Is muscarinic receptor agonist effective and tolerant for schizophrenia? A systematic review and meta-analysis

Is muscarinic receptor agonist effective and tolerant for schizophrenia? 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A systematic review and meta-analysis Xiaonan Guo, Rongshan Deng, Jianbo Lai, Shaohua Hu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5387999/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Apr, 2025 Read the published version in BMC Psychiatry → Version 1 posted 17 You are reading this latest preprint version Abstract Background: Several randomized clinical trials (RCTs) have recently examined the efficacy and tolerability of muscarinic receptor agonists in schizophrenia. However, whether therapeutics targeting muscarinic receptors improve symptom management and reduce side effects remains systemically unexplored. Methods: Embase, PubMed, and Web of Science were searched from inception until May 16, 2024. Altogether, the efficacy and safety outcomes of four RCTs (397 individuals in the muscarinic receptor agonists group, and 374 in the placebo control group) were meta-analyzed. To compare scores of positive and negative syndrome scale (PANSS), response rate, discontinuation rate, and adverse events with muscarinic receptor agonists vs placebo in patients with schizophrenia, scale changes were pooled as mean difference (MD) for continuous outcomes and risk ratio (RR) for categorical outcomes. Results: It revealed that muscarinic receptor agonists were superior to placebo in terms of decrease in the total PANSS score (MD, − 9.92; 95% CI, -12.46 to -7.37; I2 = 0%), PANSS positive symptom subscore (MD, − 3.21; 95% CI, -4.02 to -2.40; I2 = 0%), and PANSS negative symptom subscore (MD, -1.79; 95% CI, -2.47 to -1.11; I2 = 48%). According to the study-defined response rate, the pooled muscarinic receptor agonists vs placebo RR was 2.08 (95% CI, 1.59 to 2.72; I2 = 0%). No significance was found in the discontinuation rate. Muscarinic receptor agonists were associated with a higher risk of nausea (RR = 4.61, 95% CI, 2.65 to 8.02; I2 = 3%), and in particular, xanomeline-trospium was associated with risks of dyspepsia, vomiting, and constipation. Conclusions: The findings highlighted an efficacy advantage with tolerated adverse event profiles for muscarinic receptor agonists in schizophrenia. Schizophrenia Muscarinic receptor agonist xanomeline-trospium Figures Figure 1 Figure 2 Figure 3 Background Schizophrenia is a complicated and debilitating psychiatric disorder, ranking among the top 10 causes of disability worldwide [ 1 , 2 ]. Driven by the dopamine hypothesis, the promising therapeutic effect of antipsychotics in D2 dopamine receptor blockade was a milestone in the management of schizophrenia [ 3 , 4 ], especially with clozapine [ 5 – 7 ]. However, due to their limited effectiveness in addressing the entire core symptoms (especially negative and cognitive symptoms) and burdensome adverse effects (e.g., extrapyramidal motor symptoms, hyperprolactinemia, and metabolic aberrations), there is still an urgent need for mechanistically distinct, and better-tolerated therapeutic agents to treat schizophrenia effectively [ 8 – 16 ]. The development of novel drugs targeting muscarinic acetylcholine receptors (mAChRs), which are implicated in the pathophysiology of schizophrenia, has been the first novel class of antipsychotic medications after the launch of second-generation antipsychotic drugs [ 9 , 13 , 14 ]. As reported, M1 receptors are located on projection neurons in the striatum (an essential region responsible for dysregulated dopamine in patients with schizophrenia) and throughout the prefrontal cortex [ 17 ]. Therefore, the mAChRs agonists, which are devoid of direct D2 dopamine receptor-blocking activity, might indirectly modulate dopaminergic systems in tandem with cholinergic function [ 18 – 20 ]. In preclinical studies, compounds targeting mAChRs have proved great efficacy in antipsychotic-like effects as well as negative and/or cognitive symptoms [ 14 , 16 , 21 – 24 ]. Recently, several randomized clinical trials (RCTs) have examined the efficacy and tolerability of mAChR agonists, especially for cholinergic M1 and M4 [ 25 – 31 ] or M4 [ 32 ] receptors, in patients with schizophrenia. Therefore, a quantitative synthesis of the results of these studies could systematically investigate the clinical evidence of mAChR agonists. Thus, we collected efficacy and safety evidence of the mAChR agonists for patients with schizophrenia in RCTs, which might guide research and clinical practice. Methods Search strategy and selection criteria This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) [ 33 ] and registered a protocol (PROSPERO-ID: CRD42024536119). We searched electronic databases (Embase, PubMed, and Web of Science) from inception until May 16, 2024. Systematic retrieval was carried out using MeSH terms and their morphological variations in sequential MeSH and free-text terms search. eMethod in Supplement 1 provided complete information on the search strategy. We limited the search to parallel-group RCTs, published in English, that compared the treatment effect of mAChRs agonists and placebo in patients with schizophrenia. The effective dosage of different drugs was not constricted. Study screening and data extraction The primary efficacy outcome was a total decrease score in the positive and negative syndrome scale (PANSS) from baseline at the treatment endpoint [ 34 ]. Secondary efficacy outcomes included score decreases from baseline in positive or negative symptom subscores of PANSS, Clinical Global Impression–Severity (CGI-S) scale [ 35 ], and response rates to the treatment according to the study design at the primary endpoint. To investigate the tolerability of the mAChRs agonists, the discontinuation rate, and any adverse event rate were extracted. The common adverse events that occurred in at least 5% of cases more than three times were selected for detailed adverse events analysis. Study screening, data extraction, and quality assessment were conducted independently by RSD and XNG. Studies that met the inclusion criteria on the title and abstract or could not be excluded based on information provided in the abstract, were reviewed at a full-text level. Data was obtained in the eligible paper. If the graph data cannot be manually extracted, a semi-automated tool (WebPlotDigitize) would be used to help reverse numerical data from images. For the trial of emraclidine [ 32 ], the combined results of the 30mg qd group and 20mg bid group in Part B were used in the analyses. The risk of bias for the primary outcomes was evaluated using the Cochrane Handbook Risk of Bias Tool for RCTs . After reviewing the primary publications, quality assessment results were visualized via Review Manager (5.4.1. version). All discrepancies during each stage of study selection, data extraction, and quality assessment were resolved by re-checking source papers. Data analysis Meta-analyses were conducted using Review Manager (5.4.1. version). Statistical tests were used to evaluate the pooled effect and heterogeneity of the whole group or subgroup. Sensitivity analyses were omitted due to the constricted number of trials. Publication bias was not examined due to the constricted number of trials. Continuous variables were reported as mean difference (MD), along with the confidence interval (95% CI). The normal likelihood was used for continuous outcomes. Relative risk (RR) and 95% CI were used for pooling binary variables. Heterogeneity among the included studies was assessed using the I 2 index, with an I 2 of 25%, 50%, and 75% indicating mild, moderate, and high heterogeneity, respectively, and was shown in the forest plots. Results of I 2 lower than 50% would be analyzed with a fixed effect model, and others would be analyzed with a random effect model. All P values were two-tailed, and significance was considered < 0.05. Results Five RCTs [ 25 – 27 , 32 , 36 ] had been identified according to the search criteria in Embase, PubMed, and Web of Science (Fig. 1 ). Four trials(NCT03697252, register date: 2018-10-03; NCT04136873, register date: 2019-10-21; NCT04659161, register date: 2020-12-02; NCT04738123, register date: 2021-02-01) had no risk of bias [ 25 , 26 , 32 , 36 ]. One pilot trial had unclear risks of bias related to randomization processes and incomplete outcome data reporting [ 27 ] ( eFigure 1–2 in Supplement 1 ). Thus, we excluded this trial in the meta-analysis but listed the findings together with evidence in other RCTs ( eTable1 in Supplement 1 ). In general, 771 patients with current acute exacerbation or relapse of schizophrenia were enrolled in four trials, with a mean age of 43.5 (SD, 10.9) years, males accounting for 75.8% (584/771), average BMI of 28.9 (SD, 5.3) Kg/m 2 , Black and African American for 69.8% (538/771), and White for 27.0% (208/771), and average PANSS score of 97.1 (SD, 9.0), positive subscore of 26.4 (SD, 3.5), and negative subscore of 22.7 (SD, 3.9) at baseline. Three trials assessed xanomeline–trospium (KarXT; xanomeline: peripheral and central M1 and M4-preferring agonism; trospium: peripheral restricted pan-muscarinic receptor antagonist to mitigate peripheral cholinergic agonism of xanomeline [ 37 ]) lasted five weeks [ 25 , 26 , 36 ], and one trial assessed emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, lasted six weeks [ 32 ]. All trials were conducted in inpatient units. Efficacy evaluation In the main analysis, the total PANSS score displayed a significant decrease (MD, − 9.92; 95% CI, -12.46 to -7.37; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 356, placebo control group = 347) in mAChRs agonist group (Fig. 2 A). In terms of positive symptoms, a significant PANSS positive symptom subscore decrease was also detected (MD, − 3.21; 95% CI, -4.02 to -2.40; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 356, placebo control group = 347) (Fig. 2 B). In terms of negative symptoms, the therapeutic effect was detected in PANSS negative symptom subscore decrease with high heterogeneity (MD, -1.79; 95% CI, -2.47 to -1.11; I 2 = 48%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 356, placebo control group = 347) (Fig. 2 C). On the scale of CGI-S, mAChRs agonist group showed a significantly lower score than the placebo (MD, − 0.58; 95% CI, -0.73 to -0.42; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 356, placebo control group = 347) ( eFigure 3 in Supplement 1 ). According to the study-defined response rate, the pooled mAChRs agonist vs placebo RR was 2.08 (95% CI, 1.59 to 2.72; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 309, placebo control group = 304) (Fig. 2 D). Despite moderate heterogeneity in the PANSS negative symptom subscore, all treatment effects were uncovered with low heterogeneity. Of note, a subgroup analysis that specifically excluded emraclidine [ 32 ], revealed that KarXT was effective in reducing total PANSS score (MD, − 9.74; 95% CI, -12.39 to -7.09; I 2 = 0%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 314, placebo control group = 326), PANSS positive symptom subscore (MD, − 3.20; 95% CI, -4.04 to -2.36; I 2 = 0%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 314, placebo control group = 326), and PANSS negative symptom subscore (MD, − 1.55; 95% CI, -2.28 to -0.82; I 2 = 23%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 314, placebo control group = 326) ( eFigure 4 in Supplement 1 ). Meanwhile, KarXT also displayed improvement in CGI-S scores (MD, − 0.57; 95% CI, -0.73 to -0.41; I 2 = 0%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 314, placebo control group = 326) ( eFigure 3 in Supplement 1 ). Concerning response rate, KarXT was superior to the placebo, as the pooled mAChRs agonist vs placebo RR was 2.03 (95% CI, 1.55 to 2.67; I 2 = 0%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 255, placebo control group = 277) ( eFigure 4 in Supplement 1 ). Safety evaluation The serious adverse event, severe adverse event, and discontinuation reasons were listed in eTable2-4 in Supplement 1 . The pooled mAChRs agonist vs placebo RR was 1.17 for discontinuation rate (95% CI, 0.92 to 1.49; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 395, placebo control group = 376) (Fig. 3 A). Similar results can also be observed in the KarXT subgroup analyses ( eFigure 5 in Supplement 1 ). Considering any adverse events, the pooled mAChRs agonist vs placebo RR was 1.30 with significance (95% CI, 1.15 to 1.46; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 394, placebo control group = 370) (Fig. 3 B). The pooled mAChRs agonist vs placebo RR in nausea was 4.61 with significance (95% CI, 2.65 to 8.02; I 2 = 3%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 394, placebo control group = 370) (Fig. 3 C). The pooled mAChRs agonist vs placebo RR in headache was 1.07 with no significance (95% CI, 0.73 to 1.56; I 2 = 0%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 394, placebo control group = 370) ( eFigure 6 in Supplement 1 ). The pooled mAChRs agonist vs placebo MD in body weight increase was − 0.28 (95% CI, -0.82 to 0.25; I 2 = 23%; 4 RCTs [ 25 , 26 , 32 , 36 ]; mAChRs agonist group n = 362, placebo control group = 345) ( eFigure 7 in Supplement 1 ). For KarXT subgroup, the pooled mAChRs agonist vs placebo RR was 1.32 for any adverse events (95% CI, 1.17 to 1.50; I 2 = 0%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 340, placebo control group = 343) ( eFigure 5 in Supplement 1 ). Similar frequencies of nausea and headache events in the whole group were observed in the KarXT group ( eFigure 5–6 in Supplement 1 ). Additionally, KarXT was associated with elevated risks of dyspepsia (RR, 3.26; 95% CI, 1.91 to 5.59; I 2 = 49%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 340, placebo control group = 343), vomiting (RR, 7.81; 95% CI, 1.30 to 46.94; I 2 = 70%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 340, placebo control group = 343), and constipation (RR, 2.77; 95% CI, 1.73 to 4.45; I 2 = 0%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 340, placebo control group = 343), while no association risk of diarrhea was found (RR, 1.79; 95% CI, 0.80 to 4.00; I 2 = 49%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 340, placebo control group = 343), compared to placebo control ( eFigure 8 in Supplement 1 ). The pooled mAChRs agonist vs placebo MD in body weight increase was − 0.30 with moderate heterogeneity (95% CI, -0.86 to 0.26; I 2 = 47%; 3 RCTs [ 25 , 26 , 36 ]; KarXT group n = 308, placebo control group = 318) ( eFigure 7 in Supplement 1 ). Discussion Together, in four RCTs [ 25 , 26 , 32 , 36 ], mAChRs agonists revealed superior effects to placebo in total PANSS score, PANSS positive symptom subscore, CGI-S score, and study-defined response rate with low heterogeneity, and PANSS negative symptom subscore with moderate heterogeneity (which possibly caused by the race difference in one trial [ 36 ]), at the primary endpoint. Thus, mAChRs agonists have the potential for the management of both acute psychotic and negative symptoms. As reported, the occurrence of cognitive decline was observed following the onset of schizophrenia, despite heterogeneity in cognitive function among patients [ 38 – 41 ]. Traditional antipsychotic treatment for cognitive impairment associated with schizophrenia only exerted limited effect [ 42 , 43 ]. Importantly, the application of mAChRs agonists for the treatment of dementia served as a marked impetus for studies examining their impact on cognitive benefits in patients with schizophrenia [ 44 ]. However, the cognitive outcomes could not be obtained due to insufficient data on cognition outcomes. Only one trial reported the cognition outcome, showing that emraclidine did not improve cognition performance in the Brief Assessment of Cognition in Schizophrenia symbol coding test [ 32 ]. Of note, the administration of xanomeline as a single agent has demonstrated efficacy in enhancing the cognitive function of Alzheimer's disease in a dose-dependent manner (17 sites; n = 343) [ 45 ], and schizophrenia in a pilot trial, exemplified by improved verbal learning and short-term memory function [ 27 ]. In addition, a post-hoc analysis yielded a robust and significant benefit in Cogstate Brief Battery among patients with cognitive impairment after taking KarXT (KarXT n = 23, placebo n = 37; d = 0.50; P = 0.03) [ 29 ]. Thus, future studies should be carried out to examine whether or which mAChRs agonist has a treatment role among patients who exhibit a prototypical degree of cognitive impairment. However, caution is warranted to characterize the cognitive outcomes due to the potential pseudospecific effects caused by mitigation in positive symptoms [ 29 ]. Considering the safety and tolerability, the incidences of nausea were more frequent under the intervention of mAChRs agonists. However, side effects of antipsychotic drugs including extrapyramidal motor symptoms and hyperprolactinemia were not reported in adverse events that occurred in at least 5% of cases. Meanwhile, the discontinuation rate, headache, and body weight changes of mAChRs agonists were similar to placebo control at the primary endpoint, supporting the recommendation for mAChRs agonists with a mild to moderate side-effect profile. Additionally, although the xanomeline monotherapy trial received suspension due to frequent gastrointestinal adverse events [ 27 ], the application of trospium chloride, a non-selective muscarinic antagonist that has been previously used for the treatment of overactive bladder [ 46 ], has mitigated 46% peripheral cholinergic side effects in the healthy volunteers with co-administration of xanomeline [ 37 , 47 ]. Indeed, the overall percentage of participants who discontinued the trial in combined therapy with trospium and xanomeline, was similar between the KarXT and placebo groups (28% vs 24%). The majority of KarXT-related adverse events still mainly consisted of gastrointestinal reactions (nausea, dyspepsia, vomiting, and constipation), with elevated risks identified in all three trials, compared to placebo control. They usually occurred within the early stage and were tolerated before the endpoint of the trial [ 26 , 28 , 36 ]. Subanalyses of the KarXT subgroup displayed consistent efficacy and safety with whole-group analyses of mAChRs agonists, implying the promising future of KarXT in the management of schizophrenia. However, caution should be paid to gastrointestinal reactions, since the side effect impact might be mitigated by inpatient settings. Meanwhile, because the crystal structures of M1 and M4 receptors were identified [ 48 ], it was promising to target the specific therapeutic site to design drugs, which might reduce undesirable reactions. Given the possibility that a quarter of patients with schizophrenia will develop treatment-resistant at the early stages of treatment [ 49 ], analyses of the durability of effect and long-term safety after the conduction of larger and longer trials are warranted [ 50 ]. The primary endpoints in the studies were around five weeks after the current acute exacerbation or relapse, requiring a longer assessment duration. Fortunately, three 52-week trials for outpatients are underway (KarXT: NCT04659174, register date: 2020-12-02 and NCT04820309, register date: 2021-03-24; Emraclidine: NCT05443724, register date: 2022-06-29). Promisingly, the breakthrough of mAChRs agonists might revolutionize the treatment of schizophrenia. Key limitations inherent in the systematic review and meta-analysis were listed below. 1) the small number of eligible studies; 2) insufficient data for cognition outcome evaluation; 3) lack of comparable efficacy with antipsychotic drugs. Conclusion In summary, the systematic meta-analysis highlighted the potential management of mAChRs agonists for individuals with schizophrenia in both positive and negative symptoms. While the overall tolerated adverse event profiles were reported, mAChRs agonists were associated with a risk of nausea, and in particular, KarXT was also associated with risks of dyspepsia, vomiting, and constipation. As such, evidence-based treatment of mAChRs agonists for schizophrenia held the key to characterizing the therapeutic effects on core symptoms and shredded the light on the future drug design [ 51 ]. Declarations Supplementary Materials: See Supplementary Materials. Contributions: XNG, SHH, and JBL conceived the research; XNG and RSD screened, extracted, and analyzed data; XNG wrote the initial manuscript; all the authors polished the manuscript. Human ethics and consent to participate statement Our manuscript was not applied to human beings and thus requires no ethical approval. Clinical trial number Not applicable. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding: This work was supported by funding from the National Key Research and Development Program of China (2023YFC2506200), the Leading Talent of Scientific and Technological Innovation - "Ten Thousand Talents Program" of Zhejiang Province (No. 2021R52016), the Zhejiang Provincial Key Research and Development Program (No. 2021C03107), the Innovation team for precision diagnosis and treatment of major brain diseases (No. 2020R01001), and the Fundamental Research Funds for the Central Universities (226-2022-00193, 226-2022-00002, 2023ZFJH01-01, 2024ZFJH01-01). Author Contribution XNG, SHH, and JBL conceived the research; XNG and RSD screened, extracted, and analyzed data; XNG wrote the initial manuscript; all the authors polished the manuscript. 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Safety and Efficacy in Randomized Controlled Trials of Second-Generation Antipsychotics Versus Placebo for Cognitive Impairments in Schizophrenia: A Meta-Analysis. J Clin Psychopharmacol. 2022;42:227–9. Carruthers SP, Gurvich CT, Rossell SL. The muscarinic system, cognition and schizophrenia. Neurosci Biobehav Rev. 2015;55:393–402. Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997;54:465–73. Halaska M, Ralph G, Wiedemann A, Primus G, Ballering-Brühl B, Höfner K, et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World J Urol. 2003;20:392–9. Kidambi N, Elsayed OH, El-Mallakh RS. Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia. Neuropsychiatr Dis Treat. 2023;19:1145–51. Thal DM, Sun B, Feng D, Nawaratne V, Leach K, Felder CC, et al. Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature. 2016;531:335–40. Siskind D, Orr S, Sinha S, Yu O, Brijball B, Warren N, et al. Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis. Br J Psychiatry J Ment Sci. 2022;220:115–20. Tramazzo S, Lian W, Ajnakina O, Carlson G, Bromet E, Kotov R et al. Long-Term Course of Remission and Recovery in Psychotic Disorders. Am J Psychiatry. 2024;:appiajp20230189. Fu L, Luo Y, Niu L, Lin Y, Chen X, Zhang J, et al. M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study. Bioorg Med Chem. 2024;105:117728. Additional Declarations No competing interests reported. Supplementary Files Supplementary1.docx Cite Share Download PDF Status: Published Journal Publication published 02 Apr, 2025 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 27 Dec, 2024 Reviews received at journal 25 Dec, 2024 Reviews received at journal 21 Dec, 2024 Reviewers agreed at journal 13 Dec, 2024 Reviews received at journal 12 Dec, 2024 Reviewers agreed at journal 12 Dec, 2024 Reviewers agreed at journal 11 Dec, 2024 Reviews received at journal 06 Dec, 2024 Reviews received at journal 18 Nov, 2024 Reviewers agreed at journal 17 Nov, 2024 Reviewers agreed at journal 17 Nov, 2024 Reviewers agreed at journal 15 Nov, 2024 Reviewers invited by journal 15 Nov, 2024 Editor invited by journal 13 Nov, 2024 Editor assigned by journal 11 Nov, 2024 Submission checks completed at journal 11 Nov, 2024 First submitted to journal 04 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5387999","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381348684,"identity":"c39554d6-d633-4ac1-a6c1-f4be498e165c","order_by":0,"name":"Xiaonan Guo","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaonan","middleName":"","lastName":"Guo","suffix":""},{"id":381348685,"identity":"f7b381da-c4a1-4073-8feb-3e071cb5dd7f","order_by":1,"name":"Rongshan Deng","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rongshan","middleName":"","lastName":"Deng","suffix":""},{"id":381348686,"identity":"f7b996d1-c01c-4421-bf14-466cc2a80696","order_by":2,"name":"Jianbo Lai","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianbo","middleName":"","lastName":"Lai","suffix":""},{"id":381348687,"identity":"d783703b-7b54-4b95-8a1e-c9f3d47359d3","order_by":3,"name":"Shaohua Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYDCCAwxsYJJBAkh9AHMYDIjXwjiDZC3MPBAx/Fr4jvc+e8zz5448v3SP4WebP3yJDezN2yQYau7g1CJ55ri5MW/bM8OZc84YS+fwsCU28Bwrk2A49gynFoMbaWzSvA2HGTfcyDGQzpEAapHIMZNgbDiMXwvPn8P2QC3Gvy0MgFrk3xCjhe1wIlCLmTRDAsgWHvxaJM8cY5Oc23Y4eeaMtDLLngNsxm08acUWCcdwa+E73sYm8ebPYdt+ieTNN378OSbbz354440PNbi1oINjkMhMIFoDA0MNCWpHwSgYBaNgpAAA9e1Upggo+5EAAAAASUVORK5CYII=","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Shaohua","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2024-11-04 12:23:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5387999/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5387999/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12888-025-06662-1","type":"published","date":"2025-04-02T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71513625,"identity":"31b0c67c-658e-42ab-b900-b2134e5af25e","added_by":"auto","created_at":"2024-12-16 10:48:08","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":474709,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flowchart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5387999/v1/228c205bf8108ff12d0014ce.jpeg"},{"id":71513627,"identity":"1a740aba-34fe-49b5-9774-6e63079828fa","added_by":"auto","created_at":"2024-12-16 10:48:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":367205,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficacy outcomes for mAChRs agonist in patients with schizophrenia.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Total score changes of PANSS.\u003c/p\u003e\n\u003cp\u003eB. Score changes of PANSS positive symptom subscore.\u003c/p\u003e\n\u003cp\u003eC. Score changes of PANSS negative symptom subscore.\u003c/p\u003e\n\u003cp\u003eD. Study-defined response rate at primary endpoint.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5387999/v1/c8c39496b9d2e7b473223eac.png"},{"id":71513628,"identity":"9b99d7fe-4062-4102-9457-3ac8cb93ee0a","added_by":"auto","created_at":"2024-12-16 10:48:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":272906,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSafety outcomes for mAChRs agonist in patients with schizophrenia.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Discontinuation rate.\u003c/p\u003e\n\u003cp\u003eB. Any adverse event rate.\u003c/p\u003e\n\u003cp\u003eC. Nausea events.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5387999/v1/bcbce99a332a99d979fa4629.png"},{"id":80082249,"identity":"893a6d62-8609-418f-b3b6-d1b529c20246","added_by":"auto","created_at":"2025-04-07 16:07:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1940462,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5387999/v1/df3a4c74-b639-4bcc-98fc-4680f6ebb7ff.pdf"},{"id":71513626,"identity":"91b8e0ca-8946-4ab1-8bd9-225d78a38e31","added_by":"auto","created_at":"2024-12-16 10:48:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1628316,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5387999/v1/7004a6b9753f07e4be193126.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Is muscarinic receptor agonist effective and tolerant for schizophrenia? A systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eSchizophrenia is a complicated and debilitating psychiatric disorder, ranking among the top 10 causes of disability worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Driven by the dopamine hypothesis, the promising therapeutic effect of antipsychotics in D2 dopamine receptor blockade was a milestone in the management of schizophrenia [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], especially with clozapine [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, due to their limited effectiveness in addressing the entire core symptoms (especially negative and cognitive symptoms) and burdensome adverse effects (e.g., extrapyramidal motor symptoms, hyperprolactinemia, and metabolic aberrations), there is still an urgent need for mechanistically distinct, and better-tolerated therapeutic agents to treat schizophrenia effectively [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe development of novel drugs targeting muscarinic acetylcholine receptors (mAChRs), which are implicated in the pathophysiology of schizophrenia, has been the first novel class of antipsychotic medications after the launch of second-generation antipsychotic drugs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. As reported, M1 receptors are located on projection neurons in the striatum (an essential region responsible for dysregulated dopamine in patients with schizophrenia) and throughout the prefrontal cortex [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, the mAChRs agonists, which are devoid of direct D2 dopamine receptor-blocking activity, might indirectly modulate dopaminergic systems in tandem with cholinergic function [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In preclinical studies, compounds targeting mAChRs have proved great efficacy in antipsychotic-like effects as well as negative and/or cognitive symptoms [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recently, several randomized clinical trials (RCTs) have examined the efficacy and tolerability of mAChR agonists, especially for cholinergic M1 and M4 [\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] or M4 [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] receptors, in patients with schizophrenia. Therefore, a quantitative synthesis of the results of these studies could systematically investigate the clinical evidence of mAChR agonists. Thus, we collected efficacy and safety evidence of the mAChR agonists for patients with schizophrenia in RCTs, which might guide research and clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy and selection criteria\u003c/h2\u003e \u003cp\u003eThis meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and registered a protocol (PROSPERO-ID: CRD42024536119).\u003c/p\u003e \u003cp\u003eWe searched electronic databases (Embase, PubMed, and Web of Science) from inception until May 16, 2024. Systematic retrieval was carried out using MeSH terms and their morphological variations in sequential MeSH and free-text terms search. \u003cb\u003eeMethod in Supplement 1\u003c/b\u003e provided complete information on the search strategy. We limited the search to parallel-group RCTs, published in English, that compared the treatment effect of mAChRs agonists and placebo in patients with schizophrenia. The effective dosage of different drugs was not constricted.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy screening and data extraction\u003c/h3\u003e\n\u003cp\u003eThe primary efficacy outcome was a total decrease score in the positive and negative syndrome scale (PANSS) from baseline at the treatment endpoint [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Secondary efficacy outcomes included score decreases from baseline in positive or negative symptom subscores of PANSS, Clinical Global Impression\u0026ndash;Severity (CGI-S) scale [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and response rates to the treatment according to the study design at the primary endpoint. To investigate the tolerability of the mAChRs agonists, the discontinuation rate, and any adverse event rate were extracted. The common adverse events that occurred in at least 5% of cases more than three times were selected for detailed adverse events analysis.\u003c/p\u003e \u003cp\u003eStudy screening, data extraction, and quality assessment were conducted independently by RSD and XNG. Studies that met the inclusion criteria on the title and abstract or could not be excluded based on information provided in the abstract, were reviewed at a full-text level. Data was obtained in the eligible paper. If the graph data cannot be manually extracted, a semi-automated tool (WebPlotDigitize) would be used to help reverse numerical data from images. For the trial of emraclidine [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], the combined results of the 30mg qd group and 20mg bid group in Part B were used in the analyses. The risk of bias for the primary outcomes was evaluated using the \u003cem\u003eCochrane Handbook Risk of Bias Tool for RCTs\u003c/em\u003e. After reviewing the primary publications, quality assessment results were visualized \u003cem\u003evia\u003c/em\u003e Review Manager (5.4.1. version). All discrepancies during each stage of study selection, data extraction, and quality assessment were resolved by re-checking source papers.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003e Meta-analyses were conducted using Review Manager (5.4.1. version). Statistical tests were used to evaluate the pooled effect and heterogeneity of the whole group or subgroup. Sensitivity analyses were omitted due to the constricted number of trials. Publication bias was not examined due to the constricted number of trials. Continuous variables were reported as mean difference (MD), along with the confidence interval (95% CI). The normal likelihood was used for continuous outcomes. Relative risk (RR) and 95% CI were used for pooling binary variables. Heterogeneity among the included studies was assessed using the I\u003csup\u003e2\u003c/sup\u003e index, with an I\u003csup\u003e2\u003c/sup\u003e of 25%, 50%, and 75% indicating mild, moderate, and high heterogeneity, respectively, and was shown in the forest plots. Results of I\u003csup\u003e2\u003c/sup\u003e lower than 50% would be analyzed with a fixed effect model, and others would be analyzed with a random effect model. All \u003cem\u003eP\u003c/em\u003e values were two-tailed, and significance was considered\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFive RCTs [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] had been identified according to the search criteria in Embase, PubMed, and Web of Science (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Four trials(NCT03697252, register date: 2018-10-03; NCT04136873, register date: 2019-10-21; NCT04659161, register date: 2020-12-02; NCT04738123, register date: 2021-02-01) had no risk of bias [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. One pilot trial had unclear risks of bias related to randomization processes and incomplete outcome data reporting [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] (\u003cb\u003eeFigure 1\u0026ndash;2 in Supplement 1\u003c/b\u003e). Thus, we excluded this trial in the meta-analysis but listed the findings together with evidence in other RCTs (\u003cb\u003eeTable1 in Supplement 1\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eIn general, 771 patients with current acute exacerbation or relapse of schizophrenia were enrolled in four trials, with a mean age of 43.5 (SD, 10.9) years, males accounting for 75.8% (584/771), average BMI of 28.9 (SD, 5.3) Kg/m\u003csup\u003e2\u003c/sup\u003e, Black and African American for 69.8% (538/771), and White for 27.0% (208/771), and average PANSS score of 97.1 (SD, 9.0), positive subscore of 26.4 (SD, 3.5), and negative subscore of 22.7 (SD, 3.9) at baseline. Three trials assessed xanomeline\u0026ndash;trospium (KarXT; xanomeline: peripheral and central M1 and M4-preferring agonism; trospium: peripheral restricted pan-muscarinic receptor antagonist to mitigate peripheral cholinergic agonism of xanomeline [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]) lasted five weeks [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and one trial assessed emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, lasted six weeks [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. All trials were conducted in inpatient units.\u003c/p\u003e\n\u003ch3\u003eEfficacy evaluation\u003c/h3\u003e\n\u003cp\u003eIn the main analysis, the total PANSS score displayed a significant decrease (MD, \u0026minus;\u0026thinsp;9.92; 95% CI, -12.46 to -7.37; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;356, placebo control group\u0026thinsp;=\u0026thinsp;347) in mAChRs agonist group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In terms of positive symptoms, a significant PANSS positive symptom subscore decrease was also detected (MD, \u0026minus;\u0026thinsp;3.21; 95% CI, -4.02 to -2.40; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;356, placebo control group\u0026thinsp;=\u0026thinsp;347) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). In terms of negative symptoms, the therapeutic effect was detected in PANSS negative symptom subscore decrease with high heterogeneity (MD, -1.79; 95% CI, -2.47 to -1.11; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;48%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;356, placebo control group\u0026thinsp;=\u0026thinsp;347) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). On the scale of CGI-S, mAChRs agonist group showed a significantly lower score than the placebo (MD, \u0026minus;\u0026thinsp;0.58; 95% CI, -0.73 to -0.42; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;356, placebo control group\u0026thinsp;=\u0026thinsp;347) (\u003cb\u003eeFigure 3 in Supplement 1\u003c/b\u003e). According to the study-defined response rate, the pooled mAChRs agonist vs placebo RR was 2.08 (95% CI, 1.59 to 2.72; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;309, placebo control group\u0026thinsp;=\u0026thinsp;304) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Despite moderate heterogeneity in the PANSS negative symptom subscore, all treatment effects were uncovered with low heterogeneity.\u003c/p\u003e \u003cp\u003eOf note, a subgroup analysis that specifically excluded emraclidine [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], revealed that KarXT was effective in reducing total PANSS score (MD, \u0026minus;\u0026thinsp;9.74; 95% CI, -12.39 to -7.09; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;314, placebo control group\u0026thinsp;=\u0026thinsp;326), PANSS positive symptom subscore (MD, \u0026minus;\u0026thinsp;3.20; 95% CI, -4.04 to -2.36; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;314, placebo control group\u0026thinsp;=\u0026thinsp;326), and PANSS negative symptom subscore (MD, \u0026minus;\u0026thinsp;1.55; 95% CI, -2.28 to -0.82; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;23%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;314, placebo control group\u0026thinsp;=\u0026thinsp;326) (\u003cb\u003eeFigure 4 in Supplement 1\u003c/b\u003e). Meanwhile, KarXT also displayed improvement in CGI-S scores (MD, \u0026minus;\u0026thinsp;0.57; 95% CI, -0.73 to -0.41; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;314, placebo control group\u0026thinsp;=\u0026thinsp;326) (\u003cb\u003eeFigure 3 in Supplement 1\u003c/b\u003e). Concerning response rate, KarXT was superior to the placebo, as the pooled mAChRs agonist vs placebo RR was 2.03 (95% CI, 1.55 to 2.67; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;255, placebo control group\u0026thinsp;=\u0026thinsp;277) (\u003cb\u003eeFigure 4 in Supplement 1\u003c/b\u003e).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSafety evaluation\u003c/h2\u003e \u003cp\u003eThe serious adverse event, severe adverse event, and discontinuation reasons were listed in \u003cb\u003eeTable2-4 in Supplement 1\u003c/b\u003e. The pooled mAChRs agonist vs placebo RR was 1.17 for discontinuation rate (95% CI, 0.92 to 1.49; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;395, placebo control group\u0026thinsp;=\u0026thinsp;376) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Similar results can also be observed in the KarXT subgroup analyses (\u003cb\u003eeFigure 5 in Supplement 1\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eConsidering any adverse events, the pooled mAChRs agonist vs placebo RR was 1.30 with significance (95% CI, 1.15 to 1.46; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;394, placebo control group\u0026thinsp;=\u0026thinsp;370) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The pooled mAChRs agonist vs placebo RR in nausea was 4.61 with significance (95% CI, 2.65 to 8.02; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;394, placebo control group\u0026thinsp;=\u0026thinsp;370) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). The pooled mAChRs agonist vs placebo RR in headache was 1.07 with no significance (95% CI, 0.73 to 1.56; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;394, placebo control group\u0026thinsp;=\u0026thinsp;370) (\u003cb\u003eeFigure 6 in Supplement 1\u003c/b\u003e). The pooled mAChRs agonist vs placebo MD in body weight increase was \u0026minus;\u0026thinsp;0.28 (95% CI, -0.82 to 0.25; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;23%; 4 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; mAChRs agonist group n\u0026thinsp;=\u0026thinsp;362, placebo control group\u0026thinsp;=\u0026thinsp;345) (\u003cb\u003eeFigure 7 in Supplement 1\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eFor KarXT subgroup, the pooled mAChRs agonist vs placebo RR was 1.32 for any adverse events (95% CI, 1.17 to 1.50; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;340, placebo control group\u0026thinsp;=\u0026thinsp;343) (\u003cb\u003eeFigure 5 in Supplement 1\u003c/b\u003e). Similar frequencies of nausea and headache events in the whole group were observed in the KarXT group (\u003cb\u003eeFigure 5\u0026ndash;6 in Supplement 1\u003c/b\u003e). Additionally, KarXT was associated with elevated risks of dyspepsia (RR, 3.26; 95% CI, 1.91 to 5.59; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;49%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;340, placebo control group\u0026thinsp;=\u0026thinsp;343), vomiting (RR, 7.81; 95% CI, 1.30 to 46.94; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;70%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;340, placebo control group\u0026thinsp;=\u0026thinsp;343), and constipation (RR, 2.77; 95% CI, 1.73 to 4.45; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;340, placebo control group\u0026thinsp;=\u0026thinsp;343), while no association risk of diarrhea was found (RR, 1.79; 95% CI, 0.80 to 4.00; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;49%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;340, placebo control group\u0026thinsp;=\u0026thinsp;343), compared to placebo control (\u003cb\u003eeFigure 8 in Supplement 1\u003c/b\u003e). The pooled mAChRs agonist vs placebo MD in body weight increase was \u0026minus;\u0026thinsp;0.30 with moderate heterogeneity (95% CI, -0.86 to 0.26; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;47%; 3 RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; KarXT group n\u0026thinsp;=\u0026thinsp;308, placebo control group\u0026thinsp;=\u0026thinsp;318) (\u003cb\u003eeFigure 7 in Supplement 1\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTogether, in four RCTs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], mAChRs agonists revealed superior effects to placebo in total PANSS score, PANSS positive symptom subscore, CGI-S score, and study-defined response rate with low heterogeneity, and PANSS negative symptom subscore with moderate heterogeneity (which possibly caused by the race difference in one trial [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]), at the primary endpoint. Thus, mAChRs agonists have the potential for the management of both acute psychotic and negative symptoms. As reported, the occurrence of cognitive decline was observed following the onset of schizophrenia, despite heterogeneity in cognitive function among patients [\u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Traditional antipsychotic treatment for cognitive impairment associated with schizophrenia only exerted limited effect [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Importantly, the application of mAChRs agonists for the treatment of dementia served as a marked impetus for studies examining their impact on cognitive benefits in patients with schizophrenia [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. However, the cognitive outcomes could not be obtained due to insufficient data on cognition outcomes. Only one trial reported the cognition outcome, showing that emraclidine did not improve cognition performance in the Brief Assessment of Cognition in Schizophrenia symbol coding test [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Of note, the administration of xanomeline as a single agent has demonstrated efficacy in enhancing the cognitive function of Alzheimer's disease in a dose-dependent manner (17 sites; n\u0026thinsp;=\u0026thinsp;343) [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], and schizophrenia in a pilot trial, exemplified by improved verbal learning and short-term memory function [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In addition, a post-hoc analysis yielded a robust and significant benefit in Cogstate Brief Battery among patients with cognitive impairment after taking KarXT (KarXT n\u0026thinsp;=\u0026thinsp;23, placebo n\u0026thinsp;=\u0026thinsp;37; d\u0026thinsp;=\u0026thinsp;0.50; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Thus, future studies should be carried out to examine whether or which mAChRs agonist has a treatment role among patients who exhibit a prototypical degree of cognitive impairment. However, caution is warranted to characterize the cognitive outcomes due to the potential pseudospecific effects caused by mitigation in positive symptoms [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsidering the safety and tolerability, the incidences of nausea were more frequent under the intervention of mAChRs agonists. However, side effects of antipsychotic drugs including extrapyramidal motor symptoms and hyperprolactinemia were not reported in adverse events that occurred in at least 5% of cases. Meanwhile, the discontinuation rate, headache, and body weight changes of mAChRs agonists were similar to placebo control at the primary endpoint, supporting the recommendation for mAChRs agonists with a mild to moderate side-effect profile.\u003c/p\u003e \u003cp\u003eAdditionally, although the xanomeline monotherapy trial received suspension due to frequent gastrointestinal adverse events [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], the application of trospium chloride, a non-selective muscarinic antagonist that has been previously used for the treatment of overactive bladder [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], has mitigated 46% peripheral cholinergic side effects in the healthy volunteers with co-administration of xanomeline [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Indeed, the overall percentage of participants who discontinued the trial in combined therapy with trospium and xanomeline, was similar between the KarXT and placebo groups (28% vs 24%). The majority of KarXT-related adverse events still mainly consisted of gastrointestinal reactions (nausea, dyspepsia, vomiting, and constipation), with elevated risks identified in all three trials, compared to placebo control. They usually occurred within the early stage and were tolerated before the endpoint of the trial [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Subanalyses of the KarXT subgroup displayed consistent efficacy and safety with whole-group analyses of mAChRs agonists, implying the promising future of KarXT in the management of schizophrenia. However, caution should be paid to gastrointestinal reactions, since the side effect impact might be mitigated by inpatient settings. Meanwhile, because the crystal structures of M1 and M4 receptors were identified [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], it was promising to target the specific therapeutic site to design drugs, which might reduce undesirable reactions.\u003c/p\u003e \u003cp\u003eGiven the possibility that a quarter of patients with schizophrenia will develop treatment-resistant at the early stages of treatment [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], analyses of the durability of effect and long-term safety after the conduction of larger and longer trials are warranted [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The primary endpoints in the studies were around five weeks after the current acute exacerbation or relapse, requiring a longer assessment duration. Fortunately, three 52-week trials for outpatients are underway (KarXT: NCT04659174, register date: 2020-12-02 and NCT04820309, register date: 2021-03-24; Emraclidine: NCT05443724, register date: 2022-06-29). Promisingly, the breakthrough of mAChRs agonists might revolutionize the treatment of schizophrenia.\u003c/p\u003e \u003cp\u003eKey limitations inherent in the systematic review and meta-analysis were listed below. 1) the small number of eligible studies; 2) insufficient data for cognition outcome evaluation; 3) lack of comparable efficacy with antipsychotic drugs.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, the systematic meta-analysis highlighted the potential management of mAChRs agonists for individuals with schizophrenia in both positive and negative symptoms. While the overall tolerated adverse event profiles were reported, mAChRs agonists were associated with a risk of nausea, and in particular, KarXT was also associated with risks of dyspepsia, vomiting, and constipation. As such, evidence-based treatment of mAChRs agonists for schizophrenia held the key to characterizing the therapeutic effects on core symptoms and shredded the light on the future drug design [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eSupplementary Materials:\u003c/h2\u003e\n\u003cp\u003eSee Supplementary Materials.\u003c/p\u003e\n\u003ch2\u003eContributions:\u003c/h2\u003e\n\u003cp\u003eXNG, SHH, and JBL conceived the research; XNG and RSD screened, extracted, and analyzed data; XNG wrote the initial manuscript; all the authors polished the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman ethics and consent to participate statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur manuscript was not applied to human beings and thus requires no ethical approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eThis work was supported by funding from the National Key Research and Development Program of China (2023YFC2506200), the Leading Talent of Scientific and Technological Innovation - \u0026quot;Ten Thousand Talents Program\u0026quot; of Zhejiang Province (No. 2021R52016), the Zhejiang Provincial Key Research and Development Program (No. 2021C03107), the Innovation team for precision diagnosis and treatment of major brain diseases (No. 2020R01001), and the Fundamental Research Funds for the Central Universities (226-2022-00193, 226-2022-00002, 2023ZFJH01-01, 2024ZFJH01-01).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eXNG, SHH, and JBL conceived the research; XNG and RSD screened, extracted, and analyzed data; XNG wrote the initial manuscript; all the authors polished the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\n\u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e\n\u003ch2\u003eData availability:\u003c/h2\u003e\n\u003cp\u003eData from this study are available on request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcCutcheon RA, Reis Marques T, Howes OD. 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Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis. Br J Psychiatry J Ment Sci. 2022;220:115\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTramazzo S, Lian W, Ajnakina O, Carlson G, Bromet E, Kotov R et al. Long-Term Course of Remission and Recovery in Psychotic Disorders. Am J Psychiatry. 2024;:appiajp20230189.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu L, Luo Y, Niu L, Lin Y, Chen X, Zhang J, et al. M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study. Bioorg Med Chem. 2024;105:117728.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Schizophrenia, Muscarinic receptor agonist, xanomeline-trospium","lastPublishedDoi":"10.21203/rs.3.rs-5387999/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5387999/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eSeveral randomized clinical trials (RCTs) have recently examined the efficacy and tolerability of muscarinic receptor agonists in schizophrenia. However, whether therapeutics targeting muscarinic receptors improve symptom management and reduce side effects remains systemically unexplored.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eEmbase, PubMed, and Web of Science were searched from inception until May 16, 2024. Altogether, the efficacy and safety outcomes of four RCTs (397 individuals in the muscarinic receptor agonists group, and 374 in the placebo control group) were meta-analyzed. To compare scores of positive and negative syndrome scale (PANSS), response rate, discontinuation rate, and adverse events with muscarinic receptor agonists vs placebo in patients with schizophrenia, scale changes were pooled as mean difference (MD) for continuous outcomes and risk ratio (RR) for categorical outcomes.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eIt revealed that muscarinic receptor agonists were superior to placebo in terms of decrease in the total PANSS score (MD, \u0026minus;\u0026thinsp;9.92; 95% CI, -12.46 to -7.37; I2\u0026thinsp;=\u0026thinsp;0%), PANSS positive symptom subscore (MD, \u0026minus;\u0026thinsp;3.21; 95% CI, -4.02 to -2.40; I2\u0026thinsp;=\u0026thinsp;0%), and PANSS negative symptom subscore (MD, -1.79; 95% CI, -2.47 to -1.11; I2\u0026thinsp;=\u0026thinsp;48%). According to the study-defined response rate, the pooled muscarinic receptor agonists vs placebo RR was 2.08 (95% CI, 1.59 to 2.72; I2\u0026thinsp;=\u0026thinsp;0%). No significance was found in the discontinuation rate. Muscarinic receptor agonists were associated with a higher risk of nausea (RR\u0026thinsp;=\u0026thinsp;4.61, 95% CI, 2.65 to 8.02; I2\u0026thinsp;=\u0026thinsp;3%), and in particular, xanomeline-trospium was associated with risks of dyspepsia, vomiting, and constipation.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eThe findings highlighted an efficacy advantage with tolerated adverse event profiles for muscarinic receptor agonists in schizophrenia.\u003c/p\u003e","manuscriptTitle":"Is muscarinic receptor agonist effective and tolerant for schizophrenia? 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