Xanomeline-trospium (KarXT), a Novel Treatment for Schizophrenia
Standard treatments for schizophrenia typically involve antipsychotic medications that target D2 dopamine receptors, but these drugs often fall short in addressing all symptoms and can cause significant side effects such as motor impairments, metabolic issues, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia, or TD (read Dr. Danish’s blog on TD, here).
Recent research on xanomeline-trospium (KarXT) for the treatment of schizophrenia has shown promising results, particularly in long-term efficacy, safety, and metabolic outcomes. This review delves into the current findings and explores the novel mechanisms through which KarXT operates in the treatment of schizophrenia.
Mechanism of Action
Unlike traditional antipsychotics, which exert their antipsychotic efficacy by blocking dopamine receptors in the mesolimbic pathway to reduce the positive symptoms (such as hallucinations and delusions), KarXT acts on muscarinic receptors in a variety of ways.
Muscarinic acetylcholine receptors (mAChRs) are a type of acetylcholine receptor that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. There are 5 subtypes of muscarinic receptors (M1 through M5) and their activation results in a myriad of cellular, neurologic, and body changes that vary depending on which are activated, and where in the body they are activated.
KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Xanomeline can cross the blood-brain barrier (BBB) to stimulate muscarinic receptors in the brain, potentially improving both positive and negative symptoms of schizophrenia. Trospium, which does not cross the BBB, acts peripherally to mitigate side effects associated with xanomeline.
Long-Term Efficacy
EMERGENT-4 Trial: Interim results from the Phase 3 EMERGENT-4 trial demonstrated that long-term treatment with KarXT led to continued improvements in schizophrenia symptoms over 52 weeks. More than
75% of participants achieved over 30% improvement in symptoms from baseline, as measured by the Positive and Negative Syndrome Scale (PANSS) total score. Significant symptom reduction was observed as early as week two and was maintained throughout the treatment period.
Symptom Improvement: The improvements were consistent across all efficacy measures, including positive, negative, and cognitive symptoms of schizophrenia. This suggests that KarXT could be a comprehensive treatment option for various symptom domains of schizophrenia.
Safety and Tolerability
Metabolic Profile: KarXT showed a favorable long-term metabolic profile, with most patients experiencing stability or improvements in metabolic parameters over the 52-week treatment period.
Notably, 65% of patients experienced reductions in weight, with an average weight decrease of 2.6 kg at one year.
Side Effects: The drug was generally well tolerated, with side effects mainly mild to moderate in severity and transient.
Importantly, KarXT was not associated with significant changes in prolactin levels or clinically meaningful changes in movement disorder scale scores, which are common side effects of many antipsychotic medications.
Mechanism of Action
Muscarinic Receptor Agonist: KarXT is a dual M1/M4 muscarinic acetylcholine receptor agonist, which differentiates it from traditional antipsychotics that primarily target dopamine receptors. This novel mechanism is thought to improve a broader range of schizophrenia symptoms without the typical side effects associated with dopamine receptor antagonism.
Clinical Implications
Given the limitations of current schizophrenia treatments, which often have significant side effects or limited efficacy, KarXT represents a potential new therapeutic option. Its ability to improve a wide range of symptoms with a favorable side effect profile could make it a valuable addition to the treatment landscape for schizophrenia.
As of this writing, KarXT is anticipated to be available by the fourth quarter of 2024. Dr. Danish and his team at Philadelphia Integrative Psychiatry are dedicated to staying updated on the latest research and are particularly enthusiastic about this new medication, which targets muscarinic receptors, offering new hope for effective symptom management with fewer side effects.
Related Blogs:
Read more about Tardive Dyskinesia (TD) in this blog, here.
Citations:
https://link.springer.com/article/10.1007/s40261-024-01377-9
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2823%2902190-6/fulltext
