Trospium chloride 20mg tablets

ImportanceA significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.ObjectiveTo evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.Design, setting, and participantsEMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023.InterventionsParticipants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.Main outcomes and measuresThe prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated.ResultsA total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P Conclusions and relevanceXanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.Trial registrationClinicalTrials.gov Identifier: NCT04738123.

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Although the dopamine hypothesis of schizophrenia explains the effects of all the available antipsychotics in clinical use, there is an increasing need for developing new drugs for the treatment of the positive, negative, and cognitive symptoms of chronic psychoses. Xanomeline–trospium (KarXT) is a drug combination that is based on the essential role played by acetylcholine in the regulation of cognitive processes and the interactions between this neurotransmitter and other signaling pathways in the central nervous system, with a potential role in the onset of schizophrenia, Alzheimer’s disease, and substance use disorders. A systematic literature review that included four electronic databases (PubMed, Cochrane, Clarivate/Web of Science, and Google Scholar) and the US National Library of Medicine database for clinical trials detected twenty-one sources referring to fourteen studies focused on KarXT, out of which only four have available results. Based on the results of these trials, the short-term efficacy and tolerability of xanomeline–trospium are good, but more data are needed before this drug combination may be recommended for clinical use. However, on a theoretical level, the exploration of KarXT is useful for increasing the interest of researchers in finding new, non-dopaminergic, antipsychotics that could be used either as monotherapy or as add-on drugs.

Abstract licence: CC BY 4.0

BackgroundAntipsychotic drugs are the established treatment for acute schizophrenia but differ in receptor-binding profiles. In 2024, a new-in-class muscarinic receptor agonist (xanomeline-trospium) was licenced, acting upstream of antidopaminergic agents, and providing hope to decrease the adverse effects burden of antipsychotics. We aimed to compare the efficacy and tolerability of antipsychotics by performing network meta-analysis of randomised controlled trials (RCTs).MethodsThis systematic review (PROSPERO, CRD42022380708) included blinded and open RCTs investigating antipsychotic drugs in participants of any age with acute psychotic symptoms of schizophrenia over 3 weeks to 3 months. Included antipsychotics comprised 23 primarily dopamine-receptor blocking medications and the muscarinic receptor agonist xanomeline-trospium in different applications. We searched Cochrane Schizophrenia group's register, previous reviews, and five Chinese databases for trials published from database inception until July 26, 2024 and contacted authors to assess trials' methodological quality; only trials with appropriate randomisation indicated were included. The primary outcome was rating scale-measured overall symptoms of schizophrenia (efficacy) analysed with random-effects frequentist network meta-analysis. Secondary outcomes comprised 32 further efficacy and tolerability outcomes. The confidence in the estimates was assessed using the Confidence in Network Meta-Analysis approach.FindingsAfter screening 18 859 references and contacting authors of 5428 trials, we included 438 RCTs. Of those, 388 RCTs with 78 193 participants (28 448 women and 49 745 men) provided usable data for at least one outcome. 5117 Chinese trials were identified but most were excluded because authors did not reply or reported serious methodological concerns. 256 double-blind studies with 58 948 participants provided usable data for the primary outcome. All antipsychotics reduced symptoms more than placebo with standardised mean differences ranging from -0·90 (95% CI -1·03 to -0·77) to -0·23 (-0·39 to -0·06). Particularly clozapine, as well as amisulpride, olanzapine, and risperidone were more efficacious than at least three other antipsychotics (confidence in estimates were low-to-moderate). Adverse effects varied across medications.InterpretationThis network meta-analysis provides evidence for small-to-medium clinically relevant differences between antipsychotics in efficacy; this finding warrants stronger and more specific emphasis in clinical guidelines. Nonetheless, important differences in tolerability need to be considered for individualised drug choice, with partial dopamine agonists having overall better tolerability and xanomeline-trospium lacking adverse effects of dopamine-blocking agents but resulting in cholinergic and anticholinergic adverse events. Future research should directly compare xanomeline-trospium with other antipsychotics to confirm its efficacy; modern trials using clozapine early in schizophrenia are needed to establish whether it improves outcomes and prevents chronification.FundingGerman Research Foundation, German Ministry of Research, Technology and Space, and National Natural Science Foundation of China.

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The high prevalence, persistence and clinical burden of cognitive impairment on health outcomes in persons with schizophrenia and bipolar disorder invites the need for innovative, mechanistically informed pharmacotherapeutic interventions. Evidence implicates dysregulation of muscarinic signalling as a mediator of cognitive dysfunction, identifying it as a potential therapeutic target. In accordance with the PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. Databases were searched from inception to May 1, 2025. Study screening and selection was performed by three reviewers (K.V., B.S., and B.W.). Included studies reported on the effects of xanomeline and/or xanomeline trospium on cognitive function. A total of 24 studies were included in this review. Preclinical and clinical studies consistently demonstrate that xanomeline trospium is well tolerated in both short and long-term evaluations. Furthermore, xanomeline trospium has been associated with cognitive improvements in both animal models and clinical populations (e.g., Alzheimer's disease (AD), schizophrenia), including improvements in verbal learning, delayed memory, and reaction time. Xanomeline trospium, an FDA approved muscarinic M1/M4 partial agonist with demonstrated safety, tolerability, and efficacy, represents a novel pharmacological intervention for the treatment of schizophrenia. The convergence of preclinical and clinical findings supports the hypothesis that xanomeline trospium exerts direct pro cognitive effects in persons with schizophrenia, bipolar disorder, and potentially other neuropsychiatric conditions (e.g., AD). Limitations of the current study include limited indications investigated and the absence of a comprehensive analysis of xanomeline's overall neurobiologic effects.

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BackgroundAntipsychotics are often insufficient for schizophrenia, but the optimal next-step strategies for non-response remain uncertain. Guidelines recommend some pharmacological, psychological, and non-invasive brain stimulation (NIBS) approaches, but we do not know which one works best. We summarized current evidence for schizophrenia non-responsive to antipsychotics.MethodsWe searched the Cochrane Schizophrenia Group registry (up till January 13, 2025), and PubMed up till January 8, 2026 for randomized controlled trials (RCTs) of patients non-responsive to prior antipsychotic treatment, with persistent symptoms after at least one adequate 4-week antipsychotic trial. Raters needed to be masked. The primary outcome was change in overall symptoms analyzed using random-effects network meta-analyses of standardized mean differences (SMDs) with 95% confidence intervals (CIs). The protocol was pre-registered (https://osf.io/wcs5d/).FindingsFifty-nine RCTs (5409 participants; mean age 39.8 years; 3416 men, 1441 women) were included; 5013 contributed to the primary analysis. Antipsychotic combination therapy (k = 18; n = 575; SMD -0.25, 95% CI -0.46 to -0.04; CINeMA: very low) and electroconvulsive therapy (ECT; k = 5; n = 97; SMD -0.51, -0.96 to -0.06; very low) might be more efficacious than continuing the same antipsychotic. Cognitive behavioral therapy for psychosis (CBTp) showed weak evidence of benefit over continuing the same antipsychotic (k = 5; n = 340; SMD -0.23, -0.58 to 0.11; very low). Other strategies-xanomeline-trospium augmentation, dose escalation, transcranial magnetic stimulation, and switching to clozapine or other antipsychotics-were inconclusive. Combination therapy increased adverse events (OR 1.93, 1.26-3.00). We found no evidence of subgroup difference among non-clozapine- and clozapine-non-response.InterpretationThe results were very uncertain. More head-to-head trials are needed. We found no evidence supporting dose-escalation nor switching to clozapine. Very weak evidence suggested efficacy of antipsychotic combination and ECT augmentation and they might be considered, but with substantial caution.FundingThis study was funded by the German Research Foundation (DFG, #468853597) and the Federal Ministry of Research, Technology, and Space (BMTR, #01EE2303B), and partly by a grant from SENSHIN Medical Research Foundation given to YF, DAAD fellowship to NHS and CSC scholarship to YHW.

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