Efficacy, tolerability, and safety of xanomeline-trospium chloride for schizophrenia: A systematic review and meta-analysis.

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.