What is known about the safety and efficacy of xanomelune?

Xanomeline-Trospium (KarXT): A Novel Muscarinic Agonist for Schizophrenia

Xanomeline-trospium (marketed as KarXT) is the first FDA-approved antipsychotic medication that works through muscarinic receptor agonism rather than dopamine D2 receptor blockade, representing a fundamentally new mechanism for treating schizophrenia. 1, 2

Mechanism of Action

• Xanomeline is a dual M1/M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, distinguishing it from all previously available antipsychotic medications 2, 3, 4
• Trospium chloride is combined with xanomeline as a peripherally-restricted muscarinic receptor antagonist to reduce peripheral cholinergic adverse effects (such as gastrointestinal symptoms) while preserving central nervous system efficacy 2, 3
• The combination allows for higher doses of xanomeline to reach the brain without causing intolerable peripheral side effects 3

Clinical Efficacy

The drug demonstrated robust efficacy across three phase 3 trials (EMERGENT-1, EMERGENT-2, and EMERGENT-3) in patients with acute psychosis:

• In EMERGENT-2, xanomeline-trospium reduced PANSS total scores by 9.6 points more than placebo (Cohen's d effect size = 0.61, p<0.0001) at 5 weeks 2
• In EMERGENT-3, the drug reduced PANSS total scores by 8.4 points more than placebo (Cohen's d effect size = 0.60, p<0.001) at 5 weeks 4
• The Number Needed to Treat (NNT) for achieving ≥30% reduction in PANSS total score was 5 (95% CI: 4-8), indicating clinically meaningful benefit 5
• All secondary endpoints were met, including improvements in positive symptoms, negative symptoms, and Clinical Global Impression-Severity scores 2, 4

Dosing and Administration

Standard dosing regimen:

• Days 1-2: 50 mg xanomeline/20 mg trospium twice daily 2
• Days 3-7: 100 mg xanomeline/20 mg trospium twice daily 2
• Day 8 onwards: Flexible dosing with optional increase to 125 mg xanomeline/30 mg trospium twice daily based on tolerability, with option to return to lower dose 2, 4
• The maximum tolerated dose in Alzheimer's disease patients was 100 mg three times daily (300 mg/day total), which is two-fold higher than in healthy elderly volunteers 6

Safety Profile and Adverse Events

The most common adverse events are gastrointestinal and anticholinergic in nature:

• Nausea (19% vs 6% placebo), vomiting (14-16% vs 1% placebo), constipation (12-21% vs 4-10% placebo), and dyspepsia (16-19% vs 2-8% placebo) 2, 4
• Discontinuation rates due to adverse events were similar to placebo (6-7% vs 5-6%) 2, 4
• The Number Needed to Harm (NNH) for most common adverse events was >10, except for nausea and vomiting, but discontinuation due to these GI symptoms remained low (NNH=49) 5

Critical safety advantages over traditional antipsychotics:

• Zero incidence of extrapyramidal symptoms (EPS) in clinical trials (0% vs 0% placebo) 2
• No akathisia (1% vs 1% placebo) 2
• No weight gain (0% vs 1% placebo) 2
• Somnolence rates similar to placebo (5-6% vs 4-5% placebo) 2, 4
• No elevation in prolactin levels (unlike typical D2 antagonists) 3

Contraindications and Warnings

Based on FDA labeling, xanomeline-trospium is contraindicated:

• In patients with known hypersensitivity to any ingredients 7
• Should not be used on wounds or damaged skin 7
• Avoid contact with eyes and mucous membranes 7
• Do not use with heating devices or pads 7

Clinical Context and Guidelines

The 2025 INTEGRATE guidelines from The Lancet Psychiatry position xanomeline-trospium as a significant advancement:

• The guidelines note that xanomeline-trospium has recently been approved and represents a promising treatment with a novel mechanism of action 1
• The guidelines anticipate that prompt appraisal of its position in treatment algorithms will be required as more real-world data accumulates 1
• Future iterations of treatment guidelines will need to integrate this new class of medications that act via non-postsynaptic dopamine antagonism mechanisms 1

Likelihood to Be Helped or Harmed (LHH)

The benefit-risk profile strongly favors treatment:

• LHH assessments demonstrated an overall benefit of xanomeline-trospium versus placebo for all assessed outcomes 5
• In indirect comparisons with other approved antipsychotics, xanomeline-trospium exhibited comparable or more robust NNT estimates and was the least likely agent to cause weight gain or somnolence/sedation 5

Common Pitfalls and Clinical Pearls

Key considerations for prescribing:

• Start with the lower dose (50 mg/20 mg twice daily) for the first 2 days to assess tolerability before escalating 2
• Anticipate gastrointestinal side effects in the first weeks of treatment and counsel patients that these often improve with continued use 2, 4
• The flexible dosing after day 8 allows for individualization based on tolerability without compromising efficacy 2
• Unlike traditional antipsychotics, there is no need to monitor for metabolic syndrome, weight gain, or movement disorders 2, 4
• The absence of D2 blockade means no risk of tardive dyskinesia, a major advantage for long-term treatment 3, 4