Adherence to antipsychotics is poor due to the presence of adverse effects.¹ Xanomeline is a muscarinic receptor agonist which lacks dopaminergic activity but causes considerable cholinergic reactions.¹ In a double-blind, phase 2 randomized clinical trial, xanomeline was combined with a peripherally restricted muscarinic receptor blocker, trospium, which has minimal activity on the central nervous system.² Compared to placebo, the group receiving xanomeline-trospium had a greater reduction of Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S) score.

Xanomeline is an oral muscarinic cholinergic receptor agonist which activates M1 and M4 muscarinic cholinergic responses.² Although xanomeline could effectively reduce psychotic symptoms in schizophrenic patients, non-specific activation of the peripheral muscarinic cholinergic system frequently led to cholinergic adverse events such as nausea, vomiting and sweating which negatively affect quality-of-life and result in poor treatment adherence.² Trospium chloride is an oral muscarinic receptor blocker with highly polar amine moiety which precludes its entry into the cerebrospinal fluid. In this connection, the effect of muscarinic blockade by trospium is largely peripheral with negligible biological action on the central nervous system.² In a phase 1 clinical trial, healthy individuals receiving xanomeline with trospium had a 50% lower incidence of cholinergic sequelae as compared to those receiving xanomeline alone.²

Following the favorable results from the initial study, a phase 2 clinical trial was further conducted to evaluate the efficacy and safety of this dual formulation on patients with primary diagnosis of schizophrenia hospitalized for acute exacerbation of psychosis.² All participants were inpatients but did not receive antipsychotic medications over two weeks before recruitment. Patients with a baseline PANSS total score of less than 79 points or CGI-S score lower than 4 were excluded from the study. To this end, eligible patients were randomly assigned to receive either xanomeline-trospium (n=83) or placebo (n=87) and followed up for over five weeks. The dosage schedule started with 50mg xanomeline and 20mg trospium twice daily and increased stepwise to a maximum of 125mg xanomeline and 30mg trospium twice daily. In case of intolerance, physicians could reduce the dosage to 100mg xanomeline and 20mg trospium twice daily.

At baseline, both the treatment and placebo groups were comparable in terms of average PANSS total score (97.7 vs. 96.6), positive symptom subscore (26.4 vs. 26.3), negative symptom subscore (22.6 vs. 22.8), and the CGI-S score (5.0 vs. 4.9).² At week 5, the PANSS total score in the xanomeline-trospium group was reduced by 17.5 points as compared to 5.9 point reduction in the placebo group (p<0.001).² Likewise, the score distribution of CGI-S also favored xanomeline-trospium (p<0.001).² The percentage of treatment discontinuation was similar between the treatment and placebo groups (20% vs. 21%).² However, 54% of patients in the treatment group reported adverse events as compared to 43% in the placebo group.² The most common side effects observed in the xanomeline-trospium group were constipation (17%), nausea (17%), dry mouth (9%), and dyspepsia (9%).² However, these adverse effects did not result in the discontinuation of xanomeline-trospium.²

In conclusion, this five-week phase 2 trial showed that a combination of xanomeline with trospium could better resolve psychotic symptoms when compared to placebo.² While the extrapyramidal symptoms and weight gain were similar between the xanomeline-trospium and placebo groups, but more cholinergic adverse effects were observed with the xanomeline-trospium treatment.