Schizophrenia remains one of the most common psychiatric disorders. The World Health Organization (WHO) approximates that 24 million individuals worldwide are afflicted (Meyer et al., 2025), with a global point prevalence of 1 in 300 for the general population and 1 in 222 for adults. The disease most often begins in late adolescence and young adulthood, with men falling ill earlier than women (WHO, 2026). Over the past 2 decades, the prevalence and incidence of schizophrenia have risen by 37% and 65%, respectively (Vasiliu et al., 2024). Schizophrenia consistently ranks among ten highest contributors to disability globally (JMCP, 2026), indicating the imperative need for novel therapeutic strategies (Vasiliu et al., 2024).

The standard treatment of schizophrenia is based on dopaminergic antipsychotic medication, commonly associated with many side effects. These include metabolic syndrome, hyperprolactinemia, QT interval prolongation, extrapyramidal symptoms, and malignant neuroleptic syndrome (JMCP, 2026; Ramey and Almodóvar, 2025). As a result, antipsychotic treatment may be limited by those effects, often contributing to poor adherence. Non-adherence, in turn, exacerbates the clinical symptoms of schizophrenia and further reduces the overall effectiveness of therapy (Menegaz d et al., 2025).

Additionally, dopaminergic antipsychotics mainly suppress the positive symptoms of schizophrenia, leaving patients burdened by negative symptoms and cognitive impairments (Meyer et al., 2025; Jamanetwork, 2025). Studies report that more than 75 percent of patients under antipsychotics experience at least one side effect; women and polypharmacy users are at particular risk (Iversen et al., 2018).

D₂ receptor overactivation was observed in the associative striatum of untreated patients with schizophrenia, which may be involved in the occurrence of schizophrenia symptoms (Saint-Georges et al., 2025). Also, recent observations of transgenic organisms showed that overexpressing D₂ receptors in the striatum is relevant to cognitive impairment (Kegeles et al., 2010). Dopamine hypoactivity in the prefrontal cortex, caudate, and alterations of D₃ receptor activity are probably responsible for the negative and cognitive symptoms of schizophrenia. The cognitive deficits are also linked to reduced dopamine transmission in the neocortex and other cortical structures (Foster et al., 2021; Collo et al., 2020). Saint-Georges et al. review findings suggest that the cholinergic system is implicated in the development of psychosis by controlling the dopamine release in the striatum (Saint-Georges et al., 2025). Especially, the cholinergic M₁ and M₄ receptors show a strong relationship with the regulation of dopamine secretion (Dean et al., 2023). Neuroimaging and post-mortem studies demonstrate a link to dysregulated acetylcholine function in the pathomechanism of schizophrenia (Saint-Georges et al., 2025).

Acetylcholine is a key modulator in cortical and subcortical neurotransmission through muscarinic acetylcholine receptors. Of the five muscarinic receptor subtypes (M₁-M₅), M₁ and M₄ receptors especially are relevant to the pathophysiology of schizophrenia, as they are involved in cognitive processing and dopaminergic regulation. M₁ receptors are predominantly expressed in cortical and hippocampal pyramidal neurons coupled with G_q proteins, leading to phospholipase C activation and intracellular calcium signaling. M₄ receptors are mostly found in striatal regions and on presynaptic dopaminergic terminals, where their activation inhibits dopamine release via G_i/o protein–mediated pathways. This complementary modulation of cortical and subcortical circuits provides a mechanistic framework for targeting muscarinic receptors as an alternative to direct dopamine receptor antagonism in schizophrenia (Yohn et al., 2022).

Among patients on standard antipsychotic drug treatment, about 30% develop resistance, of which less than half would respond to clozapine, a drug for treatment-resistant schizophrenia (Vasiliu et al., 2024; Smith et al., 2025). Using clozapine is associated with serious side effects, including agranulocytosis, myocarditis, seizures, and typical symptoms such as drowsiness, weight gain, excessive salivation, and constipation. Due to the risk of serious complications, clozapine was withdrawn from the market in 1976. In 1990-1991, after studies confirmed its effectiveness, it was reapproved for use (Wright et al., 2024).

Xanomeline-trospium (KarXT) is a combination of xanomeline, an M₁ and M₄ receptor agonist, and trospium chloride, a peripheral cholinergic receptor antagonist with no ability to cross the blood-brain barrier (Vasiliu et al., 2024). Muscarinic M₁ and M₄ receptors are instrumental in controlling glutamatergic and dopaminergic pathways. This neuromodulatory strategy achieves antipsychotic efficacy, limiting adverse effects typically associated with D₂ receptor antagonism, as KarXT does not directly interfere with dopamine pathways (Hasan and Abid, 2024).

Trospium, by its antagonistic activity, reduces the incidence of xanomeline-induced peripheral cholinergic adverse effects (Azargoonjahromi, 2024). In various studies, KarXT effectively reduced psychotic symptoms of schizophrenia and was generally well tolerated (Jamanetwork, 2025; Correll et al., 2023; Kaul et al., 2025; Yeung et al., 2025). By modulating cholinergic system activity, it also influences GABAergic transmission, which is involved in the regulation of cognitive function, psychosis, and addiction (Vasiliu et al., 2024). This approach represents a new treatment paradigm focused on restoring the physiological balance of neurotransmitters.

Efficacy was assesed using changes in Positive and Negative Syndrome Scale (PANSS), a scale designed to asses symptoms of schizophrenia. Reductions in PANSS scores are generally associated with effective symptom control, whereas minimal or absent changes may indicate limited therapeutic efficacy or treatment resistance. A 20%–30% reduction in PANSS total score is generally considered to represent a clinically meaningful improvement, while a ≥30% reduction indicates a clear and clinically noticeable response (Si et al., 2021; Leucht et al., 2019).

The second scale which was used is Clinical Global Impression–Severity scale (CGI-S). It assesses the clinical severity of schizophrenia at a given time point. It provides global clinical evaluation that complements a specified scale, such as PANSS. It is a 7-point scale, thus the change of even one point is clinically significant (Si et al., 2021).

This narrative review aims to provide a comprehensive overview of the current knowledge about KarXT in schizophrenia treatment. To identify the most relevant clinical evidence regarding the efficacy of KarXT, an extensive literature search was performed in various academic databases: PubMed, Scopus, Embase, ClinicalTrials.gov, and Web of Science.

The inclusion criteria involve clinical studies performed on adult patients diagnosed with schizophrenia (according to ICD-10, DSM-5, or DSM-IV); studies performed in the exacerbation of schizophrenia and focusing on KarXT in the context of schizophrenia psychopharmacotherapy. Due to the novelty of the drug KarXT, we did not impose a publication date regime, and we also included older papers on xanomeline and trospium as drugs used in treatment relative to each other independently.

The exclusion criteria include preclinical or animal-only studies, studies focused on unrelated indications, and use of KarXT in a non-standard formulation.

We used the following keywords: xanomeline-trospium, KarXT, xanomeline, trospium, Cobenfy, muscarinic receptors, cholinergic modulation, schizophrenia, psychosis, PANSS score.

The most important information was obtained and presented in a narrative approach, with particular emphasis on pharmacokinetic aspects, receptor selectivity, and clinical trial results. In addition, the quality and validity of scientific research were taken into account in order to present a reliable and up-to-date state of knowledge on the topic presented.

All works meeting our criteria turned out to be in English only.

KarXT represents a novel therapeutic strategy in schizophrenia by selectively targeting central muscarinic acetylcholine receptors, thereby offering a non-dopaminergic approach to symptom control. Unlike conventional antipsychotics, its mechanism of action is grounded in cholinergic modulation, addressing long-standing pathophysiological hypotheses implicating muscarinic signaling in psychosis (Dean and Scarr, 2020).

Accordingly, this section outlines KarXT as a case example of cholinergic modulation in schizophrenia, progressing from its neurobiological and pharmacokinetic rationale (Section 3.1), through evidence on clinical efficacy, safety, and tolerability (Section 3.2), to recent formulation advances designed to optimize its clinical usability (Section 3.3).

Xanomeline is a drug originally developed in the 1990s as a new substance with potential in the treatment of Alzheimer’s disease. At the clinical trial stage, the drug has shown beneficial effects on cognitive function and has reduced psychotic symptoms in dementia patients (Bodick et al., 1997; Fisher, 2025; Avery et al., 1997). However, due to persistent side effects associated with activation of peripheral Muscarinic Acetylcholine Receptors (mAChRs) - mainly from the gastrointestinal and autonomic systems (i.e., diarrhea, sweating, nausea) - studies on its clinical use were discontinued (Shekhar et al., 2008).

The most important clinical challenge was to reduce the peripheral side effects of muscarinic receptor agonism without compromising the beneficial central effects of xanomeline. In this context, trospium - previously used in the management of overactive bladder (OAB) - has been applied (Staskin et al., 2010). The resulting fixed-dose drug combination, KarXT, was officially registered by the FDA on 26 September 2024, for the treatment of schizophrenia in adults (Commissioner of the FDA, 2024). Karuna Therapeutics is responsible for the pharmaceutical combination, selling the product under the name Cobenfy™; the prefix “Kar” in KarXT reflects the company’s name, while “XT” denotes its components (FDA, 2025). Available meta-analyses indicate that KarXT has a promising therapeutic profile, including high clinical efficacy, favorable safety of use, and good tolerability in patients with schizophrenia (Fabiano et al., 2025; Mohammed et al., 2025; Guo et al., 2025). Specifically, the meta-analysis by Menegaz de Almeida et al. identified premature discontinuation rates primarily driven by gastrointestinal adverse events, especially nausea and vomiting, despite overall favorable efficacy outcomes. These findings highlight tolerability as a clinically relevant limitation, rather than lack of antipsychotic effectiveness (Menegaz d et al., 2025). Similarly, Wright AC et al. emphasized that evidence regarding long-term durability of symptom control, adherence, and rare adverse events remains limited. The authors underscored the need for extended-duration studies to better characterize KarXT’s role in chronic schizophrenia management and to facilitate comparisons with established long-term antipsychotic therapies (Wright et al., 2024).

Xanomeline exhibits high affinity for muscarinic M1 and M4 receptors. Its functional relevance in schizophrenia is attributed to expression and involvement of these receptors in key brain regions implicated in psychosis and cognition, including the cerebral cortex, hippocampus, and nucleus accumbens (Thorn et al., 2019). Owing to its ability to cross the blood–brain barrier, xanomeline modulates central cholinergic signaling, which has been associated with improvements in cognitive performance and reductions in psychotic symptoms such as delusions and hallucinations in clinical studies (Shekhar et al., 2008; Guo et al., 2025; Harvey et al., 2025).

Trospium, due to its hydrophilic (polar) structure, does not penetrate the blood-brain barrier (Rovner, 2004) and acts peripherally, primarily protecting the intestines, bladder, and sweat glands. It prevents side effects of xanomeline outside the central nervous system, including diarrhea, nausea, and increased sweating (Breier et al., 2023).

Xanomeline-trospium represents a promising direction in the treatment of schizophrenia as the first FDA-approved based on cholinergic modulation. Thanks to its innovative mechanism of action, the drug reduces positive symptoms as well as brings significant improvements in cognitive deficits and negative symptoms, which have been a major therapeutic problem until now (Paul et al., 2024; Kaul et al., 2024a; Kaul et al., 2024b; Brannan et al., 2021; Weiden et al., 2022).

Short-term (5-week) studies reported statistically significant and clinically meaningful reductions in PANSS total score, with effect sizes of moderate to large (average d = 0.65). Long-term studies of EMERGENT-4 and EMERGENT-5, covering 52 weeks of therapy, showed durability of the therapeutic effect, as well as a stable tolerability profile with no cumulative toxicity (Psychiatrictimes, 2025). Adverse effects - mainly on the gastrointestinal side - were mostly mild to moderate and did not lead to a significant rate of therapy discontinuation, in contrast to previous therapeutic options (Kaul et al., 2024a; Kaul et al., 2024b; Brannan et al., 2021; Correll et al., 2022; Lieberman et al., 2005).

The absence of the usual extrapyramidal symptoms, hyperprolactinemia or metabolic syndrome typical of D₂ antagonists is of high importance. This makes KarXT an encouraging alternative for patients who are poorly tolerant of existing antipsychotics, as well as those with drug-resistant schizophrenia, for whom clozapine currently remains the only treatment option (Fenton and Kang, 2023).

Of particular interest in the context of further development of cholinergic therapy is TerXT, a new prodrug form of xanomeline and trospium being developed by Terran Biosciences. KarXT requires twice-daily administration, which is a significant therapeutic problem in patients with schizophrenia. TerXT is designed as a drug taken once a day in oral form and in a depot version (TerXT LAI) - administered intramuscularly with prolonged action. Both formulations are expected to provide more stable concentrations of the drug, reduce side effects and improve treatment adherence (Beaney, 2024).

From a systemic perspective the cost of therapy can be a significant challenge. According to estimates, the annual price of KarXT in the U.S. is about $22,500, which exceeds ICER’s recommended cost-effectiveness threshold ($16,000-20,000 per QALY). Nevertheless, the drug has been deemed “promising but inconclusive” (Icer, 2025). The manufacturer, Karuna Therapeutics (now part of BMS), is considering patient support programs and price negotiations, which may facilitate the drug’s availability on the market. Importantly, Bristol speculates that 80% of the population treated with KarXT will be covered by Medicare and Medicaid within 12–18 months of the drug’s launch (Satija et al., 2024).

Although no direct head-to-head trials comparing KarXT with typical or atypical antipsychotics are currently available, several clinically relevant distinctions can be drawn based on mechanism of action and observed safety profiles. Unlike typical antipsychotics, which exert antipsychotic effects primarily through D₂ receptor antagonism and are associated with a high risk of extrapyramidal symptoms, KarXT does not directly interfere with dopaminergic transmission, thereby largely avoiding motor side effects and hyperprolactinemia (Yohn et al., 2022; Paul et al., 2024; Kaul et al., 2024a; Kaul et al., 2024b; Brannan et al., 2021; Leucht et al., 2013; Haddad and Wieck, 2004).

Compared with atypical antipsychotics, KarXT similarly demonstrates efficacy in reducing positive symptoms, but with a distinct adverse event profile characterized predominantly by transient gastrointestinal effects rather than metabolic disturbances, weight gain, or sedation. Importantly, muscarinic M₁ receptor engagement offers a plausible advantage in addressing cognitive and negative symptoms, domains in which both typical and many atypical antipsychotics show limited efficacy. These differences suggest that KarXT may occupy a complementary therapeutic niche rather than directly competing with existing dopamine-based agents (JMCP, 2026; Lobo et al., 2022; Icer, 2025).

The prespecified secondary measures were also negative; however, post hoc analyses indicated a greater effect when background therapy excluded risperidone. The add-on result suggests that efficacy demonstrated in acute monotherapy settings may not translate into short-term adjunctive benefit for residual symptoms (Weiden et al., 2022). These findings highlight important limitations of the current evidence and underscore the need for further well-designed studies, particularly in patients with predominant negative symptoms or cognitive impairment, and with longer treatment durations.

Overall, KarXT represents a potentially transformative therapeutic option for schizophrenia with a unique mechanism of action that may provide significant benefits in addressing negative symptoms and cognitive deficits. It offers a favorable safety profile, a real improvement in patients’ functioning and a potential change in the approach to schizophrenia pharmacotherapy in the coming years. Its further development, monitoring of efficacy in real-world populations, and regulatory decisions regarding availability and price will determine its place in future treatment standards.