Jonathan Meyer, MD: Cognitive Gains, Dopamine-Free Schizophrenia Treatment with Xanomeline Trospium Chloride

Muscarinic modulators, particularly drugs like the recently approved xanomeline tropism chloride capsules (Copenfy), have offered fresh insights into schizophrenia’s neurobiology by confirming animal model findings in humans.¹

Research on muscarinic modulators in animals has shown positive symptoms of psychosis stem from too much dopamine release in the mesolimbic pathway.² The same thing occurs in humans but in a different path.

“…the fact that we have now a muscarinic agonist, which does seem to reduce the positive symptoms of schizophrenia, really confirms something that we always suspected,” Jonathan Meyer, MD, a clinical professor from the University of California, San Diego, told HCPLive.

HCPLive sat down in an interview with Meyer following his presentation on muscarinic modulators at the 2024 Southern California Psychiatry Conference on September 14, 2024. In the interview, he discussed the positive outcomes he anticipates with muscarinic modulators, especially regarding cognitive boost.

He said how people on xanomeline trospium chloride capsules had improvements in cognitive symptoms. This was particularly true among patients with low M1 receptor expression which accounts for a quarter of the patient population with schizophrenia.

A report on composite data stated that although patients on this medication received improvements in negative symptoms, the improvement was independent of the improvement of positive or total symptoms.

“These are sometimes hard to tease out when you make schizophrenia better,” Meyer said. “Overall, everything gets better, including negative symptoms… The question is, does it improve them more or disproportionately than you might expect with a degree of overall improvement? I'm not sure about that.”

Meyer said xanomeline trospium chloride capsules come with unusual warnings that clinicians should be aware of, including concerns about urinary retention, constipation, and not taking centrally acting muscarinic antagonists.

He added how xanomeline trospium chloride capsules offer the opportunity to treat schizophrenia symptoms without the d2-related adverse events, including proactive-related problems and movement disorders such as tardive dyskinesia.

“This is exciting that we might also get some cognitive benefit…but I think most people would have been very happy with just with the fact that we have a drug which doesn't do a lot of the things that we got from d2 binding antipsychotics,” Meyer said. “For the future of schizophrenia, we now have come away from the need to have to use the d2 receptor as part of the mechanism to a whole other way to modulate the symptoms of schizophrenia, especially the positive symptoms with a muscarinic activating agent.”

Relevant disclosures for Meyer include Alkermes, Inc, Teva Pharmaceuticals, Neurocrine Biosciences, Inc, Axsome Therapeutics, ITI, Inc, and ABBVIE Inc.

References

1. ^{Meyer, J. Expert Perspectives on Muscarinic Modulators for the Management of Schizophrenia. Southern California Psychiatry Conference on September 14, 2024, in Huntington Beach, California.}
2. ^{Iasevoli F, Avagliano C, D'Ambrosio L, et al. Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal. Biomedicines. 2023;11(3):895. Published 2023 Mar 14. doi:10.3390/biomedicines11030895}