Targeting muscarinic receptors in schizophrenia treatment: Novel antipsychotic xanomeline/trospium chloride

Abstract

This minireview explores the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia and summarizes the latest data on xanomeline/trospium chloride, a novel antipsychotic approved by the United States Food and Drug Administration in September 2024. Evidence suggests that cholinergic dysfunction, particularly an imbalance in the expression of the M1 and M4 muscarinic receptors, may contribute to the pathophysiology and symptoms of schizophrenia. Xanomeline/trospium chloride combines xanomeline, an M1 and M4 receptor agonist, with trospium chloride, a non-selective peripheral muscarinic receptor antagonist that reduces peripheral cholinergic side effects. Clinical trials have demonstrated significant reductions in the positive and negative symptoms of schizophrenia, with improvements in Positive and Negative Syndrome Scale scores observed as early as two weeks. A post-hoc analysis of one trial revealed cognitive improvements in patients with baseline cognitive impairment. This medication was generally well-tolerated, with mild-to-moderate gastrointestinal symptoms being the most common adverse events. While these results are promising, further research is needed to better understand its effectiveness and safety in real-world clinical practice, and to define its optimal role in managing this complex psychiatric disorder.

Key Words: Muscarinic receptors; Schizophrenia; Antipsychotic; Xanomeline; Trospium chloride; Review

Core Tip: Xanomeline/trospium chloride is a potential new treatment option for a wide range of schizophrenia symptoms, offering a relatively favorable tolerability and safety profile. However, additional research is required to better understand its effectiveness and safety in real-world clinical practice, and to define its optimal role in managing this complex psychiatric disorder. As new evidence emerges, it is vital to evaluate it critically.

INTRODUCTION

Schizophrenia is a chronic, severe, heterogeneous, and debilitating psychiatric disorder that affects approximately 1% of the population[1,2]. It is characterized by three main groups of symptoms: Positive, negative, and cognitive[2-5]. Positive symptoms include hallucinations, delusions, and disorganized thinking[2-4,6], whereas negative symptoms represent heterogeneous dimensions and include anhedonia, avolition, alogia, asociality, and blunted affect[7]. Cognitive symptoms include impairments in attention, concentration, processing speed, learning, memory, reasoning, problem solving, and social cognition[8].

The biological basis of schizophrenia is complex and involves multiple factors (e.g., neurodevelopmental, genetic, environmental, and immunological)[1,5]. Although dopamine dysfunction has long been associated with schizophrenia, growing evidence suggests that dysfunction in other signaling pathways, such as the serotonergic, glutamatergic, gamma-aminobutyric acid (GABA), and cholinergic systems, may also contribute to its pathophysiology[3,9].

Antipsychotics are the cornerstone of schizophrenia treatment[10]. These medications primarily act as antagonists or partial agonists of dopamine (e.g., D2, D3, and D4) and serotonin receptors[2,6,10]. These drugs can cause a range of adverse effects that vary among individual drugs[5,6,11]. For example, typical antipsychotics are commonly associated with extrapyramidal side effects and hyperprolactinemia, whereas atypical antipsychotics are more likely to cause metabolic syndrome and weight gain[5,6,11]. Furthermore, they are mostly effective in alleviating positive symptoms but have limited efficacy in addressing negative and cognitive symptoms[5,6,11]. Additionally, a significant proportion of patients either fail to respond or experience only partial improvement with these medications[5,6,11]. In September 2024, the United States Food and Drug Administration (FDA) approved a novel antipsychotic agent targeting muscarinic receptors for the treatment of schizophrenia[12]. This first-in-class medication combines xanomeline, an agonist of muscarinic M1 and M4 receptors, with trospium chloride, a nonselective peripheral muscarinic receptor antagonist, added to reduce the adverse effects from peripheral muscarinic receptors activation[13-15].

This minireview aims to provide an overview of the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia as well as the latest available data on xanomeline/trospium chloride, with a particular focus on its efficacy, safety, tolerability, prescribing information, and directions for future research.

ROLE OF ACETYLCHOLINE AND MUSCARINIC RECEPTORS IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA

Increasing evidence suggests an important role of cholinergic dysfunction in the pathophysiology of schizophrenia, which may directly or indirectly contribute to the schizophrenia symptoms by modulating the dopaminergic, GABA-ergic or glutamatergic neurotransmission in areas such as the striatum, cortex, and hippocampus[16-18].

Acetylcholine is an important neurotransmitter involved in both the peripheral and central nervous systems (CNS)[5]. It serves as the main neurotransmitter in the parasympathetic system and is involved in cognitive functions, such as memory, learning, motivation, and attention[5]. There are two main types of cholinergic receptors: Nicotinic and muscarinic[5]. Nicotinic receptors are ligand-gated ion channels and their activation triggers rapid responses, whereas muscarinic receptors are G protein-coupled receptors and their activation leads to long-lasting effects[5,19]. Muscarinic receptors are abundant in the CNS and regulate signaling pathways by activating intracellular second messengers[6].

There are five subtypes of muscarinic receptors with distinct tissue distributions: M1, M2, M3, M4, and M5[5,6,19]. These subtypes are further divided into two categories with opposing functions[6]. The first category includes the M1, M3, and M5 receptor subtypes, which are coupled to Gq/G11 proteins that activate phospholipase C to generate inositol triphosphate and other second messengers[6,19]. This activation ultimately inhibits potassium channels in many neuronal populations, thereby increasing cell excitability (i.e., stimulating and increasing neuronal activity)[6,20,21]. In contrast, the M2 and M4 receptor subtypes are coupled to Gi/Go proteins and their activation leads to the inhibition of adenylyl cyclase and a reduction in cyclic adenosine monophosphate, ultimately inhibiting voltage-gated calcium channels and decreasing cell excitability (i.e., they reduce neuronal activity)[6,19-21]. Notably, some muscarinic receptor subtypes activate multiple signal transduction pathways[22].

M2 receptors are primarily located in the heart, where they regulate heart function (their activation reduces heart rate and weakens the force of contraction)[6]. M3 receptors are widely distributed in peripheral tissues, where they mediate various physiological functions such as glandular secretion, smooth muscle contraction, and endothelium-dependent vasodilation[6]. M5 receptors are predominantly expressed in the cerebral vascular system, where they regulate cerebral vasodilation and blood flow[6]. Although all muscarinic receptor subtypes are expressed to some degree in the CNS[22], the M1 and M4 receptors seem to be the most important muscarinic receptors involved in the pathophysiology of schizophrenia[6,23,24]. M1 receptors are mainly located in the CNS, particularly in the regions associated with cognitive function, learning, and memory[6]. Their activation has a stimulatory effect on these functions owing to enhanced synaptic transmission and increased neuronal excitability[6]. M4 receptors are also predominantly expressed in the CNS, particularly in regions related to cognition, motor control, and emotion[6,23]. It should also be noted that cholinergic projections stimulate dopamine neurons in the midbrain and that activation of M1 receptors enhances the release of dopamine through dopaminergic afferents[5,25-27]. In contrast to the M1 receptor, the M4 receptor is an autoreceptor located on the presynaptic terminals[5,26]. This serves as a feedback mechanism that controls acetylcholine release from cholinergic interneurons in the striatum[5,26]. Consistent with its autoreceptor function, the activation of M4 receptors reduces acetylcholine release from these neurons, which in turn decreases dopamine neuronal activity and dopamine release[5,25].

Muscarinic receptors are located in cortical and subcortical areas where they modulate dopaminergic neurotransmission, which is considered dysfunctional in schizophrenia[28]. Key brain regions associated with classical psychotic circuits include the striatum, frontal cortex, and hippocampus, where both M1 and M4 receptors are mainly expressed[6,22]. This indicates that they are well-positioned to modulate circuits disrupted during psychosis[6,22]. M1 receptors are particularly highly expressed in cortical structures that modulate dopamine mid-circuits in a top-down manner, whereas M4 receptors are more highly expressed in subcortical regions such as the striatum[6,22]. Therefore, these receptors are well positioned to modulate dopamine circuits via a bottom-up mechanism, given that their presynaptic localization helps maintain the balance between acetylcholine and dopamine levels in the striatum[6,22]. Additionally, studies have shown a decrease in the number of muscarinic M1 receptors in patients with schizophrenia[29-31]. Moreover, in vivo molecular neuroimaging studies conducted on medication-free patients with schizophrenia or early psychosis have provided evidence linking changes in M1/M4 receptors to the severity of cognitive and positive or negative symptoms[16]. Collectively, these findings provide preliminary support for an imbalance in the expression of M1/M4 receptors in schizophrenia, which could directly affect the clinical manifestations and outcomes in patients with schizophrenia, making them potential therapeutic targets for new antipsychotic medications[16].

XANOMELINE/TROSPIUM CHLORIDE

History of development and formulation

Xanomeline was initially designed as a high-affinity agonist of M1 receptors and has been investigated for the treatment of cognitive impairment in Alzheimer’s disease[5,32,33]. Clinical research has demonstrated that xanomeline leads to a dose-dependent improvement in cognitive function and reduction in coexisting psychotic symptoms in these patients[5,34]. However, its use is associated with poor tolerability, as many patients experience adverse cholinergic effects (e.g., nausea, vomiting, diarrhea, salivary hypersecretion, and excessive sweating) due to the activation of muscarinic receptors in peripheral tissues[5,34]. Subsequently, xanomeline was found to be an agonist of M4 receptors and exhibits antipsychotic-like effects in primates and rodents[35,36]. These findings, along with a growing understanding of the role of the cholinergic system and muscarinic receptors in schizophrenia, suggest that xanomeline could be useful for the treatment of schizophrenia[28,33]. This hypothesis was tested in a small pilot study utilizing a double-blind, randomized, placebo-controlled 4-week treatment design[37]. Twenty patients entered the study and were randomly assigned to the xanomeline (titrated up to 225 mg/day) or placebo groups after tapering off any previous medications[37]. In this study, xanomeline improved the total scores on the Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale (PANSS), and patients showed improvements in short-term memory and verbal learning[37]. Given that the use of xanomeline was associated with adverse cholinergic effects, particularly gastrointestinal effects, further development focused on finding a way to reduce their occurrence[33,37,38]. Consequently, it was hypothesized that the peripheral muscarinic receptor antagonist trospium chloride, which does not cross the blood-brain barrier, could mitigate adverse cholinergic effects without interfering with its central mechanism of action[38]. Therefore, a combination of xanomeline and trospium chloride (named KarXT) was developed and used for further clinical testing[38]. A phase 1 study (NCT02831231)[39] conducted on healthy volunteers showed that the combination of xanomeline and trospium chloride reduced the incidence of adverse cholinergic effects compared to xanomeline alone, paving the way for future studies on xanomeline/trospium chloride in patients with schizophrenia[38].

Mechanism of action

The precise mechanism of action of xanomeline in the treatment of schizophrenia is unclear, but its efficacy is believed to be closely related to its agonistic activity at the M1 and M4 muscarinic receptors in the CNS[40]. The activation of M1 and M4 receptors can indirectly affect the dopaminergic system and modulate its activity[5]. Although xanomeline primarily targets M1 and M4 receptors, it can also affect other muscarinic receptors (M2, M3, and M5) at higher doses[5]. Additionally, xanomeline has an affinity for 5HT1 and 5HT2 serotonin receptors; studies indicate that it is a potent agonist of 5HT1A and 5HT1B and an antagonist of 5HT2 receptor subtypes[41]. Trospium chloride is a nonselective muscarinic receptor antagonist that helps reduce adverse effects resulting from the activation of muscarinic receptors in peripheral tissues[5,40,42].

Clinical trials evaluating the efficacy, safety, and/or tolerability of xanomeline/trospium chloride in schizophrenia

An overview of the clinical trials evaluating the efficacy, safety, and/or tolerability of xanomeline/trospium chloride in patients with schizophrenia is provided in Table 1. Xanomeline/trospium chloride was initially tested in adult patients with schizophrenia with acute exacerbation or relapse of psychosis requiring hospitalization in a 5-week phase 2 clinical trial named EMERGENT-1 (NCT03697252)[43,44]. Based on the positive results of this trial, the EMERGENT phase 3 program was initiated. This program consisted of two inpatient 5-week trials named EMERGENT-2 (NCT04659161)[14,45] and EMERGENT-3 (NCT04738123)[46,47] that used the same fundamental design as EMERGENT-1, and two outpatient 52-week open-label trials of long-term safety and tolerability, named EMERGENT-4 (NCT04659174)[48] and EMERGENT-5 (NCT04820309)[49]. EMERGENT-4 is an extension study of patients who completed the EMERGENT-2 and EMERGENT-3 trials[48], whereas EMERGENT-5 was conducted in de novo subjects with schizophrenia who had stable symptoms on a previous antipsychotic but had not been previously exposed to xanomeline/trospium chloride[49]. Additionally, an ongoing trial aims to evaluate the efficacy and safety of xanomeline/trospium chloride in acutely psychotic Chinese adult patients with schizophrenia [NCT05919823 (UNITE-001)][50], whereas one open-label trial was terminated as a result of the company’s business decision [NCT05643170 (PENNANT)][51]. Furthermore, two ongoing outpatient trials are aimed at testing adjunctive xanomeline/trospium chloride in patients with inadequately controlled symptoms of schizophrenia: A 6-week randomized double-blind placebo controlled study [NCT05145413 (ARISE)][52] and a 52-week open-label extension trial to evaluate its long-term safety and tolerability (NCT05304767)[53].

Table 1 An overview of clinical trials in schizophrenia patients listed in the ClinicalTrials.gov registry up to January 19, 2025.

ClinicalTrials.gov ID, other study IDs	Official title	Phase	Status	Duration of treatment	Start date	Completion date
NCT03697252[44], EMERGENT-1, KAR-004	A phase 2, randomized, double-blinded study to assess the safety, tolerability, and efficacy of KarXT in hospitalized adults with DSM-5 schizophrenia	2	Completed	5 weeks	September 18, 2018	September 04, 2019
NCT04659161[45], EMERGENT-2, KAR-007	A phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the efficacy and safety of KarXT in acutely psychotic hospitalized adults with DSM-5 schizophrenia	3	Completed	5 weeks	December 16, 2020	May 24, 2022
NCT04738123[46], EMERGENT-3, KAR-009	A phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the efficacy and safety of KarXT in acutely psychotic hospitalized adults with DSM-5 schizophrenia	3	Completed	5 weeks	April 06, 2021	December 07, 2022
NCT04659174[48], EMERGENT-4, KAR-008	An open-label extension study to assess the long-term safety, tolerability, and efficacy of KarXT in subjects with DSM-5 schizophrenia	3	Completed	52 weeks	February 01, 2021	October 03, 2023
NCT04820309[49], EMERGENT-5, KAR-011	An open-label study to assess the long-term safety, tolerability, and efficacy of KarXT in de novo subjects with DSM-5 schizophrenia	3	Completed	52 weeks	June 02, 2021	May 24, 2024
NCT05643170[51], PENNANT, KAR-014	A multi-center, open-label study to assess the effectiveness, long-term safety, tolerability, and durability of effect of KarXT in patients with DSM-5 diagnosis of schizophrenia	3	Terminated (company's business decision)	3 years	November 08, 2022	March 08, 2023
NCT05919823[50], UNITE-001	A phase 3, multicenter, two-part study with a 5-week double-blind part (randomized, parallel-group, placebo-controlled) followed by a 12-week open-label extension part, to evaluate the efficacy and safety of KarXT in acutely psychotic hospitalized Chinese adult subjects with DSM-5 schizophrenia	3	Recruiting	5 weeks (double-blind) + 12 weeks (open-label)	May 29, 2023	May 2025 (estimated)
NCT05145413[52], ARISE, KAR-012	A phase 3, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia	3	Recruiting	6 weeks	November 12, 2021	February 28, 2025 (estimated)
NCT05304767[53], KAR-013	An open-label extension study to assess the long-term safety and tolerability of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia	3	Recruiting	52 weeks	March 07, 2022	February 27, 2026 (estimated)

KarXT: Xanomeline/trospium chloride; DSM-5: Diagnostic and Statistical Manual of Mental Disorders, fifth edition.

In all studies, the dosing schedule for xanomeline/trospium chloride oral capsules includes an initial dose of 50 mg/20 mg twice daily on days 1 and 2, followed by 100 mg/20 mg twice daily on days 3-7, whereas from day 8 dosing is flexible, with the option to increase to 125 mg/30 mg twice daily and the option to return to 100 mg/20 mg twice daily based on tolerability[44-46,48-53].

The pooled analysis from three 5-week trials (EMERGENT-1, EMERGENT-2, and EMERGENT-3) showed that xanomeline/trospium chloride was associated with a significant decrease in the PANSS total score (-19.4 points vs -9.6 points), PANSS positive subscale score (-6.3 points vs -3.1 points), PANSS negative subscale score (-3.0 points vs -1.3 points), PANSS Marder negative factor score (-3.8 points vs -1.8 points), and the Clinical Global Impression-Severity (-1.1 points vs -0.5 points) compared with placebo[54]. There were significantly more PANSS responders (≥ 30% reduction from baseline in PANSS total score) in the xanomeline/trospium chloride group (41.4%) than in the placebo group (20.9%)[54]. Meta-analyses that combined data from these trials reached similar conclusions[55,56]. Compared to a placebo, xanomeline/trospium chloride generally showed a significant decrease in positive and negative symptoms[14,43,55-58]. The key findings from the three 5-week trials (EMERGENT-1, EMERGENT-2, and EMERGENT-3) regarding the effects of xanomeline/trospium chloride on the PANSS scores are shown in Table 2. A significantly higher response rate and improvement in the PANSS total score compared to placebo were observed as early as 2 weeks[47,54,57]. A post hoc analysis of the EMERGENT-1 data showed significant cognitive improvements after xanomeline/trospium chloride treatment only in the subgroup of patients with cognitive impairment at baseline, which seemed to be independent of improvement in other symptoms as they were poorly correlated with the total PANSS score[59]. The number needed to treat for the number of patients required to achieve a PANSS response (improvement in total PANSS score) at week 5 ranged from 3 (≥ 20% improvement) to 11 (≥ 50% improvement) in EMERGENT-1 trial[57].

Table 2 Key findings on the effects based on the positive and negative syndrome scale scores from completed 5-week clinical trials.

Variable	EMERGENT-1[43]		EMERGENT-2[14]		EMERGENT-3[47]
	KarXT vs placebo	P value	KarXT vs placebo	P value	KarXT vs placebo	P value
Number of patients (modified intention-to-treat population)	83 vs 87	-	117 vs 119	-	114 vs 120	-
Least-squares mean change from baseline in PANSS total score (points)	-17.4 vs -5.9	< 0.001	-21.2 vs -11.6	< 0.0001	-20.6 vs -12.2	< 0.0001
Least-squares mean change from baseline in PANSS positive symptom subscore (points)	-5.6 vs -2.4	< 0.001	-6.8 vs -3.9	< 0.0001	-7.1 vs -3.6	< 0.0001
Least-squares mean change from baseline in PANSS negative symptom subscore (points)	-3.2 vs -0.9	< 0.001	-3.4 vs -1.6	0.0055	-2.7 vs -1.8	0.1224
Least-squares mean change from baseline in PANSS Marder negative symptom subscore (points)	-3.9 vs -1.3	< 0.001	-4.2 vs -2.0	0.0022	-3.5 vs -2.7	0.1957

Studies included patients aged 18-60 years (EMERGENT-1) or up to 65 years (EMERGENT-2 and EMERGENT-3) with a primary diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition, experiencing an acute exacerbation or relapse of psychosis requiring hospitalization with onset within 2 months before screening. Participants were required to be free of antipsychotic medication for a specified period before the baseline assessment: In EMERGENT-1, at least two weeks for oral antipsychotics or 1.5 injection cycles for long-acting injectables (LAI); and in EMERGENT-2 and EMERGENT-3, at least five half-lives or one week (whichever was longer) for oral antipsychotics, or at least 12 weeks for LAI (24 weeks for paliperidone palmitate). KarXT: Xanomeline/trospium chloride; PANSS: Positive and Negative Syndrome Scale.

Xanomeline/trospium chloride is generally well tolerated, and the most common adverse events are primarily gastrointestinal (e.g., nausea, vomiting, constipation, and dyspepsia), transient in nature, and mild-to-moderate in intensity[14,43,47,54,60]. According to the post hoc analysis of the EMERGENT-1 data, most cholinergic and anticholinergic adverse events were mild, occurred in the first 1-2 weeks of treatment, and were transient, with a median duration ranging from 1 day (vomiting) to 13 days (dry mouth)[60]. Other clinically significant adverse events include elevated liver enzyme levels, increased heart rate, and urinary retention[14,40,42]. The most recent meta-analysis showed no significant difference between xanomeline/trospium chloride and placebo in terms of akathisia, dyskinesia, parkinsonism, somnolence, mean changes in prolactin levels, glucose, body weight, and body mass index[55]. However, the xanomeline/trospium chloride group had reduced levels of both high- and low-density lipoprotein cholesterol and a reduced risk of ≥ 7% weight gain[55]. Among the adverse events occurring in ≥ 5% of patients, xanomeline/trospium chloride was associated with a significantly increased risk of vomiting, nausea, dyspepsia, constipation, hypertension, dry mouth, elevated triglyceride levels, and supine heart rate[55].

At the time of writing, the results from the completed EMERGENT-4 and EMERGENT-5 trials have not been published in full in peer-reviewed scientific journals; however, preliminary reports indicate that xanomeline/trospium chloride was generally well tolerated and associated with significant improvements in PANSS and CGI-S scores over 52 weeks, suggesting its sustained efficacy[61,62].

Highlights of prescribing information

Xanomeline/trospium chloride capsules for oral use (brand name: COBENFY) were approved by the FDA for the treatment of schizophrenia in adults on September 26, 2024[12,40]. Xanomeline/trospium chloride is available in three doses: 50 mg/20 mg, 100 mg/20 mg, and 125 mg/30 mg[40]. The recommended starting dosage is 50 mg/20 mg capsule twice daily for at least two days, with an increase to 100 mg/20 mg capsule twice daily for at least five days[40]. Based on patient tolerability and response, the dose may be increased to a maximum of 125 mg/30 mg capsules twice daily[40]. In geriatric patients, the recommended starting dose is 50 mg/20 mg capsule twice daily, followed by slower titration up to a maximum of 100 mg/20 mg capsule twice daily[40]. Capsules should be taken at least 1 hour before or 2 hours after a meal, because the absorption of trospium chloride is significantly decreased in the presence of food[40,55,63].

Liver enzymes, bilirubin, and heart rate should be assessed before initiating treatment, and should be clinically indicated during treatment[40]. In the presence of signs or symptoms of substantial liver injury (e.g., jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times the baseline values), medication should be discontinued[40].

This medication is contraindicated in patients with moderate or severe hepatic impairment, urinary retention, gastric retention, untreated narrow-angle glaucoma, or history of hypersensitivity to active ingredients[40,63]. Its use is also not recommended for patients with mild hepatic impairment, or moderate or severe renal impairment[40,63]. Patients with hepatic impairment have a higher systemic exposure to xanomeline, which may result in an increased risk of adverse cholinergic reactions[40]. Conversely, patients with moderate and severe renal impairment have a higher systemic exposure to trospium chloride and an increased risk of adverse anticholinergic reactions[40].

The most common adverse reactions include dyspepsia, nausea, vomiting, constipation, abdominal pain, diarrhea, gastrointestinal reflux disease, tachycardia, hypertension, and dizziness[40]. Patients should be warned of the risk of urinary retention (geriatric patients and patients with incomplete bladder emptying or bladder outlet obstruction are at increased risk), angioedema, decreased gastrointestinal motility, and CNS effects; patients should be monitored for anticholinergic CNS effects, such as dizziness, confusion, hallucinations, and somnolence, particularly after starting treatment or increasing the dose, and advised not to drive or operate heavy machinery until they know how the medication affects them[40].

Regarding clinically significant drug-drug interactions, physicians should be particularly aware of the following: (1) CYP2D6 contributes significantly to the metabolism of xanomeline, which means that strong CYP2D6 inhibitors may increase its plasma concentrations; (2) Possible interactions with drugs eliminated by active tubular secretion may result in increased plasma concentrations of trospium or the concomitantly used drug due to competition for this elimination pathway; (3) Xanomeline transiently inhibits CYP3A4 and P-glycoprotein locally in the gut but not systemically, which means that concomitant use with CYP3A4 and P-glycoprotein substrates may increase their plasma concentrations; (4) Concomitant use with other antimuscarinic drugs may increase the risk of anticholinergic adverse reactions (e.g. dry mouth, constipation); and (5) Due to anticholinergic effects on gastrointestinal motility, this medication may alter the absorption of some concomitantly used drugs[40,63].

FUTURE RESEARCH

Although xanomeline/trospium chloride has shown promising results in clinical trials, further research is needed to gather further insights into its effectiveness and safety in real-world clinical settings and to determine its optimal role in managing this complex psychiatric disorder[5]. Future research is necessary to evaluate the long-term therapeutic benefits and safety of xanomeline/trospium chloride, to confirm its potential efficacy in treating cognitive symptoms, and to assess its influence on patient functionality and quality of life[55,64]. Furthermore, clinical trials conducted to date have not included an active control group. Therefore, further research consisting of head-to-head trials of xanomeline/trospium chloride with other antipsychotics is needed to draw conclusions regarding its efficacy and safety in comparison to other available antipsychotics[17,57,60]. Moreover, more studies are needed to evaluate its efficacy and safety as an add-on agent to different antipsychotics. Ongoing studies only include patients with inadequately controlled symptoms of schizophrenia who are being treated with aripiprazole, risperidone, paliperidone, or their long-acting injectable versions, ziprasidone, lurasidone, or cariprazine[52,53].

There is also a need to evaluate whether xanomeline/trospium chloride is effective in treatment-resistant schizophrenia, considering that this form of schizophrenia is listed among the exclusion criteria in both planned and conducted studies, as well as in other types of psychotic disorders. It is worth noting that there are currently ongoing studies aiming to assess its efficacy and safety in the treatment of psychosis associated with Alzheimer's disease[65-67]. Future studies are also needed to identify predictors of response to treatment with muscarinic agonists and to examine their possible prophylactic value in preventing psychosis in those at risk and relapse in patients with early course psychosis patients[23].

The safety of xanomeline/trospium chloride in patients with additional comorbidities and co-treatments requires further research. Some studies are underway to somewhat address this gap, e.g., study NCT06605950, which aims to assess its safety, tolerability and pharmacokinetics in healthy elderly Japanese participants (age 56-90 years) and the effects of omeprazole on its pharmacokinetics[68]; study NCT06729970, which aims to evaluate the effects of lithium and valproic acid on its pharmacokinetics and effects of xanomeline/trospium chloride on the pharmacokinetics of lithium and valproic acid[69]. Moreover, because medication adherence is a known issue in patients with schizophrenia[70], twice-daily oral antipsychotics may pose a challenge[71]. Therefore, the development of new formulations using a prodrug approach, with the aim of creating longer-acting combinations of the novel prodrugs of xanomeline and trospium chloride for once-daily oral administration (“TerXT”) and long-acting intramuscular injection with multi-month duration (“TerXT LAI”) has been announced[71].

CONCLUSION

Xanomeline/trospium chloride appears to be a promising new option for the treatment of a broad spectrum of schizophrenia symptoms, with a relatively favorable tolerability and safety profile. However, more research is needed to gain further insight into its effectiveness and safety in real-world clinical settings and to determine its optimal role in managing this complex psychiatric disorder.