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ABSTRACT
Introduction
We systematically reviewed extant studies evaluating the efficacy and tolerability of xanomeline and xanomeline-trospium (KarXT) for treatment of adults with schizophrenia.
Methods
In accordance with PRISMA guidelines, articles were systematically searched for in databases and clinical trial registries.
Results
A total of 4 preclinical trials and 3 randomized controlled trials (RCTs) were included in this review. A 4-week RCT observed a difference of 24.0 points (SD 21.0) in the Positive and Negative Syndrome Scale (PANSS) total score between xanomeline and placebo groups (p = 0.039). A 5-week RCT observed PANSS total score changes from baseline to week 5, including −17.4 and −5.9 points in KarXT and placebo groups, respectively (LSMD −11.6 points; 95% CI −16.1 to −7.1; p < 0.001; d = 0.75). Another 5-week RCT observed PANSS total score changes from baseline to week 5, including −21.2 (SE 1.7) and −11.6 (SE 1.6) points in KarXT and placebo groups, respectively (LSMD −9.6; 95% CI −13.9 to −5.2; p < 0.0001; d = 0.61). Side effects include constipation, nausea, vomiting, dyspepsia, and dry mouth.
Conclusion
KarXT offers an innovative non-D2 blocking approach, representing a promising treatment avenue for schizophrenia.
Article highlights
Existing pharmacological treatments are insufficiently effective in most persons with schizophrenia, especially in the treatment of negative and cognitive symptoms; in addition, existing antipsychotics have many tolerability limitations.
Statistically significant and clinically meaningful results from clinical studies reveal that xanomeline and xanomeline-trospium are promising, innovative treatments for all dimensions of schizophrenia.
Xanomeline and xanomeline-trospium differ from conventional pharmacotherapies in that these treatments utilize a presynaptic approach in modulating dopamine transmission.
Declaration of interest
R McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, Atai Life Sciences. R McIntyre is a CEO of Braxia Scientific Corporation.
T G Rhee was supported in part by the National Institute on Aging (NIA) (#R21AG070666 and #R21AG078972), National Institute of Mental Health (#R21MH117438), and National Institute on Drug Abuse (#R21DA057540) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut in the past 3 years. T G Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. T G Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. T G Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). T G Rhee is currently a co-editor-in-chief of Mental Health Science and is pending to receive honorarium payments annually from the publisher, John Wiley & Sons, Inc.
R Ho receives funding from National University of Singapore iHeathtech Other Operating Expenses (A-0001415-09-00).
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Author contributions
A Leber, F Ceban, and R S McIntyre conceptualized and designed the study. A Leber and R Ramachandra performed study search and selection. A Leber and R Ramachandra performed data extraction. A Leber and R Ramachandra performed data synthesis. A Leber and R Ramachandra performed data analyses and drafted the manuscript. All authors revised and approved the final version of the manuscript.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they were on the scientific ad board for Karuna in 2021. They have also conducted studies for Cerevel and Neurocrine. Another reviewer on this manuscript has disclosed their involvement in psychopharmacology research can be viewed as a potential conflict of interest: they have received consulting fees from Gedeon Richter and Janssen/Janssen-Cilag; speaker’s honoraria from Gedeon Richter, Hikma Pharmaceuticals, Janssen/Janssen-Cilag, KRKA, Lundbeck and Medichem Pharmaceuticals Inc. by Unilab; received research grant from Gedeon Richter; and royalties from Oxford University Press.
Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2024.2334424