Fabiano Nicholas, Wong Stanley, Zhou Carl, Correll Christoph U, Højlund Mikkel, Solmi Marco
SCIENCES Lab, Department of Psychiatry, University of Ottawa, Ottawa, Canada.
SCIENCES Lab, Department of Psychiatry, University of Ottawa, Ottawa, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
Eur Neuropsychopharmacol. 2025 Mar;92:62-73. doi: 10.1016/j.euroneuro.2024.11.013. Epub 2024 Dec 25.
The United States Food and Drug Administration approved xanomeline-trospium combination for schizophrenia on September-26-2024. We conducted a PRISMA 2020-compliant systematic review with random-effects meta-analysis on the efficacy and safety of xanomeline-trospium in randomized controlled trials in patients with schizophrenia (MEDLINE, EMBASE, Cochrane, PsycINFO, October-01-2024). Co-primary outcomes were Positive And Negative Syndrome Scale (PANSS) total score (standardized mean difference=SMD), and all-cause discontinuation (risk ratio=RR). Cochrane's Risk of Bias (RoB) Tool 2 and GRADE were used. Xanomeline-trospium (k = 3, schizophrenia acute exacerbation, RoB=low, baseline N = 690, males=75.5 %, age=44.3 + 11.0, duration=5 weeks) outperformed placebo on PANSS total (SMD=-0.56, 95 % confidence interval/CI=-0.72/-0.40), positive (SMD=-0.59, 95 %CI=-0.75/-0.43), negative (SMD=-0.33, 95 %CI=-0.49/-0.17), and Marder Factor negative symptom score (SMD=-0.36, 95 %CI=-0.60/-0.13), Clinical Global Impression-Severity (SMD=-0.54, 95 %CI=-0.71/-0.37) (GRADE=moderate), and response (≥30 % reduction from baseline: RR=2.13, 95 %CI=1.66-2.75). Risk of ≥7 % weight gain (RR=0.46, 95 %CI=0.25-0.87, NNT=19), low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol levels were reduced, while risk was increased for vomiting, hypertension, nausea, dry mouth, dyspepsia, constipation (RR=7.60, 95 %CI=1.50-38.57 to RR=2.72, 95 %CI=1.63-4.55), any adverse event (RR=1.33, 95 %CI=1.18-1.51, NNT=6), triglyceride levels and supine heart rate (GRADE=moderate to high). Conversely, the risk was not increased for any other, serious, or severe adverse events or all-cause discontinuation. In post-hoc analyses, xanomeline-trospium outperformed placebo regarding response (≥20 % and ≥30 % threshold) starting at week 2, negative symptoms in patients with prominent negative symptoms, and cognitive symptoms in patients ≥1 standard deviation below the general population norm. Further, pro-/anti-cholinergic side effects were mild-moderate and mostly transient. Xanomeline-trospium is an effective treatment for schizophrenia with a unique tolerability profile, potentially addressing unmet needs.
2024年9月26日，美国食品药品监督管理局批准了 xanomeline - 曲司氯铵组合用于治疗精神分裂症。我们按照PRISMA 2020标准进行了一项系统评价，并对xanomeline - 曲司氯铵在精神分裂症患者随机对照试验中的疗效和安全性进行了随机效应荟萃分析（检索MEDLINE、EMBASE、Cochrane、PsycINFO，检索时间截至2024年10月1日）。共同主要结局指标为阳性与阴性症状量表（PANSS）总分（标准化均数差=SMD）和全因停药率（风险比=RR）。使用了Cochrane偏倚风险（RoB）工具2和GRADE方法。Xanomeline - 曲司氯铵（k = 3，精神分裂症急性加重，RoB=低，基线样本量N = 690，男性占75.5%，年龄=44.3 ± 11.0，疗程=5周）在PANSS总分（SMD=-0.56，95%置信区间/CI=-0.72/-0.40）、阳性症状（SMD=-0.59，95%CI=-0.75/-0.43）、阴性症状（SMD=-0.33，95%CI=-0.49/-0.17）、Marder阴性症状因子评分（SMD=-0.36，95%CI=-0.60/-0.13）、临床总体印象-严重程度（SMD=-0.54，95%CI=-0.71/-0.37）（GRADE=中等）以及应答率（较基线降低≥30%：RR=2.13，95%CI=1.66 - 2.75）方面均优于安慰剂。体重增加≥7%的风险（RR=0.46，95%CI=0.25 - 0.87，需治疗人数=NNT=19）、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平降低，而呕吐、高血压、恶心、口干、消化不良、便秘的风险增加（RR=7.60，95%CI=1.50 - 38.57至RR=2.72，95%CI=1.63 - 4.55）、任何不良事件（RR=1.33，95%CI=1.18 - 1.51，NNT=6）、甘油三酯水平和仰卧心率（GRADE=中等至高）。相反，其他任何严重或重度不良事件或全因停药的风险并未增加。在事后分析中，xanomeline - 曲司氯铵在第2周开始的应答率（降低≥20%和≥30%阈值）、以明显阴性症状为主的患者的阴性症状以及认知症状方面优于安慰剂，这些认知症状出现在比总体人群均值低1个标准差的患者中。此外，拟胆碱/抗胆碱能副作用为轻至中度，且大多为短暂性。Xanomeline - 曲司氯铵是一种治疗精神分裂症的有效药物，具有独特的耐受性特征，可能满足未被满足的需求。
