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Xanomeline/trospium - novel antipsychotic, muscarinic agonist

xanomeline/trospium antipsychotic muscarinic agonist karxt

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#1 Galaxyshock

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Posted 29 February 2024 - 03:43 AM


Possibly very interesting new way to treat psychotic disorders through cholinergic system thus avoiding the rather broad range of side effects that common antipsychotics cause.

 

 

Xanomeline/trospium,also known under the brand name KarXT, is an investigational oral dual-drug fixed-dose combination of xanomeline and trospium. It is undergoing a phase 3 clinical trial for the treatment of schizophrenia. Xanomeline is a functionally preferring muscarinic M4 and M1 receptor agonist that readily passes into the central nervous system (CNS) to stimulate these receptors in key areas of the brain. Trospium is a non-selective muscarinic antagonist that does not cross into the CNS and reduces peripheral cholinergic side effects associated with xanomeline.

Mechanism of action
Preclinical data supports the hypothesis that xanomeline’s central mechanism of action is mediated primarily through stimulation of brain muscarinic M4 and M1 receptors.[1] M4 muscarinic receptors are most highly expressed in the midbrain, which controls motor and action planning, decision-making, motivation, reinforcement, and reward perception. M1 muscarinic receptors are most highly expressed in the cerebral cortical regions, which regulate higher-level processes including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence, and personality.[2] Unlike direct dopamine D2 and serotonin 5HT2A blocking antipsychotic medications, M4 and M1 receptor stimulation indirectly rebalances dopaminergic and glutamatergic circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and Alzheimer’s disease. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate both psychosis and cognitive symptom domains and M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.[3][4]

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#2 Galaxyshock

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Posted 29 February 2024 - 04:48 AM

Many antipsychotics currently used have the opposite effect - muscarinic antagonism (on top of antagonizing serotonin and dopamine receptors etc.). Perhaps that is a reason for their sometimes lacking efficacy for psychotic symptoms and also worsening of cognition? Well on top of that they sometimes prescribe anticholinergic drugs such as Biperiden to treat the side effects of APs further blocking the muscarinic receptors which may in fact be very relevant in the pathophysiology of psychotic disorders.

 

Hopefully these new APs like Xanomeline/trospium and serotonin-dopamine activity modulators turn the course of psychotic disorders treatment to people functioning better.


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#3 Galaxyshock

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Posted 03 March 2024 - 08:01 AM

Just typing muscarinic receptors and schizophrenia to google immediately shows bunch of studies about the new interest in them in treatment of Schizophrenia and psychotic disorders. So it seems like the next big thing in antipsychotic development.

 

Muscarinic receptors as a target for drugs treating schizophrenia

https://pubmed.ncbi....h.gov/12769625/

 

Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia

https://ajp.psychiat...pi.ajp.21101083

 

Targeting Muscarinic Receptors to Treat Schizophrenia

https://www.ncbi.nlm...les/PMC8006961/

 

Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic

https://www.scienced...165614722002024

 

But I do wonder that probably muscarinic agonists still aren't the end-all psychosis treatment knowing the very complex nature of schizophrenia and psychotic disorders. But if they do offer strong efficacy against psychosis and lack the side effect profile of current antipsychotics, it's definitely step towards right direction.

 

I don't know if there are any supplemental muscarinic agonists? They could provide at least some adjunctive help combined with current antipsychotics while waiting for these novel APs to hit the market.



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#4 Galaxyshock

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Posted 06 March 2024 - 05:52 AM

New schizophrenia medications could signal a comeback for psychiatric drugs

Muscarinic agonists may reignite Big Pharma’s interest in psychiatry

 

https://cen.acs.org/...comeback/102/i7







Also tagged with one or more of these keywords: xanomeline/trospium, antipsychotic, muscarinic, agonist, karxt

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