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Abstract

Few pharmacologic options exist for patients with clozapine-resistant schizophrenia (CRS) or schizoaffective disorder. Xanomeline/trospium represents a new class of antipsychotic medication that has efficacy as monotherapy for schizophrenia. Despite distinct mechanistic differences from standard antipsychotics, phase III evidence suggest limited benefit of xanomeline/trospium in the augmentation of non-clozapine antipsychotics. Research on the use of xanomeline/trospium in patients with clozapine-resistant illness or with partial response to clozapine is even more limited. Two cases of this combination are described with a discussion on key considerations for the management of CRS. The first case is a 42-year-old patient whose clozapine dose was limited by supratherapeutic clozapine levels in response to minor infections. She was ultimately stabilized on a combination of clozapine and xanomeline/trospium, with yet further improvements from electroconvulsive therapy (ECT). The second case is a 31-year-old patient who elected to discontinue clozapine and ECT due to cognitive side effects, despite improvement in psychosis. The addition of xanomeline/trospium to clozapine caused sialorrhea and did not produce observable clinical benefits and was thus discontinued. These case reports describe clozapine-resistant patients who were trialed on xanomeline/trospium combined with clozapine and still required consideration of ECT for symptom control. Overall, future investigation into xanomeline/trospium effectiveness as an augmentation agent or as monotherapy for CRS is necessary to guide clinical decision-making.

Keywords

case report clozapine augmentation clozapine-resistant schizophrenia electroconvulsive therapy xanomeline/trospium

Introduction/Background

Schizophrenia and schizoaffective disorders are debilitating and often difficult to treat.¹ After two or more unsuccessful trials of antipsychotics, clozapine is considered the next treatment step.² Yet, clozapine-resistant schizophrenia (CRS) and schizoaffective disorder are common, in which at least half of patients receiving clozapine still experience impairing psychotic symptoms.³ Unfortunately, available evidence for antipsychotic augmentation to clozapine suggests little to no additional benefit, especially when low-quality studies are excluded from analysis.³

Research of new pharmacologic agents is therefore warranted to identify potential effective combination strategies. Xanomeline/trospium is the newest antipsychotic to receive FDA approval and is the first agent in over 50 years to offer a novel mechanism to treat schizophrenia. Whereas most antipsychotics primarily target dopamine receptors, xanomeline/trospium’s antipsychotic action occurs through muscarinic-1 (M1) and muscarinic-4 (M4) receptor agonism in the central nervous system. Trospium’s peripheral antimuscarinic activity offsets the muscarinic side effects of xanomeline to confer greater tolerability. Xanomeline/trospium’s distinct mechanism of action suggests potential utility to augment antipsychotics with dopaminergic mechanisms, though more research is needed. Given that other antipsychotics have off-target muscarinic receptor affinity in the periphery, it is unknown if adverse drug reactions from xanomeline/trospium, such as constipation, sialorrhea, or urinary symptoms, may be potentiated. Clozapine’s partial agonism at M4 and antagonism at M1, M2, and M3 may add other potential pharmacodynamic considerations.⁴ The commercial availability of xanomeline/trospium will likely limit the execution of randomized-controlled trials (RCTs) to assess evidence behind augmentation strategies. Experience from clinical practice, including data from cases and retrospective studies, may provide earlier awareness of important clinical and practical considerations before more robust evidence from RCTs becomes available. Following the CARE guidelines (see Supplemental File),⁵ we describe two patients with CRS who received a combination of clozapine and xanomeline/trospium with mild to no improvement in psychotic symptoms.

Case 1

A 42-year-old female with schizophrenia was transferred from acute inpatient psychiatric care to residential care with psychotic disorganization. Her symptoms began in college at age 18 and included auditory hallucinations, delusions, and severe thought disorganization with word salad. Because of symptom severity, she completed only 1 year of college and could not function independently, so she lived with her mother, who established guardianship. Throughout her illness, multiple antipsychotics were unsuccessful due to ineffectiveness or intolerability. Clozapine had been most effective but intermittently discontinued due to patient or guardian preference.

After a 5-week hospitalization, she was deemed sufficiently stable for transfer to residential care, although psychotic symptoms persisted. By the time of transfer, clozapine was increased from a pre-hospital dose of 150–300 mg daily at bedtime (trough level = 279 ng/mL). As a part of routine residential treatment care, Saint Louis University Mental Status Exam (SLUMS)⁶ and Positive and Negative Syndrome Scale (PANSS)⁷ scores were periodically tracked. SLUMS is scored from 1 to 30, where a lower score indicates a higher degree of cognitive impairment; PANSS is scored from 30 to 210, where a higher score indicates a greater degree of symptoms from schizophrenia. On admission day (AD 1), her SLUMS was 11, and her PANSS was 120.

Due to residual thought disorganization, irritability, and executive dysfunction, clozapine was advanced from 300 to 450 mg daily in 50 mg increments over approximately 2 months (AD 2-59) to help mitigate worsening of baseline hypersomnolence and dyspepsia. She remained on clozapine 450 mg for another 2 months. Corresponding trough levels ranged from 570 to 624 ng/mL, but elevated levels (718, 797, and 1920 ng/mL) occurred in the context of mild upper respiratory infections, which led to increased sedation and need for temporary dose reductions. During treatment with clozapine 450 mg, her thought process improved, and wandering behaviors decreased, with the corresponding ability to attend appointments and social outings. However, cognitive impairments, particularly in the executive function domain, persisted along with sporadic periods of nonsensical speech.

Because of sensitivity to supratherapeutic clozapine levels with minor illness, xanomeline/trospium was proposed to target residual symptoms, including cognitive symptoms, which were thought to limit functional progress. In addition, the team queried whether xanomeline/trospium could replace clozapine and minimize metabolic side effects, which were evident despite treatment with metformin (BMI 30.75 kg/m²). These potential benefits were weighed against the risk of additive peripheral antimuscarinic side effects from trospium with clozapine, as well as unknown potential for clozapine to antagonize the central mediated muscarinic effects of xanomeline.

Xanomeline/trospium was started at 50 mg/20 mg BID alongside clozapine 450 mg, which she tolerated well (AD 275). With this combination, she began to initiate conversations. The dose of xanomeline/trospium was thus advanced in stepwise fashion with reduction of clozapine to 375 mg over several weeks. With clozapine 375 mg and xanomeline/trospium 100 mg/20 mg BID, she self-initiated tasks, including showering, dental hygiene, and meal preparation (AD 261; SLUMS: 20; PANSS 95). Reducing clozapine to 300 mg and increasing xanomeline/trospium to 125 mg/30 mg BID led to recurrence of irritability and oppositionality and was associated with nausea, though dyspepsia pre-dated initiation of xanomeline/trospium (AD 275; SLUMS: 16; PANSS: 109). Increasing clozapine (375 mg) and reducing xanomeline/trospium (125 mg/30 mg in the morning and 100 mg/20 mg at night) was associated with decreased irritability and return to self-initiated behaviors (AD 303; SLUMS: 21; PANSS: 87). While the SLUMS was similar to the combination of clozapine 375 mg + xanomeline/trospium 100 mg/20 mg BID (AD 261), her PANSS further improved with the higher morning dose of xanomeline/trospium. Clozapine was then raised to 400 mg while the xanomeline/trospium dose remained the same (AD 309; SLUMS: 21, PANSS: 84). At this combination, she began reading newspapers independently, and her engagement in groups significantly increased.

In AD 310, bitemporal ECT was pursued, given residual symptoms despite medication optimization, with the right to consent to ECT court-granted to her guardian. With three times weekly ECT, PANSS further improved to 63. Three weeks later, as ECT was tapered to weekly, PANSS increased to 72, and SLUMS was 17 with improved engagement in activities of daily living. The patient remained on weekly ECT and clozapine 400 mg at bedtime. No significant changes were observed when xanomeline/trospium was increased to 125 mg/30 mg BID. The treatment plan continues without change to the point of current follow-up with the patient reporting satisfaction.

Case 2

A 31-year-old woman with schizoaffective disorder was admitted to residential care for persistent psychosis and impaired functioning. Her symptoms began in college about a decade prior, when she experienced depression followed by progression to psychosis with delusions, paranoia, and disorganized behavior. Multiple medication trials, including selective serotonin reuptake inhibitors (SSRIs), lithium, divalproex sodium, aripiprazole, quetiapine, lurasidone, gabapentin, alprazolam, clonazepam, dextroamphetamine/amphetamine, and lisdexamfetamine, were either ineffective or exacerbated manic and psychotic symptoms, such that she attempted suicide, which led to extensive injuries while on a combination of an SSRI and lisdexamfetamine.

On admission to the facility, symptomatic history, Minnesota Multiphasic Personality Inventory (MMPI), and clinical observation supported a diagnosis of schizoaffective disorder, bipolar type. A combination of lamotrigine 200 mg daily and clozapine 400 mg nightly was associated with severe hypersomnia and functional impairment, along with residual paranoia (AD 1).

Due to poor symptom control on clozapine and lamotrigine, on AD 18, ECT was initiated twice a week for 2 weeks, followed by weekly treatments until AD 70. During that time, clozapine was decreased to 150 mg daily with improvement in hypersomnia and a significant reduction in psychotic symptoms such that she became employed. However, because of ECT-associated memory problems and post-anesthesia grogginess, the patient requested to stop ECT and clozapine. Alternative antipsychotics, including risperidone and aripiprazole, both individually and in combination, failed to reduce delusions and disorganized behaviors (AD 70-126). A temporal observation of excessive showering behaviors with aripiprazole led to initial suspicion for aripiprazole-induced impulsivity/compulsions. ECT was briefly reinitiated as aripiprazole was tapered and clozapine restarted. ECT provided benefit, but she again wanted to stop treatments. Clozapine was titrated to 300 mg, which she tolerated without hypersomnolence (AD 168). Though psychotic symptoms reduced, she did not experience the same level of improvement compared to treatment with clozapine and ECT. Though compulsions resolved after discontinuation of aripiprazole, showering behaviors re-emerged when clozapine was increased to 325 mg to target residual disorganization (AD 216). Increasing the lamotrigine was unhelpful. Though clozapine-induced obsessive-compulsive disorder was considered, reducing clozapine had no impact on compulsive showering and instead led to increased disorganization. Despite the combination of clozapine and ECT, shower compulsions persisted, which were then thought to represent behavioral disorganization.

Due to multiple past medication trials, the treatment team started xanomeline/trospium in combination with clozapine 325 mg (AD 244), which she initially tolerated. She was maintained on the maximum dose of 125 mg/30 mg BID for 8 days, but due to sialorrhea and nausea, along with lack of further improvement in psychotic symptoms, xanomeline/trospium was tapered and discontinued. She remained ambivalent about ECT and was inconsistently adherent to treatments, such that ECT was also discontinued. Instead, clozapine was titrated to a level of 701 ng/mL at 600 mg (AD 315). She experienced initial drowsiness and sialorrhea, but overall tolerated the higher dose and experienced some improvement in symptoms, with the absence of delusions, paranoia, hallucinations, and reduction in excessive showering. Lamotrigine was eventually tapered and replaced with divalproex sodium for augmentation, which she remains on at the time of last follow-up.

Discussion

Presented are two cases that raise questions regarding the utility of xanomeline/trospium with clozapine. Xanomeline/trospium chloride was FDA-approved for the treatment of schizophrenia in September 2024 after three separate monotherapy clinical trials (EMERGENT-1, EMERGENT-2, and EMERGENT-3) demonstrated clinically significant symptom reduction in patients with schizophrenia over a 5-week period.^8–10 Due to muscarinic side effects that rendered xanomeline intolerable in earlier trials for Alzheimer’s disease,¹¹ trospium chloride, a peripherally acting muscarinic antagonist, was added to offset the peripheral action of xanomeline. With this combination, the EMERGENT trials demonstrated improved tolerability with reduced peripheral muscarinic side effects, without impacting central muscarinic activity that confers efficacy for psychotic symptoms.

As a novel M1 and M4 agonist, xanomeline/trospium offers a new option for the treatment of patients with schizophrenia with less concern for drug-induced movement disorder, metabolic adverse effects, or QT interval prolongation.^8,12 The effectiveness of xanomeline/trospium in large, real-world settings has yet to be described, and the large effect size of xanomeline/trospium may be secondary to “unusually low placebo response” in clinical trials.¹³ The benefits of xanomeline/trospium as an augmentation agent can also be questioned. In the phase III ARISE trial, there were no statistically significant improvements with xanomeline/trospium augmentation to other non-clozapine antipsychotics.¹⁴ Even less is known about xanomeline/trospium in treatment-resistant schizophrenia, since this population was specifically excluded from clinical trials. To date, limited information has been published related to concomitant xanomeline/trospium with or after clozapine, and published reports are highlighted in Table 1.^15–19

Table 1.

Reports of xanomeline/trospium in schizophrenia or schizoaffective disorder in combination with or after clozapine.

Report	Case	Outcome	Comment
Andrus and Sanghami	48-yo f with SCZ prescribed multiple antipsychotics, including clozapine 750 mg at the time of restarting an acute series of ECT. X/T was initiated while continuing weekly maintenance ECT	Reduction of psychotic symptoms noted in X/T dosage up to 100 mg/20 mg BID. Reduction of word-finding difficulties described	Glycopyrrolate during ECT did not add to ACH ADRs. Authors report no literature available suggesting blunted X/T benefits with centrally acting ACH medications. Authors suggest future research should be completed to assess if X/T can offset any cognitive side effects associated with ECT
Church, et al.	35-yo m with treatment-resistant SCA who failed clozapine 450 mg (also received four ECTs) daily was started on X/T	Improvement of AH noted after three days of starting. PANSS decreased from 86 to 52 after 5 weeks, optimizing X/T to 125 mg/30 mg.	Clozapine was discontinued due to constipation and lack of apparent effectiveness (no serum levels were reported) prior to X/T
Lanspa, et al.	33-yo m with SCZ who failed multiple antipsychotics, prescribed clozapine 700 mg total daily dose, was admitted for worsening symptoms of SCZ. The patient was switched to risperidone because it “would not be affected by hydrocarbon-induced CYP metabolism.” Due to ongoing symptoms, the decision to trial X/T was made.	X/T was started (35 days after clozapine discontinuation) as 50 mg/20 mg for four doses, followed by 100 mg/20 mg for 10 doses. Three days after X/T initiation the ANC was noted to be 2090/µL and then six days later 1030/µL. Lithium was added, which resulted in an ANC increase to 3290/µL.	Authors concluded a probable association between X/T and decrease in ANC using the Naranjo Adverse Drug Reaction Probability Scale. The patient was reported to have clinical stability with no concerns for neutropenia with continued lithium.
Price and Price*	45-yo f with SCZ and cognitive impairments who failed multiple antipsychotics due lack of benefit or side effects	X/T titrated to 100 mg/20 mg BID with remission of psychosis, improved memory and executive functioning. Tremor and gastroparesis secondary to a GLP-1 RA also resolved	Clozapine not described as a past trial, though past trials not explicitly stated
Price and Price*	75-yo f with SCZ, Alzheimer’s dementia, and OCD prescribed clozapine (dose not reported)	Clozapine tapered off over 6 weeks after X/T titrated to 100 mg/20 mg BID with reported improvement of paranoia, agitation, memory, communication, and OCD symptoms	Nicotine cravings also ceased. Authors describe decreased isolation and improved engagement
Went et al.	44-yo m SCZ on long-term clozapine who developed a VTE. Clozapine was discontinued due to “its known association with VTE”	Switching clozapine to aripiprazole with olanzapine resulted in worsening symptoms and functioning, with ultimate need for psychiatric emergency care. Aripiprazole was tapered, and X/T added to olanzapine. X/T 125 mg/30 mg BID with olanzapine 15 mg total daily dose resulted in significant clinical improvement.	Authors suggest consideration for muscarinic-dopaminergic pharmacologic combinations may be carefully considered in the setting of TRS, with prospective studies needed.

Authors reported three cases of X/T, of which two were relevant to include.

ACH, anticholinergic; ADRs, adverse drug reactions; AH, auditory hallucinations; BID, twice daily; ECT, electroconvulsive therapy; f, female; m, male; OCD, obsessive-compulsive disorder; RA, receptor agonist; SCA, schizoaffective disorder; SCZ, schizophrenia; VTE, venous thromboembolism; X/T, xanomeline/trospium; yo, year old.

Cognitive symptoms are a core domain of schizophrenia with no currently FDA-approved medications. Analyses of the EMERGENT 1 and EMERGENT-2/EMERGENT-3 studies were conducted by the manufacturer to assess the treatment effect on cognitive function.²⁰ In the full sample, there was no difference between treatment and placebo groups at 5 weeks. However, those who had baseline impairment (defined as more than 1 standard deviation below normative standards) had a statistically significant improvement in CANTAB scores. Analysis also found cognitive improvements were independent and not attributed to improvements in psychotic symptoms. However, these findings need to be replicated as the sample size overall (n = 125), and those with baseline cognitive impairments (n = 60), were limited.

Overall, given the unique mechanism of xanomeline/trospium, clinicians may turn to this non-dopaminergic agent for augmentation, but the lack of data needs acknowledgment. Until more is known, ongoing early reporting of clinical information through retrospective review may also be important. From these cases, two lessons can be highlighted:

1) Xanomeline/trospium was unable to replace clozapine, and its effects as an augmentation agent were small. In Case 1, when clozapine was reduced to 300 mg, the patient’s psychotic and cognitive symptoms significantly worsened despite co-treatment with the highest dose of xanomeline/trospium (125 mg/20 mg BID). The overall combination of xanomeline/trospium provided some improvement in psychotic symptoms, but the patient still required treatment with ECT. In Case 2, xanomeline/trospium provided no discernible benefit to clozapine. Further investigations into the effectiveness of xanomeline/trospium for augmentation will need to be explored. In addition, it should be cautioned against considering xanomeline/trospium as a means to avoid clozapine in treatment-resistant schizophrenia, given the lack of evidence. Clozapine should still be prioritized for these patients. Unfortunately, due to insurance formulary restrictions in the United States, which is common with new medications, there is often a requirement to fail several other antipsychotics before receiving coverage of xanomeline/trospium. This inherently biases consideration of xanomeline/trospium for use in treatment-resistant illness.

2) In both Case 1 and Case 2, ECT provided more benefit than xanomeline/trospium with clozapine. The American Psychiatric Association guidelines for schizophrenia highlight evidence of ECT in combination with clozapine, with most showing benefit, and suggest that maintenance ECT with clozapine can be considered when there is a response. Use of ECT in the setting of treatment-resistant illness is also congruent with other guidelines.²¹ However, a recent RCT demonstrated that ECT was not better than sham-ECT in clozapine resistance in lowering PANSS scores by at least 50% from baseline.²²

Conclusion

CRS is particularly challenging to treat with limited pharmacologic options. We describe two cases with differing outcomes. In Case 1, augmentation of clozapine with xanomeline/trospium was well tolerated and provided mild benefit for psychotic symptoms, despite potential concern for opposing action in the CNS. Although the patient’s SLUMS did not appreciably change, her day-to-day functioning and engagement in cognitive-based activities improved, although she still required maintenance ECT. In Case 2, xanomeline/trospium did not successfully augment clozapine and was not well tolerated. As xanomeline/trospium becomes more widely used, assessing its ability to augment or use after a failed clozapine trial through research and clinical reports will provide potentially impactful clinical information for patients with clozapine-resistant schizophrenia.

Supplemental Material

sj-pdf-1-tpp-10.1177_20451253261433832 – Supplemental material for Adjunctive xanomeline/trospium in clozapine-resistant schizophrenia: two case reports demonstrating limited response

Supplemental material, sj-pdf-1-tpp-10.1177_20451253261433832 for Adjunctive xanomeline/trospium in clozapine-resistant schizophrenia: two case reports demonstrating limited response by Vanessa M. Dang, John M. Powers, Matej Markota and Jonathan G. Leung in Therapeutic Advances in Psychopharmacology

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Vanessa M. Dang

Jonathan G. Leung

Supplemental material

Supplemental material for this article is available online.

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