I recently participated in the 7th Neuropsychiatric Drug Development Summit in Boston, which was a refreshing experience. Steve Moss and I co-led a workshop focused on the integration of systems and cellular neuroscience as it relates to drug discovery (more on that in the near future, as well as all cool stuff that our labs are collaborating on!).
I had the unique opportunity to hear a talk by Steve Brannan, one of the key figures behind the development of KarXT (sold as Cobenfy in the U.S.). This happened just a single day before the FDA approved Cobenfy for the treatment of schizophrenia. Steve (Moss) and I talked to Brannan for about 30 minutes after the symposium and it was quite fascinating to learn about some of the challenges their team had to overcome during the process of drug development, clinical trials and finally FDA ruling.
As many readers may already know, Brannan served as the principal investigator in the pivotal clinical trials that brought KarXT from concept to clinic, such as EMERGENT-1, EMERGENT-2 and EMERGENT-3, showing the drug’s potential to address some of the unmet needs in schizophrenia treatment.
This development is especially exciting because KarXT represents a significant shift in how we approach schizophrenia pharmacotherapy. It leverages a different cellular mechanism of action compared to traditional antipsychotics, which may be related to its potential utility in areas where previous medications have stalled.
The Unique Mechanism and Composition of KarXT
KarXT is unique among antipsychotics because it targets muscarinic acetylcholine receptors rather than the dopamine receptors that have been the primary focus of antipsychotic treatments for decades. This two-drug combination consists of xanomeline and trospium.
- Xanomeline is a muscarinic receptor agonist, meaning it stimulates these receptors, which are involved in various central nervous system processes, including cognition, mood, and motor control.
- Trospium, on the other hand, is a peripherally acting muscarinic antagonist. Its role is to block the effects of xanomeline in the peripheral nervous system, which helps to minimize side effects such as gastrointestinal and cardiovascular issues that are often associated with muscarinic activation outside the brain.
This combination allows xanomeline to act primarily in the central nervous system, where it is believed to modulate circuits involved in the symptoms of schizophrenia. The ability to target the muscarinic system with minimal peripheral side effects is what sets KarXT apart from previous attempts to develop muscarinic-based therapies.
Targeting Negative and Cognitive Symptoms
One of the most exciting aspects of KarXT is its potential to target negative and cognitive symptoms, areas where current antipsychotic medications have largely fallen short. Negative symptoms—such as emotional blunting, anhedonia, and reduced social engagement—are often more disabling for patients, but they’ve proven notoriously difficult to treat. Cognitive deficits, such as poor attention, working memory issues, and difficulties with executive function, also represent significant barriers to a better quality of life for patients.
While positive symptoms like hallucinations can be fairly well controlled with dopaminergic medications, these negative and cognitive domains have been less responsive to treatment. In secondary analyses of the KarXT trials, some promising data has emerged regarding its efficacy in improving these difficult-to-treat symptoms. Perhaps this is related to KarXT’s unique pharmacology?
Caution: Not Without Side Effects
As with any new medication, there are side effects to consider. In clinical trials, some of the common side effects associated with KarXT included gastrointestinal issues like nausea, vomiting, and constipation. These muscarinic-related side effects are different from those associated with traditional antipsychotics, but they can still impact patient adherence and quality of life.
It’s crucial that clinicians remain vigilant when prescribing this drug, balancing the potential benefits with these side effects, particularly in patients who may already have sensitivities or complications due to other medications.
The Future of Psychiatric Treatment and the Role of KarXT
Looking ahead, KarXT’s approval opens up exciting new possibilities not just as a standalone treatment but also within the context of polypharmacy, which is often necessary in treating patients. Could KarXT be used to augment other antipsychotics, especially in patients who experience partial responses to dopaminergic treatments?
KarXT’s muscarinic mechanism may complement the dopaminergic treatments already in use, targeting specific symptom clusters more effectively when used together. It’s also possible that KarXT could lead to a deeper understanding of the neurobiology of schizophrenia itself. By engaging muscarinic receptors in patients, we may gain a better understanding of how the cholinergic system may contribute to symptoms, brain readouts or computational processes in individual patients, potentially leading to more targeted therapies in the future.
This idea of tailoring treatment more precisely mirrors the principles of algorithmic psychiatry, which I explored in an earlier post titled A Blueprint for Algorithmic Psychiatry: Revolutionizing Mental Health Treatment. In that piece, I discussed how the future of mental health care might lie in predictive models that leverage latent features and neurobiological data. KarXT’s novel mechanism may well fit into such frameworks, offering ways to ‘nudge’ the system in an interpretable manner.
Conclusion
KarXT is not a magic bullet, but it represents a fresh addition to the treatment of schizophrenia. Its distinct mechanism of action, combined with encouraging data on negative and cognitive symptom improvement, makes it a valuable new option for patients and clinicians alike. Of course, as with any new treatment, there are side effects and limitations to consider, but the approval of KarXT opens the door to a more nuanced, personalized approach to managing schizophrenia.
As we learn more about how this medication fits into the broader landscape of psychiatric treatment, there is hope that KarXT’s muscarinic mechanism could inspire the development of other innovative treatments, broadening our ability to treat this complex disorder in all its dimensions.
References
- Kaul, I., Sawchak, S., Correll, C. U., Kakar, R., Breier, A., Zhu, H., Miller, A. C., Paul, S. M., & Brannan, S. K. (2024). Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet (London, England), 403(10422), 160–170. https://doi.org/10.1016/S0140-6736(23)02190-6
- Kaul, I., Sawchak, S., Walling, D. P., Tamminga, C. A., Breier, A., Zhu, H., Miller, A. C., Paul, S. M., & Brannan, S. K. (2024). Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA psychiatry, 81(8), 749–756. https://doi.org/10.1001/jamapsychiatry.2024.0785
- Brannan, S., Presentation at the 7th Neuropsychiatric Drug Development Summit, Boston, September 2024.
- FDA Approves KarXT for Schizophrenia Treatment. (2024). NPR– https://www.npr.org/2024/09/26/nx-s1-5123694/for-the-first-time-in-decades-the-fda-has-approved-a-new-type-of-schizophrenia-drug
- Previous blog post on algorithmic psychiatry. https://michaelhalassa.com/a-blueprint-for-algorithmic-psychiatry-revolutionizing-mental-health-treatment/.