Welcome back to What's it Worth! For over 70 years, the treatment of schizophrenia has been synonymous with dopamine D2 receptor blockade—until now. Join your host, Dr. Diana Langworthy, and guest Dr. Alexandra Rola (Psychiatry Clinical Pharmacist and Assistant Professor at Binghamton University) as they dive into the EMERGENT-3 trial. We're dissecting the efficacy and safety of xanomeline-trospium, a first-in-class muscarinic agonist that targets psychosis without the traditional side effects of dopamine antagonists. Is this the breakthrough psychiatry has been waiting for? Let's dive in and see what it's worth!

Key Points

• Unlike traditional antipsychotics, xanomeline is a dual M1/M4-preferring muscarinic receptor agonist. By pairing it with trospium (a peripheral muscarinic antagonist), the "KarXT" combination aims to deliver CNS antipsychotic effects while minimizing peripheral side effects like nausea and vomiting.
• In this 5-week, Phase 3 trial of 256 adults with acute psychosis, xanomeline-trospium demonstrated a statistically significant and clinically meaningful 9.4-point greater reduction in the PANSS total score compared to placebo by week 5.
• The study showed significant improvements in both the Positive Syndrome Scale (hallucinations/delusions) and the Negative Syndrome Scale (social withdrawal/apathy), suggesting a more holistic impact on schizophrenia symptoms.
• While it avoids dopamine-related side effects, KarXT is associated with cholinergic-driven GI issues; nausea, dyspepsia, and vomiting were the most frequently reported adverse events.
• What are the ethics of a placebo controlled trial in acute psychosis when we have proven medications for treatment? Join us for an important conversation about equity and ethics in clinical trials.
• Can we treat psychosis without touching a single dopamine receptor? ------> Tune in to find out!

References

1. [EPISODE TRIAL] Kaul I, Sawchak S, Walling DP, et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024;81(8):749-756. doi:10.1001/jamapsychiatry.2024.0785
2. World Medical Association. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Participants. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 75th WMA General Assembly, Helsinki, Finland, October 2024.
3. Waltz JA, Pujji SD, Colloca L. Placebo and nocebo phenomena in schizophrenia spectrum disorders: a narrative review on current knowledge and potential future directions. Psychol Med. 2025 Jul 18;55:e199. doi: 10.1017/S0033291725100901. Erratum in: Psychol Med. 2026 Feb 02;56:e37. doi: 10.1017/S0033291726103493.
4. Gara MA, Vega WA, Arndt S, et al. Influence of patient race and ethnicity on clinical assessment in patients with affective disorders. Arch Gen Psychiatry. 2012 Jun;69(6):593-600. doi: 10.1001/archgenpsychiatry.2011.2040.
5. Lawrence RE, Appelbaum PS. Ethics in placebo-controlled, acute treatment trials in schizophrenia: Two rival ethical frameworks. Schizophrenia Research 264 (2024) 372-377.

Host Information

Dr. Diana R. Langworthy, PharmD, BCPS

Clinical Associate Professor, University of Minnesota College of Pharmacy

Clinical Pharmacist - Inpatient Internal Medicine, M Health Fairview East Bank Hospital

Guest Information

Alexandra Rola, PharmD

Clinical Assistant Professor, Pharmacy Practice, Binghamton University

Psychiatry Clinical Pharmacist