Muscarinic Cholinergic Circuitry in Schizophrenia: Our Evolving Understanding

CATEGORY 1 CME

Premiere Date: December 20, 2025

Expiration Date: June 20, 2027

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ACTIVITY GOAL

To share the sequence of events that led to our understanding of the role of muscarinic cholinergic receptor activation in schizophrenia.

LEARNING OBJECTIVES

1. Describe the evolving model of the circuitry of the human brain’s muscarinic cholinergic receptors 1 and 4 (M₁ and M₄), and how activation of these receptors hypothetically improves the 3 subdomains of schizophrenia without impacting the motor system or the endocrine system.

2. Understand the role of the muscarinic cholinergic circuitry in the central and peripheral nervous systems and corresponding benefits/adverse effects of muscarinic cholinergic receptor agonism and antagonism.

3. Explain the need to combine the peripherally acting anticholinergic trospium chloride with the muscarinic cholinergic M₁ and M₄ receptor–preferring activator xanomeline to maximize efficacy and tolerability in the treatment of schizophrenia, and how this informed the development of KarXT.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Understanding the muscarinic acetylcholine (mACh) system has become essential for psychopharmacologists and psychiatric clinicians following the recent advances providing us with medications to modulate this system in the treatment of schizophrenia. Specifically, KarXT (Cobenfy),^1,2 a combination of xanomeline (a muscarinic M₁ and M₄ receptor–preferring agonist) and trospium chloride (a pan-mACh receptor antagonist that does not appreciably cross the blood-brain barrier), was approved by the US Food and Drug Administration (FDA) in September 2024 as the first medication that treats schizophrenia by a mechanism unrelated to direct dopamine (DA) activity. Psychiatry’s familiarity with mACh circuitry has primarily focused on medications with anticholinergic activity, such as benztropine, diphenhydramine, and trihexyphenidyl, which are commonly used to mitigate D₂ DA receptor antagonist–induced movement disorders. Numerous medications prescribed throughout various specialties of medicine have anticholinergic properties either as their primary mechanism of action or as an adverse effect. Additionally, anticholinergic medications are believed to significantly contribute to the etiology of delirium.³

This article will provide a basic overview of the mACh circuitry in the human brain as it relates to the etiology and treatment of schizophrenia, as well as an overview of the need for a pharmacological balance of the mACh system in the periphery to minimize adverse effects.

Acetylcholine: A Ubiquitous Neurotransmitter

The prominence of acetylcholine (ACh) during the evolution of complex living systems required the independent evolution of 2 major receptor subtypes to provide the necessary diversity for wide-ranging functionality. Approximately 2.5 billion years ago, nicotinic ACh receptors appeared, which are pentameric ionotropic channels that create rapid ion flow when activated by ACh or nicotine (from the tobacco plant) but lack any response to muscarine (a plant molecule from the mushroom Amanita muscaria).⁴

More recently, in evolutionary terms (approximately 0.5 billion years ago), mACh receptors (mAChRs) emerged as G protein–coupled, metabotropic receptors activated by ACh or muscarine but not by nicotine. Although nicotinic and muscarinic receptors colocalize across the brain and periphery and are both engaged by ACh, this introductory overview of ACh circuitry in schizophrenia focuses on the muscarinic system. Both receptor families are heterogeneous, enabling specialized functions (Figure 1).

Arecoline and mACh Receptor Activation

As Figure 1 depicts, the mACh system has 5 receptor subtypes and 2 distinct families: mAChR-1 (M₁), M₃, and M₅, which result in intracellular excitation when activated, and M₂ and M₄, which result in intracellular inhibition when activated. M₂ and M₄ commonly serve as presynaptic autoreceptors to shut down further release of ACh by the ACh neuron when activated.

Unsurprisingly, like nicotine, caffeine, cocaine, and opium, which are commonly used and abused molecules extracted from native plants, a plant molecule exists that activates all 5 of the mAChRs and results in alertness, stimulation, euphoria, improved concentration, and cognitive enhancement. This molecule, arecoline, is found in betel nuts, also known as areca nuts, from the plant Areca catechu. It is the fourth most used psychoactive drug in the world today, behind alcohol, nicotine, and caffeine. First discovered in 1891 by the German chemist E. Jahns, arecoline, as demonstrated in limited studies, significantly lowered Positive and Negative Syndrome Scale scores in individuals with schizophrenia who were betel nut chewers vs nonchewers. The betel nut chewers had lower scores on both the positive subscale (P = .001) and the negative subscale (P = .002) compared with the nonchewers.⁵

Remarkably, arecoline’s potential benefit for individuals with schizophrenia first appeared in the psychiatric literature in 1957.⁶ The publication is worth reading if only for insight into how psychiatric research was undertaken at that time and how results were reported. The authors recorded 23 trials of injecting arecoline 20 mg (the pan-mAChR agonist) mixed with methyl atropine 3 mg (the pan-mAChR antagonist that minimally crosses the blood-brain barrier) subcutaneously in the same syringe. They reported the “antischizophrenic action of arecoline begins 1 to 2 minutes after injection, reaches a peak in 5 minutes, and disappears completely in 15 to 20 minutes.” They further described that the “basic signs of improved emotional outlet such as laughing, sobbing, sighing, and yawning after arecoline are noteworthy in that they are absent uniformly in the untreated institutionalized schizophrenic patient.” The authors concluded: “Research studies should be extended to include the examination of naturally occurring metabolites that have a strong central muscarinic action, since these metabolites may be more antischizophrenic than the presently available tranquilizing drugs.” Despite Pfeiffer and Jenneys’ excitement over a potentially novel mechanism of action to treat schizophrenia, which would have to wait 40 more years to be revisited, the obsession with D₂ DA receptor antagonism crashed like a tidal wave over the mAChR agonism hypothesis and blazed the research trail forward.

From Acetylcholinesterase Inhibitors to Xanomeline for Alzheimer Disease

Another pharmacological approach to increase the brain’s activation of mAChRs is to inhibit the endogenous enzyme acetylcholinesterase in the brain, which inactivates ACh by cleaving the acetyl group from choline. Simply called cholinesterase inhibitors, 4 of these medications were FDA approved for Alzheimer disease (AD) between 1993 and 2001: tacrine in 1993 (subsequently taken off the market), donepezil in 1996, rivastigmine in 2000, and galantamine in 2001. None of these provided significant improvement in cognitive symptoms, and a huge unmet need persisted. Researchers at Lilly Research Laboratories hypothesized that the poor efficacy of the cholinesterase inhibitors was at least in part due to degenerated presynaptic cholinergic nerve terminals in AD, which decreased the amount of ACh available to be preserved. They hypothesized that M₁ receptor agonists might provide a greater therapeutic benefit, as these medications would directly activate the postsynaptic M₁ receptors in the prefrontal cortex.

Aware of the pan-mAChR activation by arecoline, Lilly Research Laboratories synthesized a series of structural analogues of arecoline. Xanomeline—an orally bioavailable, brain-penetrant M₁-preferring agonist with pharmacokinetics that support practical oral dosing—emerged as the best candidate to study for AD. Significantly, xanomeline demonstrated a high affinity at all 5 mAChRs, but functional studies demonstrated a higher potency and efficacy at M₁ and M₄ receptors than at M₂, M₃, or M₅.⁷

A 1997 study by Bodick et al was a 6-month randomized, placebo-controlled, double-blind study in the US and Canada in individuals with probable mild to moderate AD. A total of 343 participants aged 60 years or older participated in the study. Participants were randomly assigned to xanomeline 75 mg, 150 mg, or 225 mg vs placebo daily for 6 months. All doses were administered 3 times a day; hence, the 75-mg participants received 25 mg orally 3 times a day. In the 225-mg dose vs placebo groups, there was a significant improvement on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (P ≤ 0.05) and the Clinician’s Interview-Based Impression of Change Plus (P ≤ 0.02). Treatment Emergent Signs and Symptoms analysis of the Alzheimer Disease Symptomatology Scale, designed to evaluate behavioral symptoms in individuals with AD, demonstrated significant dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations (P ≤ .002).⁸

Prompted by reports of dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations, Lilly investigators conducted a follow-up study of xanomeline in schizophrenia that showed both antipsychotic and procognitive effects. However, poor tolerability—driven by peripheral cholinergic adverse effects such as nausea, vomiting, hypersalivation, sweating, and diarrhea—ultimately led to discontinuation of the xanomeline clinical programs in both AD and schizophrenia, despite evidence of symptomatic improvement.⁹

Balancing Peripheral Procholinergic With Anticholinergic

Karuna Therapeutics hypothesized that if a pan-mAChR antagonist, especially one that does not appreciably cross the blood-brain barrier, such as trospium chloride, were combined with xanomeline, then, putatively, its M₁ and M₄ receptor central nervous system activation would persist while the peripheral procholinergic adverse effects could be mitigated by the trospium chloride. This combination, KarXT, was formulated to maximize benefit and minimize adverse effects. Figure 2 lists the common consequences of procholinergic and anticholinergic effects in the central and peripheral nervous systems. Minimizing central anticholinergic activity by using trospium chloride, a drug known for its minimal propensity to cross the blood-brain barrier, would minimize cognitive impairment and the risk of delirium while allowing the xanomeline, which readily crosses the blood-brain barrier, to putatively improve cognition and decrease psychotic symptoms. The presence of both xanomeline and trospium chloride in the periphery would mitigate the drugs’ opposing peripheral effects, which would likely vary from person to person.

Interestingly, the protocol used by Pfeiffer and Jenney and reported in their 1957 publication⁶ to mitigate the procholinergic peripheral adverse effects of arecoline was, in essence, the same pharmacological approach that Karuna developed to mitigate the procholinergic peripheral adverse effects of xanomeline. In the 1950s, methyl atropine, a pan-mAChR antagonist that minimally crossed the blood-brain barrier, was added to the syringe containing arecoline, and both drugs were injected together subcutaneously. Karuna combined 2 orally administered drugs, xanomeline and trospium chloride, to accomplish the same outcome.

Xanomeline/Trospium in Schizophrenia

Once Karuna developed the optimal dosages for its combination drug xanomeline-trospium chloride (KarXT), researchers completed three 5-week (1 phase 2 and 2 phase 3) double-blind, placebo-controlled clinical trials in individuals with established schizophrenia experiencing acute psychosis and requiring inpatient hospitalization. All 3 trials were positive, with effect sizes of 0.81, 0.61, and 0.60, respectively. Adverse events included nausea, constipation, dry mouth, dyspepsia, and vomiting. On September 26, 2024, KarXT was FDA approved as Cobenfy for the treatment of schizophrenia in adults based on data from the EMERGENT 1, 2, and 3 studies^10-12 and additional analysis of the safety and tolerability of the pooled results.¹³

Evolving Understanding of the Brain’s mACh Circuitry

Unsurprisingly, we are still in the early stages of understanding the neurocircuitry of the human brain. Despite a vast published literature in neuroscience, we still cannot explain the underlying neurophysiology of how D₂ DA receptor antagonists treat psychosis, how serotonin reuptake inhibitors treat depression and anxiety, and how lithium treats mania. However, appropriately, clinical trials are designed to confirm or refute the benefits of a specific mechanism in a population of individuals with particular symptoms. Although we have significant clinical experience with the consequences of muscarinic anticholinergic drugs, our understanding of the muscarinic procholinergic system in the human brain is in its infancy. Despite that, great strides have been made in mapping out the mACh circuitry in the human brain over the past 3 decades.^14,15

A major advance over the past decade has been a refinement of our understanding of the organization of the human brain’s striatum. Most currently used diagrams of brain structures, including the figures used in this article, are based on the traditional DA hypothesis model developed from the study of rodent anatomy. New imaging studies have taught us that the human striatum is far more complicated than that of the rat, and dividing the human striatum into the “ventral” and “dorsal” regions is not accurate. The human striatum contains many subregions, and neurons originating from areas in the midbrain can project to a range of these subregions. This has significant implications for our understanding of how activation of mAChR subtypes can differentially impact one part of the striatum while having little effect on another part. In the following figures of the brain, the classical view of the rat striatum with clearly defined dorsal and ventral regions will be retained for simplicity. Additionally, the ventral tegmental area (VTA) in the midbrain is intentionally referred to as an “area” rather than a “nucleus” by neuroanatomists due to the diffuse range of neurons leading to it from the brainstem and departing from it to the striatum and prefrontal cortex. As any neurosurgeon would report, each person’s brain is uniquely wired, and this is what is expected from an organ that is always rewiring itself through the well-established processes of neuroplasticity and synaptogenesis.

Figure 3 depicts the brain structures at the core of our current pharmacological targets for the treatment of schizophrenia: D₂ DA receptor antagonists/partial agonists and M₁/M₄ receptor agonists (also called activators). In the brainstem, there are 2 cholinergic nuclei that project cholinergic neurons to the midbrain: the laterodorsal tegmentum (LDT), which primarily projects to the VTA, and the pedunculopontine nucleus (PPN), which primarily projects to the substantia nigra (SN). In the midbrain, there are DA cell bodies that send projections to the striatum: The SN’s DA neurons primarily project to the dorsal striatum, while the VTA DA neurons primarily project to the ventral striatum and the prefrontal cortex. Finally, the arcuate nucleus of the hypothalamus contains DA neuron cell bodies that project to the pituitary gland, where prolactin production and release is regulated.

Figure 4 demonstrates the potential consequences of postsynaptic D₂ DA receptor antagonism, which has been a shared pharmacological property of all FDA-approved antipsychotic medications since the introduction of chlorpromazine in the US in 1954. Four different DA pathways are impacted by this global D₂ DA receptor antagonism with the following effects, depending on the concentration of each particular medication in the cerebral spinal fluid: decreased psychotic symptoms by antagonizing D₂ DA receptors at the mesolimbic tract in the ventral striatum, increased cognitive dysfunction and negative symptoms by antagonizing D₂ DA receptors at the mesocortical tract in the prefrontal cortex, the onset of movement disorders by antagonizing D₂ DA receptors at the nigrostriatal tract in the dorsal striatum, and increased prolactin levels by antagonizing D₂ DA receptors at the tuberoinfundibular tract of the pituitary gland. This pharmacological approach has dominated the treatment of schizophrenia since the introduction of chlorpromazine, although clozapine and postclozapine antipsychotics have added activity at other receptors that also contribute to their mechanisms of action and adverse effects.

Activating M₁ and M₄ in the Brain

In 1957, arecoline introduced us to the potential role of mAChR agonism in the treatment of schizophrenia, and, from the 1990s to 2008, its synthetic analogue xanomeline, with well-characterized functional activity limited to activation of M₁ and M₄ receptors, demonstrated improvement in cognition and psychosis in patients with AD and schizophrenia. The three 5-week clinical trials with KarXT resulted in FDA approval of KarXT for the treatment of adults with schizophrenia, with no direct activity at any DA receptor. Figure 5 illustrates a hypothetical explanation as to how selective M₄ receptor activation can treat psychotic symptoms without causing movement disorders by selectively decreasing the output of DA from the VTA to the subregions of the human striatum associated with psychosis, while not significantly impacting the DA output from the SN to the subregions of the human striatum associated with movement disorders.

The cholinergic neuronal projections whose cell bodies reside in the LDT and innervate DA cell bodies in the VTA activate these DA cell bodies by releasing ACh, which binds to the M₅ excitatory receptors on the cell bodies, triggering the release of more DA in the regions of the human striatum associated with psychosis. The LDT cholinergic projections at the VTA contain M₄ autoreceptors that, when activated by too much ACh, serve to inhibit further ACh release. Hence, this decreases the M₅ receptor activation of the DA cell bodies in the VTA, which decreases DA release into the striatum, putatively decreasing psychotic symptoms. Xanomeline, by its activation of these M₄ autoreceptors, hypothetically decreases ACh output by the LDT, ultimately resulting in decreased DA release by the VTA projections to the striatum.

In contrast to the LDT, the PPN cholinergic neurons appear to require coactivation by both M₄ and M₂ autoreceptors to decrease DA release into the striatum, hence not significantly impacting the SN signaling to the striatum in the absence of M₂ receptor activation, with the result of minimal disruption to the balance of motor function. As xanomeline lacks M₂ receptor activation, this could explain its lack of movement disorders by minimally impacting dopamine output from projections of the SN. Multiple publications support this hypothesis.^16-19

The limbic, associative, and sensorimotor subregions of the striatum shown in Figure 5 provide a more realistic depiction of the human striatum, as previously discussed. This hypothetical model is consistent with the results of the three 5-week KarXT phase 2 and 3 clinical trials, in which virtually no movement disorders were observed, while there was a clinically meaningful and statistically significant improvement in symptoms of schizophrenia in adult patients. Additionally, 2 subsequent 12-month safety studies, EMERGENT-4 and -5, of KarXT demonstrated the same adverse effect potential as the 5-week studies, with no significant emergence of movement disorders.²⁰

M₁ receptor agonism in the frontal cortex (FC) is hypothesized to contribute to improvements in positive, negative, and cognitive symptoms in individuals with schizophrenia, albeit through a variety of different pathways. There is a high density of M₁ receptors in the human FC as well as the cortex in general, as demonstrated by the high density of M₁ receptor mRNA found in these regions.¹⁵ M₁ receptors are likely involved in multiple diverse circuits in the FC. Figure 6 depicts the large role that M₁ receptors have been hypothesized to play in FC functions, including one circuit that may indirectly synergize with M₄ receptors to decrease DA output from the VTA. Activated M₁ receptors on GABA interneurons in the FC would increase GABA neuronal inhibition of pyramidal glutamate neurons that are innervated by the GABA interneurons. This would decrease the pyramidal glutamate neurons’ excitation of the DA neurons they innervate in the VTA, further decreasing DA output to the striatum and improving psychotic symptoms.

Going back to the original research on xanomeline in AD, it demonstrated an improvement in cognition in the 6-month clinical trial in individuals with probable mild to moderate AD. The M₁ receptor agonism of xanomeline was the primary mechanism of action hypothesized to have improved cognition in these patients. However, increasing data support the likelihood that M₄ receptor agonism also contributes to cognitive improvement, and M₄ receptor mRNA is also prevalent in the FC. To date, the collective data looking at the possible improvement of cognitive symptoms in patients with schizophrenia by KarXT is hopeful, but it is too early to draw any strong conclusions. Post hoc analysis of the three 5-week EMERGENT trials of KarXT did not show an overall statistical improvement in cognitive function in the entire patient population studied as compared with placebo; however, it did demonstrate in all 3 studies an improvement in cognitive outcome in the subgroup of subjects with documented clinically significant cognitive impairment at baseline with Cohen’s d effect sizes of 0.5 and 0.54, respectively.^21,22

Additionally, preclinical research has demonstrated cognitive improvement in rodents and nonhuman primates with M₄ mAChR positive allosteric modulators. A large body of nonhuman research has consistently supported the important role of M₄ agonism in cognitive function. The likely role of both M₁ and M₄ in human cognitive processes is supported by significant expression of M₁ and M₄ receptor mRNA from healthy human tissue in brain regions associated with cognition.²³

The mAChR Medication Pipeline

A healthy pipeline exists with a range of compounds that target either M₁ or M₄ or both for a variety of disease states, including schizophrenia, AD, AD psychosis, AD cognition, Parkinson disease dementia, and frontotemporal dementia.²³ Mechanisms of action range from orthosteric agonists to positive allosteric modulators. NBI-1117568, a highly selective orthosteric agonist of M₄ receptors for the potential treatment of adults with schizophrenia, completed a positive phase 2 trial with the 20-mg oral daily dose in August 2024. A phase 3 clinical trial is currently underway. Emraclidine monotherapy, a highly selective positive allosteric modulator of M₄, initially showed promise in the treatment of adults with schizophrenia but reported 2 negative phase 2 trials in November 2024. The development of emraclidine as a treatment for schizophrenia continues, with the next step looking at its effectiveness as an adjunctive treatment in combination with other medications for schizophrenia.²⁴

Concluding Thoughts

The mACh circuitry in the human brain has arrived as a novel pharmacological mechanism in psychiatry with demonstrated efficacy and FDA approval of KarXT (Cobenfy) on September 26, 2024, for the treatment of adults with schizophrenia. The phase 2 and phase 3 clinical trials all demonstrated clinically significant improvement in the Positive and Negative Syndrome Scale in adult patients with schizophrenia, with notable effect sizes of 0.81, 0.61, and 0.60, respectively. This article is meant to serve as an introductory overview of this complex neuronal circuitry, and we have much to learn. In contrast to the lineage of antipsychotic medications FDA approved to treat schizophrenia, KarXT has no direct activity on DA receptors. Unsurprisingly, DA remains a part of the mechanism of action as we understand it, albeit indirectly through activity at other neurotransmitter systems, notably ACh, GABA, glutamate, and likely others.

The significance of KarXT is that, unlike D₂ DA receptor antagonists, which ubiquitously act postsynaptically on all D₂ DA receptors in the human brain and body, KarXT targets presynaptic mACh circuits that specifically appear to converge on the DA cell bodies in the VTA to decrease DA output to the striatum, which is its hypothesized mechanism for treating the positive symptoms of schizophrenia. By avoiding the D₂ DA receptor antagonism at the mesocortical tract, the nigrostriatal tract, and the tuberoinfundibular tract, xanomeline demonstrates a consistent absence of the primary adverse events that D₂ DA receptor antagonists cause, specifically worsening of cognitive/negative symptoms, movement disorders, and elevation of prolactin levels, respectively. Additionally, D₂ DA receptor antagonism at presynaptic DA neurons has the likely effect of increasing presynaptic DA release, as the presynaptic D₂ DA autoreceptor antagonism prevents DA from activating the D₂ DA autoreceptor, which would decrease presynaptic DA release. The adverse effects of KarXT relate to peripheral procholinergic and anticholinergic effects that occur immediately upon initiation as well as after the dose is increased, and most patients accommodate with continued treatment. Finally, there is a signal that KarXT may improve cognitive symptoms in the subset of patients with schizophrenia with baseline pre-KarXT cognitive impairment, and this is an area of active research.

Dr Miller is medical director, Brain Health, Exeter, New Hampshire; editor in chief, Psychiatric Times; voluntary consulting psychiatrist at Seacoast Mental Health Center, Exeter/Portsmouth, New Hampshire; and consulting psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Acknowledgment: The author would like to thank independent scholar Samantha E. Yohn, PhD, an expert in the muscarinic cholinergic circuitry, for her generous tutelage of this complex topic and her feedback/reviews of manuscript drafts.

Disclosure: The author would like to disclose that he serves on the speakers’ bureau of Bristol Myers Squibb.

References

1. Cobenfy. Prescribing information. Bristol Myers Squibb; 2024. Accessed November 5, 2025. https://packageinserts.bms.com/pi/pi_cobenfy.pdf

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16. Paul SM, Yohn SE, Brannan SK, et al. Muscarinic receptor activators as novel treatments for schizophrenia. Biol Psychiatry. 2024;96(8):627-637.

17. Mena-Segovia J, Winn P, Bolam JP. Cholinergic modulation of midbrain dopaminergic systems. Brain Res Rev. 2008;58(2):265-271.

18. Xiao C, Cho JR, Zhou C, et al. Cholinergic mesopontine signals govern locomotion and reward through dissociable midbrain pathways. Neuron. 2016;90(2):333-347.

19. Shannon HE, Rasmussen K, Bymaster FP, et al. Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res. 2000;42(3):249-259.

20. An open-label study to assess the long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia (EMERGENT-5). ClinicalTrials.gov. Updated September 17, 2025. Accessed November 5, 2025. https://clinicaltrials.gov/study/NCT04820309

21. Sauder C, Allen LA, Baker E, et al. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Transl Psychiatry. 2022;12(1):491.

22. Horan WP, Sauder C, Harvey PD, et al. The impact of xanomeline and trospium chloride on cognitive impairment in acute schizophrenia: replication in pooled data from two phase 3 trials. Am J Psychiatry. 2025;182(3):297-306.

23. Yohn SE, Harvey PD, Brannan SK, Horan WP. The potential of muscarinic M1 and M4 receptor activators for the treatment of cognitive impairment associated with schizophrenia. Front Psychiatry. 2024;15:1421554.

24. Armstrong A. AbbVie revamps emraclidine expectations after mid-stage schizophrenia failure. BioSpace. January 31, 2025. Accessed November 5, 2025. https://www.biospace.com/business/abbvie-revamps-emraclidine-expectations-after-mid-stage-schizophrenia-failure