Horan William P, Targum Steven D, Claxton Amy, Kaul Inder, Yohn Samantha E, Marder Stephen R, Miller Andrew C, Brannan Stephen K
Bristol Myers Squibb, Princeton, NJ, USA; University of California, Los Angeles, CA, USA.
Signant Health, Boston, MA, USA.
Schizophr Res. 2024 Dec;274:57-65. doi: 10.1016/j.schres.2024.08.001. Epub 2024 Sep 10.
Currently approved antipsychotics do not adequately treat negative symptoms (NS), which are a major determinant of functional disability in schizophrenia. KarXT, an M /M preferring muscarinic receptor agonist, has shown efficacy as a broad-spectrum monotherapy for the treatment of schizophrenia in participants with acute psychosis. Post hoc analyses evaluated the possibility that NS improve independently of positive symptoms with KarXT in a subgroup of participants with moderate-to-severe NS and no predominance of positive symptoms.
Data were pooled from the three pivotal trials of KarXT monotherapy in people with schizophrenia with an acute exacerbation of psychosis. All 3 studies used similar 5-week randomized, double-blind, placebo-controlled designs (modified intention-to-treat sample N = 640). PANSS criteria proposed in the literature identified a subset of study participants (n = 64) with prominent NS.
KarXT was significantly better than placebo on PANSS Marder Negative Factor Scores in the full sample (p < .001; Cohen's d = 0.42) and more so in the prominent NS subgroup (p < .001; Cohen's d = 1.18). Further, the KarXT effect in the NS subgroup remained significant after accounting for changes in positive symptoms, depression/anxiety, disorganization, and hostility.
Participants with prominent NS revealed greater improvement of NS following KarXT therapy than the full sample that persisted after accounting for positive and other symptoms. While these findings must be interpreted with caution, they are consistent with the possibility that NS improvements associated with KarXT are not secondary to improvements in other symptom domains and support further investigation in larger, stable outpatient studies.
目前已获批准的抗精神病药物不能充分治疗阴性症状（NS），而阴性症状是精神分裂症功能残疾的主要决定因素。KarXT是一种偏向M1/M4的毒蕈碱受体激动剂，已显示出作为广谱单一疗法治疗急性精神病患者精神分裂症的疗效。事后分析评估了在中度至重度阴性症状且无明显阳性症状的参与者亚组中，KarXT治疗后阴性症状独立于阳性症状改善的可能性。
汇总了KarXT单一疗法治疗急性精神病性发作的精神分裂症患者的三项关键试验的数据。所有3项研究均采用相似的5周随机、双盲、安慰剂对照设计（改良意向性治疗样本N = 640）。文献中提出的阳性和阴性症状量表（PANSS）标准确定了一部分有突出阴性症状的研究参与者（n = 64）。
在整个样本中，KarXT在PANSS Marder阴性因子评分上显著优于安慰剂（p <.001；Cohen's d = 0.42），在突出阴性症状亚组中更是如此（p <.001；Cohen's d = 1.18）。此外，在考虑阳性症状、抑郁/焦虑、紊乱和敌意的变化后，KarXT在阴性症状亚组中的效果仍然显著。
有突出阴性症状的参与者在KarXT治疗后阴性症状的改善比整个样本更大，在考虑阳性症状和其他症状后这种改善仍然持续。虽然这些发现必须谨慎解释，但它们与KarXT相关的阴性症状改善并非继发于其他症状领域改善的可能性一致，并支持在更大规模、稳定的门诊研究中进行进一步调查。
