10.3390","volume":"27","author":[{"given":"Ghaith K.","family":"Mansour","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0024-3751","authenticated-orcid":false,"given":"Ahmad W.","family":"Hajjar","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adnan H.","family":"Hajjar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, East Carolina University Medical Center, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4129-0284","authenticated-orcid":false,"given":"Abdullah","family":"Alissa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3736-5989","authenticated-orcid":false,"given":"Hatouf H.","family":"Sukkarieh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1097\/MS9.0000000000003309","article-title":"Cobenfy (xanomeline-trospium): A breakthrough FDA-approved therapy redefining schizophrenia treatment","volume":"87","author":"Bukhari","year":"2025","journal-title":"Ann. Med. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"GBD 2019 Mental Disorders Collaborators (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry, 9, 137\u2013150.","DOI":"10.1016\/S2215-0366(21)00395-3"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/epirev\/mxn001","article-title":"Schizophrenia: A Concise Overview of Incidence, Prevalence, and Mortality","volume":"30","author":"McGrath","year":"2008","journal-title":"Epidemiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Vita, A., Barlati, S., Bellomo, A., Poli, P.F., Masi, G., Nobili, L., Serafini, G., Zuddas, A., and Vicari, S. (2022). Patterns of Care for Adolescent With Schizophrenia: A Delphi-Based Consensus Study. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.844098"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0272-7358(99)00047-1","article-title":"Why does schizophrenia develop at late adolescence?","volume":"21","author":"Harrop","year":"2001","journal-title":"Clin. Psychol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1093\/schbul\/sbr030","article-title":"Age of Onset of Schizophrenia: Perspectives from Structural Neuroimaging Studies","volume":"37","author":"Gogtay","year":"2011","journal-title":"Schizophr. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhan, Z., Wang, J., and Shen, T. (2025). Results of the Global Burden of Disease study for schizophrenia: Trends from 1990 to 2021 and projections to 2050. Front. Psychiatry, 16.","DOI":"10.3389\/fpsyt.2025.1629032"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15231","DOI":"10.1007\/s00210-025-04351-0","article-title":"A comprehensive review on schizophrenia: Epidemiology, pathogenesis, diagnosis, conventional treatments, and proposed natural compounds used for management","volume":"398","author":"Anwar","year":"2025","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Peritogiannis, V., Ninou, A., and Samakouri, M. (2022). Mortality in Schizophrenia-Spectrum Disorders: Recent Advances in Understanding and Management. Healthcare, 10.","DOI":"10.3390\/healthcare10122366"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41537-025-00667-1","article-title":"What is behind the 17-year life expectancy gap between individuals with schizophrenia and the general population?","volume":"11","author":"Popa","year":"2025","journal-title":"Schizophrenia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5377","DOI":"10.4088\/JCP.22m14458","article-title":"The Economic Burden of Schizophrenia in the United States","volume":"83","author":"Kadakia","year":"2022","journal-title":"J. Clin. Psychiatry"},{"key":"ref_12","first-page":"624","article-title":"KarXT for schizophrenia\u2013effectiveness and value: A summary from the Institute for Clinical and Economic Review\u2019s New England Comparative Effectiveness Public Advisory Council","volume":"30","author":"McKenna","year":"2024","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Brisch, R., Saniotis, A., Wolf, R., Bielau, H., Bernstein, H.-G., Steiner, J., Bogerts, B., Braun, A.K., Jankowski, Z.P., and Ekumaratilake, J. (2014). The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue. Front. Psychiatry, 5, Erratum in Front. Psychiatry\u00a02014, 5, 110. https:\/\/doi.org\/10.3389\/fpsyt.2014.00110.","DOI":"10.3389\/fpsyt.2014.00110"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"355","DOI":"10.5498\/wjp.v11.i7.355","article-title":"History of the dopamine hypothesis of antipsychotic action","volume":"11","author":"Seeman","year":"2021","journal-title":"World J. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yang, A., and Tsai, S.-J. (2017). New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081689"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1017\/S1092852924002244","article-title":"How antipsychotics work in schizophrenia: A primer on mechanisms","volume":"30","author":"Meyer","year":"2025","journal-title":"CNS Spectr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"107727","DOI":"10.1016\/j.phrs.2025.107727","article-title":"IUPHAR review: Moving beyond dopamine-based therapeutic strategies for schizophrenia","volume":"216","author":"Moran","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"de Bartolomeis, A., Ciccarelli, M., De Simone, G., Mazza, B., Barone, A., and Vellucci, L. (2023). Canonical and Non-Canonical Antipsychotics\u2019 Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065945"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/wps.20693","article-title":"Dopamine and glutamate in schizophrenia: Biology, symptoms and treatment","volume":"19","author":"McCutcheon","year":"2020","journal-title":"World Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1007\/s00277-020-04215-y","article-title":"Clozapine-induced agranulocytosis","volume":"99","author":"Mijovic","year":"2020","journal-title":"Ann. Hematol."},{"key":"ref_21","first-page":"117","article-title":"Treatment-resistant schizophrenia: Current insights on the pharmacogenomics of antipsychotics","volume":"9","author":"Lally","year":"2016","journal-title":"Pharmgenom. Pers. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7932","DOI":"10.1021\/acs.jmedchem.5c00678","article-title":"The Prosperity and Adversity of M 4 Muscarinic Acetylcholine Receptor Activators in the Treatment of Neuropsychiatric Disorders","volume":"68","author":"Liu","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yuen, J.W.Y., Kim, D.D., Procyshyn, R.M., Panenka, W.J., Honer, W.G., and Barr, A.M. (2021). A Focused Review of the Metabolic Side-Effects of Clozapine. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.609240"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Pavlov, V.A. (2025). Novel opportunities for treating complex neuropsychiatric and neurocognitive conditions based on recent developments with xanomeline. Front. Psychiatry, 16.","DOI":"10.3389\/fpsyt.2025.1593341"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1177\/02698811241309620","article-title":"Haloperidol dopamine receptor occupancy and antagonism correspond to delirium agitation scores and EPS risk: A PBPK-PD modeling analysis","volume":"39","author":"Burkat","year":"2025","journal-title":"J. Psychopharmacol."},{"key":"ref_26","unstructured":"D\u2019Souza, R.S., Aslam, S.P., and Hooten, W.M. (2026). Extrapyramidal Side Effects. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1038\/s41380-023-02203-y","article-title":"Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: A systematic review and dose-response meta-analysis","volume":"28","author":"Siafis","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/S0006-3223(01)01211-2","article-title":"The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs","volume":"50","author":"Binder","year":"2001","journal-title":"Biol. Psychiatry"},{"key":"ref_29","first-page":"e23959","article-title":"Neurobiology of Schizophrenia: A Comprehensive Review","volume":"14","author":"Luvsannyam","year":"2022","journal-title":"Cureus"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1038\/s41380-024-02422-x","article-title":"Human iN neuronal model of schizophrenia displays dysregulation of chromogranin B and related neuropeptide transmitter signatures","volume":"29","author":"Podvin","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dean, B., Bakker, G., Ueda, H.R., Tobin, A.B., Brown, A., and Kanaan, R.A.A. (2023). A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1124333"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1113\/jphysiol.2014.275453","article-title":"Direct excitation of parvalbumin-positive interneurons by M 1 muscarinic acetylcholine receptors: Roles in cellular excitability, inhibitory transmission and cognition","volume":"592","author":"Yi","year":"2014","journal-title":"J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5440","DOI":"10.1038\/s41467-023-41199-5","article-title":"Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR","volume":"14","author":"Burger","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1124\/jpet.105.090134","article-title":"Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M5 Receptor","volume":"315","author":"Grant","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.euroneuro.2024.02.010","article-title":"Parvalbumin interneuron deficits in schizophrenia","volume":"82","year":"2024","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/S2215-0366(25)00296-2","article-title":"Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): Results from three phase 3 randomised controlled trials","volume":"12","author":"Keefe","year":"2025","journal-title":"Lancet Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0022-3565(25)38667-2","article-title":"Xanomeline: A novel muscarinic receptor agonist with functional selectivity for M1 receptors","volume":"269","author":"Shannon","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"pyaf015","DOI":"10.1093\/ijnp\/pyaf015","article-title":"From theory to therapy: Unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1\/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials","volume":"28","author":"Meyer","year":"2025","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_39","unstructured":"FDA (2026, May 20). Highlights of Prescribing Information 2024, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/216158s000lbl.pdf."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1007\/s11934-003-0023-1","article-title":"Trospium chloride: A quaternary amine with unique pharmacologic properties","volume":"4","author":"Pak","year":"2003","journal-title":"Curr. Urol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"701","DOI":"10.2165\/00003088-200544070-00003","article-title":"Clinical Pharmacokinetics of Trospium Chloride","volume":"44","author":"Doroshyenko","year":"2005","journal-title":"Clin. Pharmacokinet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4161","DOI":"10.1007\/s12325-025-03275-8","article-title":"Trospium Chloride in the Treatment of Overactive Bladder Syndrome and Detrusor Overactivity","volume":"42","author":"Truzzi","year":"2025","journal-title":"Adv. Ther."},{"key":"ref_43","first-page":"166","article-title":"Analytical Method Development & Validation Protocol for Trospium Chloride in Tablet Dosage Form","volume":"1","author":"Bendale","year":"2011","journal-title":"Indo Glob. J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4712","DOI":"10.1039\/C5CE00744E","article-title":"Systematic solvate screening of trospium chloride: Discovering hydrates of a long-established pharmaceutical","volume":"17","author":"Eigner","year":"2015","journal-title":"CrystEngComm"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s40261-024-01377-9","article-title":"Current Findings and Potential Mechanisms of KarXT (Xanomeline\u2013Trospium) in Schizophrenia Treatment","volume":"44","author":"Azargoonjahromi","year":"2024","journal-title":"Clin. Drug Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1755-5949.2011.00248.x","article-title":"Anticholinergics for Overactive Bladder Therapy: Central Nervous System Effects","volume":"18","author":"Chancellor","year":"2012","journal-title":"CNS Neurosci. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/S0140-6736(23)02190-6","article-title":"Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline\u2013trospium) in schizophrenia (EMERGENT-2) in the USA: Results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial","volume":"403","author":"Kaul","year":"2024","journal-title":"Lancet"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9652","DOI":"10.1038\/s41598-024-60259-4","article-title":"Agonist-selective activation of individual G-proteins by muscarinic receptors","volume":"14","author":"Nelic","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mao, L.-M., Young, L., Chu, X.-P., and Wang, J.Q. (2024). Regulation of Src family kinases by muscarinic acetylcholine receptors in heterologous cells and neurons. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1340725"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5083","DOI":"10.1038\/s41598-017-05384-z","article-title":"All muscarinic acetylcholine receptors (M1\u2013M5) are expressed in murine brain microvascular endothelium","volume":"7","author":"Radu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","unstructured":"Kudlak, M., and Tadi, P. (2026). Physiology, Muscarinic Receptor. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"16070","DOI":"10.1074\/jbc.270.27.16070","article-title":"Differential Coupling of m2 and m4 Muscarinic Receptors to Inhibition of Adenylyl Cyclase by Gi\u03b1 and Go\u03b1 Subunits","volume":"270","author":"Migeon","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1124\/mol.106.023762","article-title":"Differences in Kinetics of Xanomeline Binding and Selectivity of Activation of G Proteins at M1 and M2 Muscarinic Acetylcholine Receptors","volume":"70","author":"Dolezal","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.tins.2011.10.004","article-title":"Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia","volume":"35","author":"Lewis","year":"2012","journal-title":"Trends Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Klawonn, A.M., Wilhelms, D.B., Lindstr\u00f6m, S.H., Singh, A.K., Jaarola, M., Wess, J., Fritz, M., and Engblom, D. (2018). Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00139"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1523\/JNEUROSCI.5620-09.2010","article-title":"Striatal Muscarinic Receptors Promote Activity Dependence of Dopamine Transmission via Distinct Receptor Subtypes on Cholinergic Interneurons in Ventral versus Dorsal Striatum","volume":"30","author":"Threlfell","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_57","first-page":"43","article-title":"Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia\u2014A Brief Review of Current Data","volume":"19","author":"Singh","year":"2022","journal-title":"Innov. Clin. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1177\/10600280251324642","article-title":"Xanomeline-Trospium: A Novel Therapeutic for the Treatment of Schizophrenia","volume":"59","author":"Ramey","year":"2025","journal-title":"Ann. Pharmacother."},{"key":"ref_59","unstructured":"FDA (2026, May 20). Review of Section 10 OVERDOSAGE Labeling Language for Xanomeline and Trospium Chloride 2024, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2024\/216158Orig1s000OtherR.pdf."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1001\/jamapsychiatry.2024.0785","article-title":"Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia","volume":"81","author":"Kaul","year":"2024","journal-title":"JAMA Psychiatry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41537-024-00525-6","article-title":"Efficacy of xanomeline and trospium chloride in schizophrenia: Pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials","volume":"10","author":"Kaul","year":"2024","journal-title":"Schizophrenia"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"24m15668","DOI":"10.4088\/JCP.24m15668","article-title":"Xanomeline and Trospium Chloride for the Treatment of Agitation Associated With Schizophrenia","volume":"86","author":"Yeung","year":"2025","journal-title":"J. Clin. Psychiatry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"24m15497","DOI":"10.4088\/JCP.24m15497","article-title":"Safety and Tolerability of Xanomeline and Trospium Chloride in Schizophrenia","volume":"86","author":"Kaul","year":"2025","journal-title":"J. Clin. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"sgag002","DOI":"10.1093\/schizbullopen\/sgag002","article-title":"A Qualitative Investigation of the Experience of Taking Xanomeline and Trospium Chloride for Schizophrenia, Part 1: Perceived Impact on Symptoms","volume":"7","author":"Horan","year":"2026","journal-title":"Schizophr. Bull. Open"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"20451253221097260","DOI":"10.1177\/20451253221097261","article-title":"Effects of antipsychotics on heart rate in treatment of schizophrenia: A systematic review and meta-analysis","volume":"12","author":"Huhn","year":"2022","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1016\/S0140-6736(22)01990-0","article-title":"Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: A two-part, randomised, double-blind, placebo-controlled, phase 1b trial","volume":"400","author":"Krystal","year":"2022","journal-title":"Lancet"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.neuropharm.2017.09.012","article-title":"Positive allosteric modulation of M 1 and M 4 muscarinic receptors as potential therapeutic treatments for schizophrenia","volume":"136","author":"Yohn","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Yohn, S.E., Harvey, P.D., Brannan, S.K., and Horan, W.P. (2024). The potential of muscarinic M1 and M4 receptor activators for the treatment of cognitive impairment associated with schizophrenia. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1421554"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Rutigliano, G., Accorroni, A., and Zucchi, R. (2018). The Case for TAAR1 as a Modulator of Central Nervous System Function. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00987"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1021\/acsmedchemlett.1c00527","article-title":"Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia","volume":"13","author":"Heffernan","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1007\/s00406-023-01580-3","article-title":"Ulotaront: Review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia","volume":"273","author":"Achtyes","year":"2023","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"pyaf059","DOI":"10.1093\/ijnp\/pyaf059","article-title":"Trajectory of efficacy and safety across ulotaront dose levels in schizophrenia: A systematic review and dose\u2013response meta-analysis","volume":"28","author":"Hsu","year":"2025","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1007\/s00406-023-01576-z","article-title":"Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia","volume":"273","author":"Rosenbrock","year":"2023","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41537-025-00565-6","article-title":"Identifying neurobiological heterogeneity in clinical high-risk psychosis: A data-driven biotyping approach using resting-state functional connectivity","volume":"11","author":"Tang","year":"2025","journal-title":"Schizophrenia"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/mp.2008.28","article-title":"Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia","volume":"14","author":"Scarr","year":"2009","journal-title":"Mol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/mp.2016.195","article-title":"Changed gene expression in subjects with schizophrenia and low cortical muscarinic M1 receptors predicts disrupted upstream pathways interacting with that receptor","volume":"23","author":"Scarr","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Stuke, H. (2023). Markers of muscarinic deficit for individualized treatment in schizophrenia. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.1100030"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e00839","DOI":"10.1016\/j.neurot.2026.e00839","article-title":"Targeting muscarinic receptors for treating schizophrenia","volume":"23","author":"Paul","year":"2026","journal-title":"Neurotherapeutics"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"114910","DOI":"10.1016\/j.intimp.2025.114910","article-title":"Targeting Neuroinflammation in Schizophrenia: A comprehensive review of mechanisms and pharmacological interventions","volume":"159","author":"Huang","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Corsi-Zuelli, F.M.d.G., Brognara, F., Quirino, G.F.d.S., Hiroki, C.H., Fais, R.S., Del-Ben, C.M., Ulloa, L., Salgado, H.C., Kanashiro, A., and Loureiro, C.M. (2017). Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Activation of the Alpha-7 Nicotinic Acetylcholine Receptor. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00618"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bbi.2014.07.010","article-title":"Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation","volume":"44","author":"Dancho","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_82","first-page":"629","article-title":"Xanomeline-Trospium in schizophrenia: A detailed review and comparison with the Institute for Clinical and Economic Review\u2019s analysis","volume":"30","author":"Sutera","year":"2024","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_83","first-page":"458","article-title":"Budget impact of xanomeline and trospium chloride for the treatment of adults with schizophrenia in the United States","volume":"32","author":"Bjerke","year":"2026","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.schres.2025.12.015","article-title":"Long-term efficacy, safety, and tolerability of xanomeline and trospium chloride in schizophrenia: A 52-week, open-label trial (EMERGENT-5)","volume":"288","author":"Kaul","year":"2026","journal-title":"Schizophr. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5734\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:54:25Z","timestamp":1782435265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":84,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135734"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135734","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}