Trospium chloride 60mg modified-release capsules

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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Introduction Schizophrenia is a severe mental disorder often diagnosed in early adulthood, significantly impacting quality of life and increasing mortality risk. Xanomeline-trospium (KarXT), a combination of a muscarinic cholinergic receptor agonist and a peripheral antagonist, offers a potential new approach. Objectives We aimed to perform a systematic review and meta-analysis to assess the efficacy of KarXT compared to placebo in reducing the symptoms of schizophrenia. Methods We systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (RCTs) enrolling patients with schizophrenia treated with KarXT versus placebo. Our outcomes included the overall improvement in schizophrenia symptoms, measured by the Positive and Negative Syndrome Scale (PANSS) total score, as well as specific symptom domains assessed by the PANSS positive and PANSS negative subscales. Additionally, the Clinical Global Impressions-Severity (CGI-S) score was used to measure the overall severity of the disorder. We computed mean difference (MD) with 95% confidence intervals (CIs) using R version 4.3.2. Heterogeneity was assessed using I² statistics. Results Three RCTs were included with 640 patients, of whom 314 (49.1%) received KarXT. There were 509 males (79.5%) and 131 females (20.5%). The average body mass index (BMI) was slightly higher in the KarXT group (29.1) compared to the placebo (28.8). KarXT resulted in a greater decrease in the PANSS total score (MD: -9.74; 95% CI -12.40, -7.08; p<0.001; I²=0%; Figure 1A), PANSS positive (MD: -3.20; 95% CI -4.04, -2.36; p<0.001; I²=0%; Figure 1B), PANSS negative (MD: -1.55; 95% CI -2.28, -0.81; p<0.001; I²=22%; Figure 1C) and CGI-S score (MD: –0.60; 95% CI -0.75, -0.45; p<0.001; I²=24% Figure 2). Image 1: Image 2: Conclusions Our systematic review and meta-analysis of RCTs showed that KarXT is significantly more effective than placebo in reducing schizophrenia symptoms. Disclosure of Interest None Declared

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