Cobenfy (KarXT): A More Atypical Antipsychotic for Treatment of Schizophrenia

Cobenfy (also known as KarXT), a combination of the drugs xanomeline and trospium chloride, has been studied to be effective for the treatment of schizophrenia and has been approved by the FDA as an antipsychotic in September 2024¹. This is, however, a completely new type of schizophrenia treatment as all prior drugs are antagonists of the dopamine receptor (called typical antipsychotics), D2, and the serotonin receptor (called atypical antipsychotics), 5-HT2A²; whereas xanomeline is an acetylcholine muscarinic receptor agonist for M1 and M4 subtypes³ and trospium chloride is an acetylcholine muscarinic receptor antagonist for M1, M2 and M3 subtypes⁴. This is therefore a novel treatment for schizophrenia and elucidates the likelihood that there may be some unutilised pharmacological agents which could involve targeting acetylcholine muscarinic receptors for the treatment of schizophrenia or psychosis in general. 

Schizophrenia is a psychiatric disorder characterised by psychotic symptoms such as delusions, hallucinations and lack of motivation. This is proposed to be regulated primarily via the dopaminergic system and potentially also involves the serotonergic system⁵. However, acetylcholine muscarinic receptors are known to strongly interact with dopamine neurons influencing their release of dopamine in neuronal synapses and postsynaptic effects⁶. It is through this mechanism that a prior antipsychotic, clozapine, which antagonises serotonin and dopamine receptors, is thought to have a favourable side effect profile unlike other antipsychotics due to its antagonism of M1 acetylcholine receptors⁵. 

Three clinical randomised placebo-controlled trials used the drug combination as monotherapy for the treatment of schizophrenia patients who had an acute exacerbation of psychosis, with the trials lasting 5 weeks⁷. The drug combination significantly outperformed placebo in treating schizophrenic symptoms as measured by the PANSS (Positive and Negative Syndrome Scale) in the clinical trials, especially regarding negative symptoms such as lack of motivation and communicative deficits, suggesting it is an effective antipsychotic treatment⁷.  

The clinically demonstrated benefits of targeting the cholinergic system for the treatment of schizophrenia and psychosis demonstrates the potential for new treatments for these psychiatric disorders which may be of a favourable side effect profile when compared to typical antipsychotics. 

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References  

1. FDA News release – FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. Published 26 September 2024. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia  

2. Chokhawala K, Stevens L. Antipsychotic Medications. [Updated 2023 Feb 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519503/ 

3. Xanomeline. Science Direct. Available at https://www.sciencedirect.com/topics/neuroscience/xanomeline  

4. Rovner, E.S. Trospium Chloride in the Management of Overactive Bladder. Drugs 64, 2433–2446 (2004). https://doi.org/10.2165/00003495-200464210-00005  

5. McCutcheon, Robert A. et al. Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms. Trends in Neurosciences, Volume 42, Issue 3, 205 – 220. DOI: DOI: https://doi.org/10.1016/j.tins.2018.12.004  

6. Threlfell1 S. and Cragg  S.J., 2011. Dopamine signaling in dorsal versus ventral striatum: the dynamic role of cholinergic interneurons. Front. Syst. Neurosci., 03 March 2011. Volume 5 – 2011. DOI: https://doi.org/10.3389/fnsys.2011.00011  

7. Horan W.P., et al 2024. Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials. Schizophrenia Research. Volume 274, December 2024, Pages 57-65. DOI: https://doi.org/10.1016/j.schres.2024.08.001  

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