Antipsychotic efficacies and side-effects evaluation and head-to-head comparison of xanomeline and KarXT in preclinical rodent models of schizophrenia

Introduction

In 2024, KarXT, a novel co-formulation of xanomeline and trospium chloride, was approved by FDA for the treatment of schizophrenia in adults. While xanomeline provides central muscarinic agonism for antipsychotic efficacy, it was historically limited by intolerable peripheral cholinergic side effects, including diaphoresis (sweating), hypersalivation, and severe vomiting. The addition of trospium, a peripherally restricted muscarinic antagonist, effectively mitigates xanomeline’s peripheral toxicity without compromising its central antipsychotic activity. However, centrally mediated side effects like dizziness and somnolence persist, alongside new anticholinergic effects (e.g., constipation) induced by trospium. While the preclinical profile of xanomeline monotherapy is extensively documented, studies investigating the pharmacological dynamics of the combined KarXT formulation remain sparse.

Aims

This study aims to systematically verify the antipsychotic-like effects of xanomeline in preclinical models of schizophrenia, and to conduct a head-to-head comparison against KarXT regarding antipsychotic efficacies and sides effects.

Methods

Positive-like symptoms were evaluated using amphetamine induced hyperactivity in rodents, PCP induced hyperactivity, apomorphine induced climbing and DOI induced head-twitch response in mice. Cognitive-like symptoms were evaluated using conditioned avoidance response (CAR) test and Ketamine induced pre-pulse inhibition (PPI) deficit test in rats. General side effects and motor function were evaluated using the Irwin test and rotarod test in rodents, respectively. In addition, xanomeline monotherapy and KarXT combination were directly compared in mice amphetamine induced hyperactivity, rat CAR test, mice Irwin test and rat rotarod test. Data are presented as mean ± SEM. Ordinary one-way or repeated measures two-ways ANOVAs with appropriate post -hoc analysis were performed accordingly.

Results

Acute xanomeline (1-10 mg/kg, s.c.) dose dependently attenuated amphetamine induced hyperactivity in both mice and rats, and PCP induced hyperactivity and DOI induced head twitch response in mice. Xanomeline 1 and 3 mg/kg (s.c.) also reversed apomorphine induced climbing in mice. In rats, xanomeline (0.3-10 mg/kg, s.c.) dose dependently reduced CAR rate and increased escape latency in CAR test, and dose dependently reversed ketamine induced PPI deficit (1-10 mg/kg, s.c.). Furthermore, xanomeline (3-30 mg/kg, s.c.) induced hypoactivity, salivation, lacrimation, impaired grip reflex, hypothermia and constipation in mice, with similar but milder effects observed in rats (3-30 mg/kg, i.p.). Xanomeline (0.3-10 mg/kg, i.p. for mice and s.c. for rats) also dose dependently impaired rotarod performance.

On the other hand, a combination of xanomeline 10 mg/kg and trospium 0.75 mg/kg (s.c.) completely eliminated xanomeline 10 mg/kg (s.c.) induced salivation, without affecting all other side effects in mice. The combination regimen neither affected the motor suppression effects of xanomeline 0.3 and 10 mg/kg (s.c.) in rat rotarod test, and antipsychotic-like effects of 3 mg/kg (s.c.) in mice amphetamine induced hyperactivity, as well as 1 and 3 mg/kg (s.c.) in rat CAR test.

Conclusions

This study validated the antipsychotic efficacies of xanomeline in various preclinical rodent models of schizophrenia representing positive and cognitive symptoms, alongside its side effect profiles. Importantly, our head-to-head comparison demonstrates that KarXT selectively eliminates peripheral hypersalivation while fully preserving central antipsychotic efficacies. These findings provide critical, previously uncharacterized in vivo validation for this newly approved therapeutic combination.

References

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