Xanomeline-Trospium for the Treatment of Schizophrenia

Abstract

The objective of this review is to examine the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of the combination of xanomeline and trospium (XT) for the treatment of schizophrenia. A search was conducted of all publicly available information (including press releases) and specifically within the databases MEDLINE, Embase, and PsycINFO, from their inception to May 1, 2025, noting the keywords “muscarinic,” “schizophrenia,” “xanomeline,” and “emraclidine.” A first-in-class medication approved for the treatment of schizophrenia in adults, XT possesses no direct action on dopamine D₂ receptors. It is dosed twice daily without food and has demonstrated efficacy and safety in three 5-week double-blind, placebo-controlled trials and in two 52-week open-label studies. The pooled effect size of 0.61 (0.56 using the meta-analysis method) is greater than that for other agents approved for schizophrenia since 1996, with no risk for movement disorders, weight gain, and hyperprolactinemia. Post hoc analyses from the acute schizophrenia trials also indicate an impact on cognition among individuals with more significant baseline levels of cognitive impairment. Preliminary results of the adjunctive trial for adults with schizophrenia who are partial responders to other antipsychotics were not statistically significant, but ongoing studies are exploring XT for dementia-related psychosis and pediatric indications.

Schizophrenia is a complex psychiatric disorder consisting of three primary components: positive symptoms, negative symptoms, and cognitive dysfunction, all of which contribute to impaired psychosocial functioning (1). The lifetime prevalence is 0.3%–0.6%, but significant population growth and aging has led to a global increase in disease burden (2). Individuals who live with this disorder typically require lifelong treatment, including pharmacotherapy, psychotherapy, and social services (3). Existing antipsychotic therapies that were approved before 2024 were primarily effective at reducing positive symptom severity, with no appreciable impact on negative symptoms or cognitive deficits (4, 5). The sole exception was a double-blind, prospective study in which cariprazine demonstrated superiority over risperidone for negative symptoms (6). Approximately 30% of patients can be characterized as having treatment-resistant schizophrenia, with limited positive symptom reduction from any agent except for clozapine (7).

The goals of schizophrenia treatment are to minimize symptoms and functional impairment, avoid relapse, and promote recovery to the extent that it allows self-determination and pursuit of personal goals (1). The American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients With Schizophrenia recommends that patients with schizophrenia be treated with an antipsychotic on an ongoing basis while being monitored for medication effectiveness and adverse effects (1).

Until late 2024, all available antipsychotics possessed a common mechanism of action: dopamine D₂ receptor blockade or D₂ receptor partial agonism (7). Although clozapine possesses weak D₂ antagonism, the unique properties that allow it to be effective in ≥40% of patients with treatment-resistant schizophrenia have yet to be fully elucidated (7). In patients without treatment-resistant schizophrenia, meta-analyses indicate comparable symptom efficacy among D₂-acting antipsychotics, with differences largely confined to liability for drug-induced movement disorders, hyperprolactinemia, and metabolic adverse effects (8). On September 26, 2024, a muscarinic agonist (xanomeline) combined with a peripherally restricted anticholinergic (trospium) was approved in the United States (9), allowing for a novel mechanism to treat schizophrenia, one that is devoid of D₂ receptor binding and related adverse motor and endocrine effects (10). There were also no metabolic adverse effects and weight gain (11), and preliminary data suggested improved cognitive function in patients with higher baseline levels of cognitive dysfunction (12, 13).

Although the three pivotal phase 2b/3 xanomeline-trospium (XT) placebo-controlled trials did not include an active comparator, evidence-based ranking of XT was performed in a 2025 meta-analysis using pooled variance calculated from the reported standard errors of the means or least squared means by treatment for a specific week (11). The calculated effect size for XT using the meta-analysis method was 0.56, a value that has not been seen with any treatment approved since olanzapine (U.S. Food and Drug Administration [FDA] approval granted September 30, 1996) (11). As the mechanism of XT is completely novel, this review serves to provide detailed insight into the data supporting XT for the treatment of schizophrenia and how to implement XT in clinical practice.

DATA SOURCES

We conducted a search of all publicly available information (including press releases) and specifically within the MEDLINE, Embase, and PsycINFO databases, from their inception to May 1, 2025, noting the keywords “muscarinic,” “schizophrenia,” “xanomeline,” and “emraclidine.”

CLINICAL PHARMACOLOGY

Muscarinic cholinergic receptors are G protein–coupled receptors that produce a slower but sustained response to acetylcholine (ACh), unlike nicotinic receptors which, when stimulated, open ligand-gated ion channels (7, 14). The odd-numbered muscarinic receptors (M₁, M₃, and M₅) are stimulatory and increase levels of intracellular second messengers, whereas the even-numbered receptors (M₂ and M₄) exert opposite effects and are inhibitory (10). Xanomeline is a synthetic muscarinic receptor agonist whose binding affinity is very comparable among the five receptor subtypes but whose intrinsic activity is significantly higher at M₁ and M₄ receptors and very close to that of ACh itself at those receptor subtypes (80% and 96%, respectively) (Table 1 ) (15, 16). Xanomeline was initially developed to improve cognition in Alzheimer’s disease but, fortuitously, was found to possess antipsychotic properties despite lacking any D₂ receptor binding (17). Animal studies elucidated that the basis of xanomeline’s antipsychotic properties rested in the fact that excessive presynaptic activity in midbrain dopamine neurons (the ventral tegmental area [VTA]) is associated with positive symptoms (18). These VTA neurons receive cholinergic and glutamatergic stimulatory input, and stimulation of M₁ and M₄ receptors on certain tracts lessens the extent of this input (19). M₄ receptor activation reduces cholinergic input to VTA by acting on a midbrain cholinergic pathway, the laterodorsal tegmental nucleus (LDT) (Figure 1A) (18). LDT neurons possess inhibitory M₄ autoreceptors on axonal terminals, and stimulation of these M₄ autoreceptors decreases LDT ACh output and ACh stimulation of presynaptic VTA dopamine release (18). Although there is cholinergic stimulation of dopaminergic neurons in motor areas of the striatum, this cholinergic pathway (the pedunculopontine nucleus) is largely controlled by activity at M₂ autoreceptors (19). Thus, muscarinic M₄ receptor stimulation of the LDT reduces positive symptoms and does so without D₂ receptor binding, while sparing motor areas from clinical effects on dopamine neurotransmission (18). Within the striatum, there are striatal cholinergic interneurons (CISs) that facilitate VTA dopamine release by stimulation of nicotinic receptors on VTA axon terminals (20). CISs also express inhibitory M₄ autoreceptors, and activation of M₄ receptors on CISs results in diminished ACh output and VTA dopamine release (20). The extent to which M₄ receptor dysfunction underlies the pathophysiology of schizophrenia is not as well substantiated as the M₁-related issues discussed later, but there is some evidence for diminished M₄ receptor density in the hippocampus and striatum (21).

TABLE 1. .

In vitro binding affinity of xanomeline and intrinsic activity at muscarinic receptors ^a

Muscarinic receptor	Affinity, Ki, nMb	Intrinsic activity: PI or cAMP EC50, nM (% Emax)c
M1	7.94	355: PI (80%)
M2	8.13	2,500: cAMP (46%)
M3	7.76	1,235: PI (22%)
M4	11.22	25: cAMP (96%)
M5	9.33	7,500: PI (59%)

^aSee Bymaster et al. (15) and Bonifazi et al. (16). cAMP, cyclic adenosine monophosphate; EC₅₀, half-maximal effective concentration; E_max, maximal effect; Ki, inhibition constant; nM, nanomolar; PI, phosphoinositide hydrolysis.

^bSee Bonifazi et al. (16).

^cSee Bymaster et al. (15).

FIGURE 1. .

Theoretical basis for how M₄ muscarinic receptor activation of the LDT (19) and M₁ muscarinic receptor activation of parvalbumin-positive GABAergic interneurons in the PFC may exert antipsychotic effects in animal models (19)^a

^a Panel A shows the theoretical basis for how M₄ muscarinic receptor activation of the LDT may exert antipsychotic effects in animal models (19). Panel B shows the theoretical basis for how M₁ muscarinic receptor activation of parvalbumin-positive GABAergic interneurons in the PFC may exert antipsychotic effects in animal models (19). ACh, acetylcholine; DA, dopamine; Glu, glutamate; LDT, laterodorsal tegmental nucleus; PFC, prefrontal cortex; VTA, ventral tegmental area.

It is important to emphasize that the conceptualization of VTA dopamine overactivity based on animal models has been revised with the advent of modern imaging techniques that assay human striatal dopamine function (22). In human individuals living with schizophrenia, the locus of excessive presynaptic dopamine turnover is not in the mesolimbic pathway from VTA to ventral striatum but in an adjacent dopamine circuit that originates in the dorsomedial substantia nigra (SN) and terminates in the associative striatum and adjacent portions of the sensorimotor striatum (22). The prior terminology for the classic motor circuit, the nigrostriatal pathway, is thus overly broad when discussing human striatal dopamine neurotransmission. Of note, the motor pathway originates in the ventrolateral SN and terminates in dorsal portions of the sensorimotor striatum (22). Nonetheless, despite differences in the functional architecture between human and animal models, the consistent finding is that positive symptoms are associated with increased presynaptic dopamine release into the striatum; moreover, these dopamine tracts receive cholinergic inputs from brainstem pathways and, as noted in the following text, glutamatergic inputs from tracts that descend from the prefrontal cortex (PFC) (19).

Muscarinic M₁ receptor activation acts selectively to decrease presynaptic VTA dopamine output, but its effect on positive symptoms arises through the modulation of the stimulatory glutamate signal arising from the PFC (23). Glutamate signaling from the PFC is decreased by stimulating M₁ receptors on inhibitory parvalbumin-positive PFC GABAergic interneurons (19). Increased activity of these GABAergic interneurons acts as a brake on glutamate outflow, with the net result seen as less glutamate-stimulated VTA dopamine release and less positive symptoms (Figure 1B) (18). There are two hypothesized mechanisms by which the dysfunction of parvalbumin-positive PFC GABAergic interneurons may underlie the pathophysiology of schizophrenia: Hypoactivity of N-methyl-d-aspartate receptors on these interneurons may contribute to inadequate control of PFC glutamate output (24); and, 25% of individuals with schizophrenia have markedly diminished M₁ receptor expression, more than 75% below the expected demographic norms, impairing stimulatory inputs to the braking action of these PFC GABAergic interneurons (25).

Although PFC M₁ receptor stimulation contributes to xanomeline’s clinical activity (19), peripheral stimulation of M₁ receptors is associated with gastrointestinal adverse effects (26), so xanomeline was subsequently combined with trospium, an anticholinergic medication that does not appreciably cross the blood-brain barrier and, thus, mitigates the procholinergic adverse effects of peripheral M₁ agonism without interfering with xanomeline’s central nervous system (CNS) mechanism (9, 27–29). In general, the use of anticholinergics with extensive CNS penetration (e.g., benztropine, diphenhydramine) is strongly discouraged when treating patients living with schizophrenia because of their deleterious cognitive effects (30, 31), but there is now another reason to eschew these agents: They may interfere with the mechanism of action of muscarinic receptor–stimulating antipsychotics (32). On the basis of three positive trials, XT received FDA approval on September 26, 2024, ironically exactly 35 years after the approval for clozapine. Unlike the example of clozapine, xanomeline’s mechanism is better understood and forms the basis for a new class of muscarinic receptor–stimulating agents that are currently undergoing clinical trials for the treatment of schizophrenia and other psychotic disorders (18, 23). The obvious advantage lies in the fact that their selective presynaptic mechanism reduces dopamine overactivity but without the motor or endocrine adverse effects seen with D₂ receptor–binding antipsychotics (18).

One less understood aspect of xanomeline’s pharmacology relates to the differential contribution of M₁ and M₄ receptor stimulation to its clinical effects, and whether both are necessary. The development of new muscarinic agonists is somewhat hindered by the finding that the orthosteric binding site for ACh is highly conserved across the five muscarinic receptor subtypes, making it challenging to synthesize agonists with high selectivity for a specific subtype (19). Positive allosteric modulators (PAMs) of muscarinic receptor subtypes have been explored as an alternate strategy, especially PAMs acting on M₄, because the allosteric site varies greatly between these subtypes (19). The underlying hypothesis is that selective M₄ activity might provide sufficient positive symptom reduction without procholinergic adverse effects (33). Emraclidine is an M₄ PAM that advanced to two large, phase 2 trials (N=752) on the basis of positive results in a small, phase 1b study (N=81) (33); however, at doses up to 30 mg daily, it did not separate from placebo (https://www.prnewswire.com/news-releases/abbvie-provides-update-on-phase-2-results-for-emraclidine-in-schizophrenia-302301190.html). There are many hypotheses for these negative results, including the possible need for higher emraclidine dosages, the absence of M₁ activation, and certain unique aspects of xanomeline’s actions at M₄ receptors that might not be replicated by emraclidine. For example, xanomeline is bitopic, meaning that it has both agonist and PAM actions. Two molecules of xanomeline concomitantly bind to M₄: one to the orthosteric site and the other to the allosteric site (16, 34). Xanomeline is also a biased agonist relative to ACh at M₄ and favors G_αi2 protein activation over β-arrestin-2 recruitment and cyclic adenosine monophosphate (cAMP) accumulation (35). Which of the muscarinic agents in development might succeed is, therefore, unclear; however, future studies will clarify the necessary activities needed to achieve antipsychotic effects in patients living with schizophrenia.

PHARMACOKINETICS

Xanomeline is primarily hepatically cleared and, because of extensive first-pass metabolism, has very low oral bioavailability: 3%–7% in rats and less than 1% in nonhuman primates (36). Trospium is also hepatically cleared and also has very low bioavailability (27). The mean absolute bioavailability of a 20 mg dose in humans is 9.6% (range 4.0%–16.1%) (27). It is important to note that ingestion with food further decreases trospium exposure by 85%–90%, hence, the requirement that XT be administered either 1 hour before or 2 hours after a meal (37). (See Table 2 for details on XT pharmacokinetics.)

TABLE 2. .

Absorption, distribution, and metabolism ^a

Parameter	Xanomeline	Trospium
Tmax	2 hours	1 hour
Half-life (t1/2)	5 hours	6 hours
Oral bioavailability	<1%	9.6%
Effect of food	High-fat meal increases AUC by 30%, but no change in Cmax; No changes with low-fat meal	Regardless of fat content, Cmax decreases by 70%–75% and AUC by 85%–90%
Time to steady state	3–5 days	3–5 days
Plasma protein binding	~95%	~80%
Primary metabolic pathways	2D6, 2B6, 1A2, 2C9, 2C19, flavin monooxygenases	Ester hydrolysis and glucuronic acid conjugation
Impact of renal dysfunction on AUC0–12 hr (Reference: eGFR ≥90 ml/min)
eGFR 60–89 ml/min	↑ 1.9-fold	↑ 1.6-fold
eGFR 30–59 ml/min	↑ 2.1-fold	↑ 2.2-fold
eGFR <30 ml/min	↑ 2.4-fold	↑ 2.9-fold

^aSee (27), (36), and (37). AUC, area under the curve; C_max, maximum concentration; eGFR, estimated glomerular filtration rate; T_max, time to maximum drug concentration.

EFFICACY

Three 5-week, double-blind, placebo-controlled studies (EMERGENT-1, EMERGENT-2, and EMERGENT-3) demonstrating the efficacy, safety, and tolerability of XT were conducted (38–41). In addition to the short-term studies described earlier, two open-label, outpatient extension trials were also completed primarily to track safety and tolerability: EMERGENT-4 (N=110) (ClinicalTrials.gov ID: NCT04659174), a 52-week, open-label, extension phase 3 study with participants rolled over from the EMERGENT-2 and -3 trials; and EMERGENT-5 (ClinicalTrials.gov ID: NCT04820309), which enrolled adults with schizophrenia on quetiapine, risperidone, aripiprazole, or olanzapine. Post hoc analyses were also completed to further explore negative symptom response and cognitive outcomes (12, 13, 42). (See Table 3 for complete details regarding the clinical trials.)

TABLE 3. .

Randomized, double-blind, 5-week clinical trials with XT in adults experiencing an acute exacerbation of schizophrenia ^a

Trial	Design	Intervention	Inclusion and exclusion	Results	Conclusions
EMERGENT-1 (ClinicalTrials.gov ID: NCT03697252) (12)	Inpatient; phase 2; 5-week, double-blind, placebo-controlled, randomized controlled trial	XT at 50 mg/20 mg twice daily, then increased to 125 mg/30 mg twice daily; option to decrease to 100 mg/20 mg twice daily if adverse effects were unmanageable (N=90); placebo (N=92)	Inclusion: 18–60 yr old; diagnosis of schizophrenia according to the DSM-5 and a CGI-S score of ≥4; PANSS >80, with a score of ≥5 on one positive symptom item or ≥4 on two positive symptom items; experiencing an acute psychotic exacerbation or relapse of psychosis requiring hospitalization. Exclusion: history of treatment resistance to two adequate courses of antipsychotic medications; and/or a decrease in the PANSS total score by >20% between screening and baseline assessment	Greater decrease in PANSS total score at week 5 with XT vs. placebo (−17.4 vs. −5.9, respectively; p<0.001; Cohen’s d=0.75). Overall discontinuation rates: 20% for XT vs. 21% for placebo. Most common TEAEs were constipation (17%), nausea (17%), dry mouth (9%), dyspepsia (9%), and vomiting (9%).	XT demonstrated greater reductions than placebo in the degree of psychosis. Treatment with XT resulted in cholinergic and anticholinergic adverse effects but was not associated with higher incidences of EPS or weight gain vs. placebo.
EMERGENT-2 (ClinicalTrials.gov ID: NCT04659161) (13)	Inpatient; phase 3; 5-week, double-blind, randomized controlled trial	XT at 50 mg/20 mg for 2 days, then 100 mg/20 mg, and then, on day 8, 125 mg/30 mg as tolerated (N=126); placebo (N=126)	Inclusion: 18–65 yr old; primary diagnosis of schizophrenia by DSM-5; acute exacerbation or relapse of psychotic symptoms requiring hospital admission with onset <2 months before screening; PANSS total score of 80–120, with a score of ≥4 on at least two symptoms (delusions, disorganization, hallucinations, and suspiciousness or persecution); CGI-S score of ≥4. Exclusion: primary disorder other than schizophrenia within the past 12 months; history of treatment resistance to antipsychotic medications; decrease in PANSS total score of ≥20% between screening and baseline	Greater decrease in PANSS total score at week 5 with XT vs. placebo (−21.2 vs −11.6, respectively; p<0.0001) (Cohen’s d=0.61). Overall discontinuation rates were similar: 25% for XT vs. 21% for placebo. Most common TEAEs were constipation, dyspepsia, nausea and vomiting, hypertension, dizziness, and GERD.	XT demonstrated efficacy and safety. It was well tolerated in adults with schizophrenia with acute psychosis who received 4 weeks of treatment.
EMERGENT-3 (ClinicalTrials.gov ID: NCT04738123) (14)	Inpatient; phase 3; 5-week, double-blind, randomized controlled trial	XT at 50 mg/20 mg for 2 days, then 100 mg/20 mg, and then, on day 8, 125 mg/30 mg as tolerated (N=125); placebo (N=131)	Inclusion and exclusion criteria are the same as for the EMERGENT-2 trial	Greater decrease in PANSS total score at week 5 (−20.6 for XT vs. −12.2 for placebo; p<0.001; Cohen’s d=0.60). Overall discontinuation rates were similar: 36.8% for XT vs. 29% for placebo. Most common TEAEs were nausea and vomiting, dyspepsia, constipation, hypertension, and diarrhea.	XT was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms. It was well tolerated in adults with schizophrenia who were experiencing acute psychosis.

^aCGI-S, Clinical Global Impression Severity Scale; DSM-5, The Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; EPS, extrapyramidal symptoms; GERD, gastroesophageal reflux disease; PANSS, Positive and Negative Syndrome Scale; TEAEs, treatment-emergent adverse effects; XT, xanomeline-trospium combination.

Using a mixed-model, repeated-measures (MMRM) approach, the pooled effect size across the three registrational trials versus placebo was 0.61 (41), a value that had not been seen since olanzapine was approved in 1996. The calculated effect size in a 2025 meta-analysis is slightly lower (0.56) because of different statistical methods used in meta-analyses that rely on the reported standard errors of the means or least squared means by treatment for a specific week (11). The MMRM calculations may reflect treatment effect more accurately, but older studies did not use that method, so meta-analyses must rely on the data that are available across most studies (11).

Negative symptom improvement is seen in all antipsychotic trials of acute schizophrenia, but the reduction in negative symptom severity is considered pseudospecific, implying that it is directly related to decreases in positive symptoms (43, 44). Given the novel mechanism for XT, post hoc analyses of negative symptom response were performed using the modified intention-to-treat pooled population from each of the aforementioned trials and within the prominent negative-symptom (NS) subsample (42). The NS subsample was defined as having scores ≥24 on the Positive and Negative Syndrome Scale (PANSS) Marder negative factor, ≤19 on the PANSS Mohr positive symptom model, and ≥4 on at least two of the following PANSS core negative symptom items: blunted affect, passive-apathetic social withdrawal, or lack of spontaneity and flow of conversation. XT was significantly better than placebo on the PANSS Marder negative factor scores in the full sample of participants (effect size [Cohen’s d]=0.42, p<0.001), but more so in the NS subsample (Cohen’s d=1.18, p<0.001). This effect in the NS subsample was still seen after accounting for any changes in positive symptoms, depression or anxiety, disorganization, and hostility, thereby suggesting an independent effect on negative symptoms that is not pseudospecific.

Another area of unmet need for schizophrenia treatment is cognitive dysfunction, with existing agents demonstrating no substantial improvement (5). The standard for studies of cognitive impairment in schizophrenia is to enroll patients who are stable and modestly symptomatic, but exploratory outcomes were examined in the three acute EMERGENT studies to look for a signal of cognitive improvement that was not related to overall schizophrenia symptom improvement. In the EMERGENT-1 trial, cognitive function was tracked at baseline and endpoint with the computerized Cogstate Brief Battery. Using analysis of covariance models for participants with baseline and endpoint data (N=125), endpoint cognitive improvement was numerically, but not statistically, greater with XT compared with placebo (p=0.16); however after the removal of outliers (i.e., those with implausibly high intraindividual variability across cognitive subdomains), there was significant endpoint cognitive improvement in the subgroup with clinically meaningful cognitive impairment at baseline (Z-score≥1.0; p=0.04) (12). Moreover, these effects in the more impaired subgroup did not appear to be related to the improvement in PANSS total scores (linear regression, R²=0.03) (see Supplemental Table 1 in the online supplement to this article). In a similar fashion, cognitive outcomes in the EMERGENT-2 and -3 trials using the Cambridge Neuropsychological Test Automated Battery also revealed no significant effect in the full sample, but a statistically significant benefit was revealed compared with that of placebo for participants exposed to XT with significant baseline levels of cognitive impairment (Z-score≥1.0) (least squared mean difference=0.31; SE=0.10; d=0.54; p=0.004) (13). See Supplemental Table 2 in the online supplement to this article.

Last, a post hoc analysis of XT effects on agitation across the three EMERGENT acute trials was performed through examination of a relevant subset of PANSS items denoted as the PANSS–Excited Component (PANSS-EC), which measures excitement, tension, hostility, uncooperativeness, and poor impulse control (45). Although significant issues with pseudospecificity exist in many post hoc explorations (as discussed in the negative symptom analysis), the endpoint effect sizes for PANSS-EC change versus placebo in the three 5-week studies were as follows: EMERGENT-1, d=0.62; EMERGENT-2, d=0.43; and EMERGENT-3, d=0.62, all of which were statistically significant (45). Whether this represents a distinct effect independent of the general antipsychotic effect in acutely exacerbated patients cannot be ascertained from this analysis, but it is also an area worth exploring in future studies.

ADVERSE EFFECTS

XT treatment can be associated with certain types of adverse effects related to either the procholinergic properties of muscarinic agonism or the anticholinergic properties of trospium. In particular, the procholinergic issues of nausea and vomiting from xanomeline necessitate titration to the effective dosage range. The frequency of common adverse effects experienced during the large, phase 3 EMERGENT-2 and EMERGENT-3 trials is summarized in Table 4 (39, 40). The procholinergic adverse effects in the EMERGENT-2 and -3 trials were rated mild to moderate in intensity, typically began within the first 2 weeks of treatment, and tended to be transient in nature (39, 40). Vomiting was described as intermittent and generally mild, with about one-third of occurrences being reported as only a single episode. It is important to note that no clinically meaningful changes were reported from baseline to week 5 on motor symptom scales in either the XT or placebo groups, and no cases of tardive dyskinesia were reported in either treatment group. Additionally, XT was not associated with differences in weight, serum prolactin, or rates of somnolence compared with placebo. The mean change in body weight was 1.4 ± 3.31 kg, and the proportion of participants with a ≥7% increase in body weight from baseline to week 5 was low (5.4%–6.0%), compared with 13% in the placebo group. Mild nominal increases in systolic and diastolic blood pressure were observed in the XT group and tended to be at peak concentrations during the first week of XT treatment and partially attenuated as the medication was continued. There was a modest increase in heart rate of 5.9 beats per minute for the XT group compared with that in the placebo group, with the XT medication package insert recommending monitoring of heart rate during treatment (37, 39, 40). Monitoring of liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and bilirubin) is also recommended on the basis of differential rates of ALT/AST elevation over three times the upper limit of normal for the XT group compared with the placebo group (2.8% for XT vs. 0.4% for placebo) (37). Overall, 1.6% of participants treated with XT had elevated liver function tests at some point, but most occurred within 1 month of initiation and resolved with continued treatment (37). From this pattern, a practical monitoring strategy is to obtain baseline levels of AST, ALT, and bilirubin, and again if clinically indicated during treatment, should symptoms arise. In the absence of clinical symptoms, a repeat set of AST, ALT, and bilirubin should be obtained after 1 month of treatment to document lack of effect.

TABLE 4. .

Adverse reactions that were reported in ≥2% of patients treated with XT and that were greater than the rate for placebo in the phase 3 EMERGENT-2 and EMERGENT-3 trials ^a

Adverse effect	XT (%)	Placebo (%)
Nausea	19	4
Dyspepsia	18	5
Constipation	17	7
Vomiting	15	1
Hypertension	11	2
Abdominal pain	8	4
Diarrhea	6	2
Tachycardia	5	2
Dizziness	5	2
GERD	5	<1
Dry mouth	4	2
Somnolence	3	2
Blurred vision	3	0
Salivary hypersecretion	2	0
Orthostatic hypotension	2	1
Cough	2	1
EPS, nonakathisia	2	<1

^aSee (11). EPS, extrapyramidal symptoms; GERD, gastroesophageal reflux disease; XT, xanomeline-trospium combination.

INITIATION

The clinical trials included patients who were markedly ill, with an acute exacerbation of schizophrenia, and the titration used may not be suitable when transitioning outpatients who are less severely symptomatic. The recommended starting dose is one capsule containing 50 mg xanomeline and 20 mg trospium chloride, taken orally twice daily for at least 2 days, but the availability of blister cards with a 1-week supply permits longer periods for this dose and for the subsequent dose of 100 mg/20 mg taken orally twice daily (37). After at least 5 days taking the 100 mg/20 mg dose, one can proceed to the maximum dose of 125 mg/30 mg taken orally twice daily, on the basis of patient tolerability and response. Individuals age 65 and older should not proceed to take more than 100 mg/20 mg twice daily (37). In the EMERGENT-2 trial, 94% of participants in the XT group and 98% in the placebo group reached the highest dose, whereas 6% in the XT group and none in the placebo group had a reduction for tolerability issues. Data on the percentage of participants reaching the target dose or requiring a dose reduction were not reported for the EMERGENT-3 trial (8). It is also worth stating that no dose-response studies were performed with fixed doses of XT, so the optimal dose for any patient is unknown.

As discussed previously, XT must be administered 1 hour before a meal or at least 2 hours after a meal because of the significant loss of trospium exposure when taken with food (27). When given with either a low- or high-fat meal, exposure to trospium is reduced by 85%–90%, a unique aspect of this XT treatment that must be emphasized with patients and caregivers. This marked decrease in trospium bioavailability will lead to additional peripheral adverse effects, including nausea and vomiting, as noted in early studies of xanomeline administered without trospium (9, 26, 37). In the clinical trials, ondansetron was used as rescue medication for nausea or vomiting, but the protocols did not provide specific guidance on dosing, and this was left to the investigators’ discretion. A total of 3.4%, 8.7%, and 6.4% of participants in the XT arm of EMERGENT-1, EMERGENT-2, and EMERGENT-3, respectively, received concomitant ondansetron (Bristol Myers Squibb, data on file), but it is difficult to discern the extent to which this was effective or the optimal dosing strategy for ondansetron (i.e., the dose, or timing of the dose with respect to XT ingestion). One consideration in the management of nausea or vomiting relates to the fact that some patients may experience trospium absorption that is lower than expected, resulting in excessive procholinergic effects (27). With that in mind, in circumstances in which the clinician or patient is especially leery of nausea or vomiting or when ondansetron has not been effective, one might consider an empiric trial of an additional 20 mg trospium in the morning without food 1 hour before breakfast, bearing in mind the risks for additive anticholinergic effects (e.g., constipation, urinary retention in susceptible individuals). Morning dosing is preferred, as trospium appears to be better absorbed at that time compared with evening dosing (27). If this strategy is used, the additional trospium can be stopped once the patient appears to be tolerating higher XT dosages (e.g., 100 mg/20 mg twice daily).

NUMBER NEEDED TO TREAT AND NUMBER NEEDED TO HARM

A useful way to summarize the clinical effects of any treatment is to examine the difference from placebo in response rates and rates of adverse effects by calculating the number needed to treat (NNT) and the number needed to harm (NNH), respectively. Low values of NNT (i.e., <10) indicate clinically significant efficacy, whereas NNH values >10 are associated with greater tolerability. From data in the three 5-week, randomized, double-blind, placebo-controlled EMERGENT trials, estimates of efficacy using the response threshold of a ≥30% reduction in PANSS total score from baseline to week 5 were as follows: NNT=5 (95% confidence interval [CI]=4–8) (46). Estimates of NNH for the most common adverse effects were greater than 10, with the exception of nausea and vomiting; however, rates of discontinuation due to nausea, dyspepsia, or vomiting were low: NNH=49 (95% CI=28–182) (46). Indirect comparisons with data on available antipsychotics previously approved for schizophrenia concluded that XT exhibited NNT estimates that were comparable with or greater than those for placebo and was the least likely antipsychotic to be associated with weight gain or with somnolence or sedation (46).

PLACE IN THERAPY AND CLINICAL CONSIDERATIONS

XT is the first approved agent that possesses a new mechanism of action for the treatment of schizophrenia without direct action on the D₂ receptor, and with an effect size that has not been seen since olanzapine’s approval in 1996 (11). Moreover, XT therapy is not associated with movement disorders, weight gain, metabolic changes, or prolactin elevation. Of note, the medication package label does not contain the word “antipsychotic” or any antipsychotic class warnings regarding mortality or stroke risk in dementia-related psychosis, risk for movement disorders, metabolic or endocrine adverse effects, or QT prolongation (37). Other additional benefits include the potential impact on negative and cognitive symptoms, although this requires further confirmation in dedicated trials with participants who are clinically stable.

The biggest consideration in using XT is whether the patient is able to be adherent with a medication that is taken twice daily and that must not be taken with food. Another issue is whether the patient is on anticholinergics, peripheral or centrally acting, and the need to taper these agents when starting XT. Concern about potent, centrally acting anticholinergics emerged from preclinical studies indicating they might interfere with xanomeline’s mechanism of action (47). Conversely, peripherally acting anticholinergic medications may exert additive effects with trospium, thereby resulting in increased anticholinergic burden (e.g., delayed gastric emptying, constipation, urinary retention) (Box 1).

BOX 1. Considerations when initiating xanomeline-trospium (XT) treatment.

First-episode patients:

• There are obvious advantages, especially for tolerability, if the patient can be adherent with oral medication. Many first-episode patients with schizophrenia may not be candidates for this reason.

• Access may be a problem without prior antipsychotic trials.

Cross-tapering—primarily an issue if the current antipsychotic is anticholinergic (e.g., olanzapine, quetiapine):

• Practical strategy for olanzapine or quetiapine: Cross-taper slowly over the first month as XT is titrated.

  • If patient is on higher doses of quetiapine (e.g., >300 mg every night at bedtime), ≥2 months or more may be needed to completely taper off.

• Practical strategy for other antipsychotics (e.g., aripiprazole, risperidone, paliperidone, cariprazine): There are no pharmacodynamic interactions with antipsychotics that are not anticholinergic; may decide to taper the primary antipsychotic after XT has reached the maximum tolerated dose.

Cross-tapering centrally acting anticholinergic medications:

• Practical strategy: Many patients are on benztropine, trihexyphenidyl, or diphenhydramine for unclear reasons, especially if there is no evidence of parkinsonism. Decrease benztropine no faster than 0.5 mg/wk, with the goal of complete discontinuation. If the patient requires an antiparkinsonian medication, amantadine should be used.

Cross-tapering peripherally acting anticholinergic medications:

• History: Note the use of other anticholinergics (e.g., overactive bladder medications) when initiating, and ask about urinary tract symptoms in older male patients when starting. It should be noted that the maximum dose for geriatric patients is 100 mg/20 mg twice daily, and it is contraindicated in the presence of ongoing urinary retention.

• Practical strategy: Use slower XT titration, and taper off other anticholinergics while adding XT. During therapy initiation, ask about urinary symptoms. If the patient was on another overactive bladder medication, trospium should suffice.

Precautions and warnings:

• Supplemental Table 3 in the data supplement accompanying the online version of this article summarizes some warnings that are more specific to XT treatment.

Perhaps the biggest area of interest among clinicians rests in the possibility that XT, through its presynaptic mechanism, may work cooperatively with postsynaptic D₂ receptor–modulating antipsychotics to further improve residual symptoms, especially positive symptoms. Preclinical data suggested the possibility of synergistic activity in combined treatment using xanomeline and postsynaptic D₂ receptor–modulating antipsychotics (36, 48). To explore this in a clinical context, the adjunctive XT study (ARISE) was performed with symptomatic patients on stable doses of antipsychotics but excluding antipsychotics with significant anticholinergic properties that might interfere with the mechanism of action (e.g., olanzapine, quetiapine, and clozapine). The ARISE protocol also used a slower titration than that in the acute phase 2b/3 EMERGENT studies, based on the logic that these patients are less ill than the acute inpatients involved in the registrational trials. However, in a press release on April 22, 2025, the study sponsor reported negative findings from the ARISE adjunctive study, casting doubt on the viability of this strategy cross-sectionally (https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-ARISE-Trial-Evaluating-Cobenfy-xanomeline-and-trospium-chloride-as-an-Adjunctive-Treatment-to-Atypical-Antipsychotics-in-Adults-with-Schizophrenia/default.aspx). If a clinician chooses to pursue a combination strategy with XT, they should document whether the patient has achieved greater symptomatic relief with this strategy compared with antipsychotic monotherapy, as well as the reasons why discontinuing the prior antipsychotic is not in the patient’s best interest (e.g., the patient is on a long-acting injectable antipsychotic because of a history of oral medication nonadherence). One should also be mindful that combining XT with anticholinergic antipsychotics may pose tolerability issues, and the possibility that the activity of xanomeline may be interfered with at M₁ and M₄ receptors.

It is worth noting that XT is being investigated as monotherapy for psychosis associated with Alzheimer’s disease and in pediatric patients ages 13–17 years with schizophrenia, schizoaffective disorder, bipolar I or II disorder, attention-deficit hyperactivity disorder, Tourette’s syndrome, or autism spectrum disorder with an enteric coated formulation. (See Supplemental Table 4 in the online supplement for complete details on these trials.)

PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA

Xanomeline acts to decrease presynaptic dopamine release, but there is increasing evidence that poor response to nonclozapine antipsychotics, as is seen in individuals with treatment-resistant schizophrenia, is associated with relatively normal striatal dopamine synthesis capacity in imaging studies (49, 50). Although presynaptic dopamine release may not underlie treatment-resistant schizophrenia, patients with treatment-resistant schizophrenia do exhibit elevated anterior cingulate cortex (ACC) and striatal caudate glutamate levels. Within 12 weeks of starting clozapine, patients with treatment-resistant schizophrenia manifest a longitudinal reduction in tissue-corrected glutamate concentration (Glu_corr) in the caudate (N=23; F=7.61; df=1, 22; p=0.01) but not the ACC (N=24; F=0.02; df=1, 23; p=0.59) (51). It is important to note that the percent reduction for Glu_corr in the caudate positively correlates with the percent improvement in symptoms as measured by the PANSS total score (N=23; r=0.42; p=0.04). The conclusion from these studies is that presynaptic dopamine dysfunction does not appear to be the source of positive symptoms in treatment-resistant schizophrenia. In the absence of clinical data suggesting that muscarinic receptor–stimulating agents are effective in treatment-resistant schizophrenia, they should not be considered as a substitute for clozapine.

CONCLUSIONS

XT is the first of a completely novel class of medications that exerts its effects through muscarinic receptor agonism and has a demonstrated efficacy profile as monotherapy in the treatment of adults with schizophrenia. There are important aspects to starting XT to minimize procholinergic adverse effects, but XT treatment is not associated with weight gain or other forms of metabolic dysfunction, hyperprolactinemia, or movement disorder risk. Clinicians must discuss with patients the need to ingest XT without food, as well as the need to become astute at titrating XT slowly and using adjunctive medications to manage its procholinergic adverse effects. Clinicians should also be aware of the additive nature of the anticholinergic effects with other medications, including psychotropics, and the optimal way to taper those other medications when starting XT. The need for a patient to adhere to the dosing requirements (i.e., twice daily and without food) will certainly limit the pool of individuals who are candidates for XT, and the biology of treatment-resistant schizophrenia suggests, for now, that XT might not be a viable substitute for clozapine. Nonetheless, the novel mechanism, the absence of D₂-related adverse effects, and the possible promise of cognitive and negative symptom benefit should compel every clinician who works with patients living with schizophrenia to become adept at prescribing XT.