Horan William P, Sauder Colin, Harvey Philip D, Ramsay Ian S, Yohn Samantha E, Keefe Richard S E, Davis Vicki G, Paul Steven M, Brannan Stephen K
Bristol Myers Squibb, Boston (Horan, Sauder, Ramsay, Yohn, Paul, Brannan); University of Miami Miller School of Medicine, Miami (Harvey); Duke University School of Medicine, Durham (Keefe); Statistical Consultant, Chapel Hill (Davis).
Am J Psychiatry. 2025 Mar 1;182(3):297-306. doi: 10.1176/appi.ajp.20240076. Epub 2024 Dec 11.
Xanomeline and trospium chloride (formerly known as KarXT), a novel M/M muscarinic receptor agonist, demonstrated efficacy across phase 2 and 3 trials as monotherapy for the treatment of inpatients with acute schizophrenia on the Positive and Negative Syndrome Scale total score primary endpoint. In the phase 2 trial, xanomeline/trospium improved performance on a cognitive outcome measure in the subgroup of participants with clinically significant baseline cognitive impairment. The authors sought to confirm this finding using data from two phase 3 trials.
Data were pooled from two 5-week inpatient trials of xanomeline/trospium monotherapy in patients with acute schizophrenia. The statistical analysis plan prespecified comparisons of cognitive composite score changes between xanomeline/trospium and placebo in the full sample and the cognitively impaired (≤1 SD below norms at baseline) subgroup.
There was no significant xanomeline/trospium effect in the full sample (N=357); however, in the impaired subgroup, xanomeline/trospium (N=71) had a significantly greater benefit for cognition compared with placebo (N=66; least squares mean difference=0.31, SE=0.10; d=0.54). The xanomeline/trospium effect size increased significantly with a more stringent baseline impairment threshold (≤-1.5 SD; d=0.80). Improvements in cognition were minimally correlated with concurrent changes in total, positive, and negative symptoms in both treatment groups.
Participants with acute schizophrenia with prespecified impairments demonstrated significant cognitive improvement with xanomeline/trospium compared with placebo. This result directly confirms earlier findings. This benefit is not attributable to changes in symptoms, despite substantial evidence of efficacy for psychosis. Evaluation of xanomeline/trospium's potential for cognitive enhancement in a well-controlled trial of stable patients with cognitive impairment is warranted.
新型M/M毒蕈碱受体激动剂 xanomeline 和氯化曲司氯铵（原称 KarXT）在2期和3期试验中作为单一疗法，以阳性和阴性症状量表总分作为主要终点，治疗急性精神分裂症住院患者时显示出疗效。在2期试验中，xanomeline/曲司氯铵在基线存在临床显著认知障碍的参与者亚组中，改善了认知结局指标的表现。作者试图利用两项3期试验的数据来证实这一发现。
汇总两项针对急性精神分裂症患者的xanomeline/曲司氯铵单一疗法的5周住院试验数据。统计分析计划预先设定了在全样本以及认知受损（基线低于常模≤1个标准差）亚组中，比较xanomeline/曲司氯铵与安慰剂之间认知综合评分的变化。
在全样本（N = 357）中，xanomeline/曲司氯铵没有显著效果；然而，在受损亚组中，与安慰剂（N = 66）相比，xanomeline/曲司氯铵（N = 71）对认知的益处显著更大（最小二乘均值差异 = 0.31，标准误 = 0.10；d = 0.54）。随着基线损伤阈值更为严格（≤ -1.5个标准差；d = 0.80），xanomeline/曲司氯铵的效应量显著增加。两个治疗组中，认知改善与总分、阳性和阴性症状的同时变化的相关性最小。
与安慰剂相比，预先确定存在损伤的急性精神分裂症参与者使用xanomeline/曲司氯铵后认知有显著改善。这一结果直接证实了早期的发现。尽管有大量证据表明其对精神病有效，但这种益处并非归因于症状的变化。有必要在一项针对稳定的认知受损患者的对照良好的试验中评估xanomeline/曲司氯铵增强认知的潜力。
