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

In this brief 2026 season opener, host Diana Langworthy, PharmD, BCPS pauses to acknowledge the weight of the moment—particularly here in Minnesota—where uncertainty, fear, and harm are being felt in very real ways across communities.

This episode is not about policy analysis or debate. It's a reflection on what it means to hold space for thinking, teaching, and care when the world feels unstable—and why asking good questions, slowing down our reasoning, and practicing intellectual humility still matter in healthcare education and clinical practice.

Diana also shares how What's It Worth? will move forward this season, and how the podcast, Substack (whatsitworthpodcast.substack.com), and future TikTok (Diana the Pharm.D.etective - @whatsitworthrx) content will work together as connected—but distinct—spaces for evidence critique, reflection, and public-facing curiosity.

Welcome back What's it Worth? listeners.

This episode steps away from traditional trial critique. It's a year-end reflection on what it means to practice evidence-based healthcare at a moment when trust in science, institutions, and clinicians is eroding—and when evidence itself is increasingly being misused to create fear rather than understanding.

This episode is for frontline healthcare professionals and future providers who feel the weight of that shift and are asking how to respond without becoming part of a polarized conversation.

The answer, I believe, is not louder certainty—but better questions.

As we move into the next year, evidence-based practice will require more than knowing the literature. It will require clinicians who are willing to defend evidence with transparent communication, clarity, humility, and compassion—and who can help patients ask not just "Is there a study?" but "What's it worth?"

Learn more and continue the conversation:
Substack: https://whatsitworthpodcast.substack.com/
Email: whatsitworthpodcast@gmail.com

Secondary prophylaxis after spontaneous bacterial peritonitis (SBP) has long been considered standard of care—but how strong is the evidence behind it?

In this episode, host Dr. Diana Langworthy is joined by Dr. Ben Webber (hospital medicine physician) and Danielle Luettel (PharmD Candidate 2026) to unpack a contemporary observational study examining outcomes associated with SBP prophylaxis. Together, they explore how historical trials, modern resistance patterns, and guideline recommendations intersect—and where uncertainty still remains.

As care evolves over time, it is important to revisit standard practices to ensure they still make sense. How we revisit them is important and strong internal validity is still what we need to make practice changing claims.

• Secondary SBP prophylaxis is rooted in strong historical evidence but largely based on older trials.
• Contemporary observational data raise important questions about mortality benefit and patient selection.
• Guideline recommendations still support prophylaxis, but resistance patterns and evolving microbiology matter.
• Association does not equal causation—especially in retrospective database studies.
• Does this retrospective cohort study rise above the rest? ---> Tune in to find out!

Silvey S, Patel NR, Tsai, SY, et al. Higher Rate of Spontaneous Bacterial Peritonitis Recurrence With Secondary Spontaneous Bacterial Peritonitis Prophylaxis Compared With No Prophylaxis in 2 National Cirrhosis Cohorts. The American Journal of Gastroenterology 120(5):p 1066-1075, May 2025. | DOI: 10.14309/ajg.0000000000003075

Diana Langworthy, PharmD, BCPS
Associate Professor, University of Minnesota College of Pharmacy

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

Ben Webber, MD
Associate Professor, Division of Hospital Medicine
Senior Medical Director, Adult Med/Surg
University of Minnesota Medical Center – East Bank

Danielle Luetell
PharmD Candidate, Class of 2026

Subscribe to the What's it Worth? Podcast on Substack

If you want to get new episode alerts, bonus content, and continue reflecting on what studies like this mean for real clinicians and real patients—head over to the What's it Worth? substack.

Have a study you'd like us to decode on a future episode?
Email whatsitworthpodcast@gmail.com or share how you're navigating evidence in practice—I love hearing how clinicians and learners think through uncertainty.

Additional References & Guidelines

• American Association for the Study of Liver Diseases (AASLD)
  • Biggins, Scott W.*,1; Angeli, Paulo2; Garcia‐Tsao, Guadalupe3,4; et al. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 74(2):p 1014-1048, August 2021. | DOI: 10.1002/hep.31884
• European Associate for the Study of the Liver
  • EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology, Volume 53, Issue 3, 397 - 417
• Foundational Trial for Secondary Prophylaxis
  • Ginés P, Rimola A, Planas R, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology. 1990 Oct;12(4 Pt 1):716–724. doi:10.1002/hep.1840120416. PMID:2210673.

Episode Summary

SURMOUNT-5 delivers the first head-to-head comparison of tirzepatide vs semaglutide in adults with obesity but without diabetes.
In this episode, host Dr. Diana Langworthy and expert guest Dr. Kylee Funk (clinical pharmacist in primary care at Mill City Clinic specializing in weight management and diabetes) unpack the trial's design, results, interpretation, safety considerations, and what these findings mean for real-world clinical practice.

• Tirzepatide achieved greater weight loss than semaglutide over 72 weeks.

• Both drugs improved cardiometabolic markers with similar safety profiles.

• Open-label design and exclusion criteria affect how broadly results apply.

• Clinical decisions still hinge on access, coverage, tolerability, and goals.

Want the full trial breakdown?
I created a deeper analysis, including statistics, estimands, subgroup data, and my extended critique on my What's it Worth? Substack.
Subscribe there for extra trial notes, bonus insights, and updates between episodes.

Aronne LJ, Bade Horn D, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025;393(1):26-36. doi:10.1056/NEJMoa2416394.

Diana Langworthy, PharmD, BCPS – Associate Professor, University of Minnesota College of Pharmacy

Kylee Funk, PharmD, BCPS – Clinical Pharmacist in Primary Care, Mill City Clinic (focus: weight management & diabetes)

Have a study you'd like us to decode on a future episode? Email whatsitworthpodcast@gmail.com.
Share comments or takeaways — I love hearing how you're using evidence in practice.
And for full-length study breakdowns and bonus content, subscribe at whatsitworthpodcast.substack.com.

Could a medication designed for weight loss change how we think about migraine prevention?
In this episode, host Diana Langworthy sits down with returning guest Dr. Natalie Heinrich, PharmD and student contributor Nena Abosi, PharmD Candidate 2026 to unpack a 2025 Headache pilot study evaluating liraglutide as an add-on therapy for adults with obesity and high-frequency or chronic migraine. The team breaks down study design, results, and limitations while questioning whether the observed benefit stems from weight loss, intracranial-pressure changes, or something else entirely.

• Study Design: Prospective open-label pilot (n = 31) using liraglutide 1.2 mg daily × 12 weeks in adults with BMI > 30 kg/m² and ≥ 8 headache days/month unresponsive to ≥ preventives.
• Results: Headache days decreased by ~9 per month (≈ 50 % reduction); disability scores improved significantly, but BMI change was minimal.
• Mechanism: Benefit appeared independent of weight loss—raising curiosity about GLP-1 effects on intracranial pressure and CGRP release.
• Tolerability: Mild GI symptoms (~40 %), no discontinuations.
• Caveats: Small sample, no control group, single center — results are hypothesis-generating, not practice-changing.
• Clinical Pearl: Pilot studies like this spark conversation and awareness for emerging mechanisms while reminding clinicians to stay evidence-curious.

• Braca S, Russo CV, Stornaiuolo A, et al. Effectiveness and tolerability of liraglutide as add-on treatment in patients with obesity and high-frequency or chronic migraine: A prospective pilot study. Headache. 2025; 00: 1–8. doi:10.1111/head.14991

• Natalie Heinrich, PharmD, BCPS – Clinical Pharmacist in Neurology, M Health Fairview
• Nena Abosi, PharmD Candidate (2026) – University of Minnesota College of Pharmacy

• Diana Langworthy, PharmD, BCPS – Associate Professor, University of Minnesota College of Pharmacy

Have a study you'd like us to decode on a future episode? Send it our way at whatsitworthpodcast@gmail.com.
We'd also love to hear your thoughts—drop a comment, share your takeaways, or let us know how you're using this evidence in practice.