Rankings / Mood, Anxiety & Stress
Xanomeline-trospium (KarXT / Cobenfy)
Mood, Anxiety & Stress · M1/M4 muscarinic agonist + peripheral antagonist
Tier B
What this is
Bristol Myers Squibb (acquired Karuna 2024). First fundamentally new schizophrenia mechanism since clozapine (1989). Avoids dopamine D2 blockade entirely — sidesteps weight gain, EPS, prolactin elevation, and tardive dyskinesia. Active investigation in Alzheimer's psychosis, ADHD, BPD. Major clinical advance even though efficacy is comparable to atypicals.
Mechanism
Combination drug: xanomeline is a centrally acting M1/M4 muscarinic acetylcholine receptor agonist (developed in 1990s but shelved due to peripheral cholinergic side effects); trospium is a peripherally restricted muscarinic antagonist that blocks the GI/cardiac side effects without crossing the BBB — allowing the central effect to be tolerated; first novel mechanism for schizophrenia in 50+ years
Dose & route
50/20 mg twice daily, titrate up to 125/30 mg twice daily
Citations
- https://pubmed.ncbi.nlm.nih.gov/42006053/
- https://pubmed.ncbi.nlm.nih.gov/41786037/
- https://pubmed.ncbi.nlm.nih.gov/41634905/
- https://doi.org/10.24304/kjcp.2026.36.1.60
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This is an independent synthesis of published research by a non-clinician. Scores are opinions supported by citations, not prescriptions. See the full disclaimer and methodology for how this score was produced and what it does and doesn't mean.