From schizophrenia to dementia: Is Cobenfy a potential treatment for behavioral and psychological symptoms of dementia?

Abstract

Behavioral and psychological symptoms of dementia significantly impact patient outcomes, caregiver burden, and healthcare costs. Current pharmacologic treatments are limited by efficacy and safety concerns. Cobenfy, a novel combination of xanomeline and trospium chloride, has shown efficacy in schizophrenia and presents a promising alternative for treating behavioral and psychological symptoms of dementia. This editorial explores the potential role of Cobenfy in the management of behavioral and psychological symptoms of dementia. To date, no trials of Cobenfy for behavioral and psychological symptoms of dementia have been completed; however, multiple trials are underway to investigate this medication for psychosis and agitation in Alzheimer’s disease. Cobenfy may offer a safer pharmacologic option for behavioral and psychological symptoms of dementia compared with existing treatments. Further research in older adult populations is warranted.

Keywords

Dementia Alzheimer’s disease agitation xanomeline trospium chloride

Introduction to behavioral and psychological symptoms of dementia

Behavioral and psychological symptoms of dementia (BPSD) represent a diverse collection of neuropsychiatric disturbances that manifest throughout the disease process. These symptoms are common, occurring in more than 90% of patients with dementia during the course of the disease.^1,2 BPSD include cognitive or perceptual disturbances (i.e. delusions and hallucinations), aberrant motor behaviors, agitation or aggression, emotional dysregulation (i.e. dysphoria, anxiety, apathy, lability, and irritability), and vegetative symptoms (i.e. sleep and appetite disturbances).^1,3 The prevalence of individual symptoms varies, with apathy being the most common (48%–92%), followed by anxiety (21%–60%) and delusions (16%–70%).³ The presence of BPSD has been associated with increased morbidity, a higher risk of nursing home placement, poorer quality of life, more rapid cognitive decline, earlier mortality, and increased caregiver burden and burnout.^1,2 In addition to the human toll of BPSD, these symptoms confer a financial burden, with studies identifying significantly increased direct costs of care in patients with BPSD.^4,5

Several neurotransmitter pathways, along with decreased integrity of various brain regions, have been associated with BPSD. Decreased glucose metabolism in cortical brain regions (the right frontal and right temporal lobes and the bilateral cingulate cortex) as well as an imbalance in the activity of subcortical structures and the prefrontal cortex have been linked to agitation in Alzheimer’s disease (AD).^6,7 Prior studies have also found increased prolactin levels, decreased serotonergic activity, dysregulation of dopamine in the striatum, and increased norepinephrine signaling to be associated with greater levels of aggression in AD.^8,9

The evaluation of BPSD involves patient and caregiver input and an assessment of interpersonal, environmental, and medical factors that may be contributing to symptoms. Kales et al.¹⁰ proposed a structured method for evaluating BPSD known as the DICE (Describe, Investigate, Create, Evaluate) approach. This assessment begins with the caregiver thoroughly describing the problematic behavior, including the context and social and physical environment in which the behavior is occurring. Next, the provider investigates possible underlying causes of the behavior, such as medical contributors (e.g. pain, medication side effects, and medical conditions), psychiatric comorbidities, sleep hygiene, functional limitations, and sensory changes. The provider and caregiver then collaborate to create a treatment plan. Finally, the provider evaluates the effectiveness of the plan through an iterative process. Standardized and validated assessment tools may also aid in the evaluation of BPSD. Common scales include the Neuropsychiatric Inventory (NPI), the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD), and the Cohen–Mansfield Agitation Inventory-International Psychogeriatric Association (CMAI-IPA).

Nonpharmacologic interventions, such as caregiver training, massage, music therapy, and multisensory stimulation, are first-line treatments for BPSD.² However, if these approaches are ineffective or patients pose a threat to themselves or others, pharmacologic treatments may be used. To date, only one medication, brexpiprazole, is approved by the Food and Drug Administration (FDA) for BPSD, specifically for the treatment of agitation in dementia.¹¹ Other, off-label medications used to treat BPSD include antipsychotics (e.g. risperidone, quetiapine, olanzapine, and aripiprazole), antidepressants (e.g. citalopram, sertraline, and trazodone), cholinesterase inhibitors, and memantine.^2,12–14 In addition to pharmacologic treatment, neuromodulation interventions have shown promise in managing BPSD. There is a growing body of literature supporting the use of electroconvulsive therapy (ECT) for BPSD, specifically to address severe agitation and aggression.¹⁵ Similarly, research on repetitive transcranial magnetic stimulation has demonstrated benefit in treating BPSD, particularly in alleviating apathy.¹⁶ Several algorithms for BPSD have emerged to guide these treatment decisions.^17,18 For example, the IPA Consensus Algorithm provides step-by-step guidance on interventions for episodes of mild-to-severe agitation in dementia,¹⁷ starting with oral medications and escalating to ECT.

The decision to implement pharmacologic treatment for BPSD requires a careful risk–benefit analysis, particularly because these interventions are not first-line and may confer serious adverse effects in older adults.¹ Antipsychotics, in particular, require cautious use, as they have been associated with an increased risk of mortality among older patients with dementia-related psychosis and therefore carry an FDA black box warning.¹⁹ Medications should be used for short-term treatment at the lowest effective dose.

Cobenfy as a potential treatment for BPSD

Given the paucity of current pharmacologic treatments for BPSD and the risks these symptoms often pose, identifying safer and more efficacious treatment options is essential. This editorial explores the available research investigating Cobenfy for the treatment of BPSD. We compiled relevant information through searches in PubMed and ClinicalTrials.gov using terms including “Cobenfy,” “xanomeline,” “trospium chloride,” “dementia,” and “behavioral and psychological symptoms of dementia.”

History of Cobenfy

Cobenfy (xanomeline and trospium chloride), also known as KarXT, has emerged as a novel treatment for schizophrenia. Cobenfy is a combined formulation of xanomeline, a preferential M1 and M4 muscarinic receptor agonist, and trospium, a pan-muscarinic receptor antagonist that does not cross the blood–brain barrier. This combination allows for muscarinic agonism in the brain with limited peripheral cholinergic side effects.²⁰ Mechanistically, Cobenfy targets pathways implicated in schizophrenia. Neuropathological and clinical studies of patients with schizophrenia have identified reduced M1 and M4 receptor density in the caudate, putamen, and prefrontal cortex, and these receptors are understood to downregulate dopamine production.²¹ M1 receptor agonism is thought to downregulate dopamine signaling via a top–down process, in which activation of M1 enhances the activity of GABAergic interneurons, leading to reduced glutamatergic drive onto N-methyl-D-aspartate (NMDA) receptors located on dopamine neurons projecting to the nucleus accumbens. In contrast, M4 receptor agonism is believed to act via a bottom–up mechanism, whereby M4 activation decreases acetylcholine release in the ventral tegmental area, resulting in reduced excitability of dopamine neurons. Additionally, M4 autoreceptors on cholinergic interneurons in the nucleus accumbens directly decrease acetylcholine release, thereby lowering dopamine release.²²

In two pivotal phase 3 clinical trials (EMERGENT-2 (NCT04659161)²³ and EMERGENT-3 (NCT04738123)),²⁴ patients with schizophrenia were treated twice daily for 5 weeks with flexible dosing of Cobenfy (maximum dose: 125 mg xanomeline and 30 mg trospium twice daily). The treatment group demonstrated a statistically significant reduction in total Positive and Negative Syndrome Scale (PANSS) scores compared with the placebo group (−20.6 vs. −12.2; least squares mean difference, −8.4; 95% confidence interval (CI), −12.4 to −4.3; P < 0 .001). Cobenfy was generally well-tolerated, with the most common adverse events including nausea (19%), constipation (16%–21%), dyspepsia (16%–19%), vomiting (14%–16%), hypertension (6%–10%), dizziness (9%), gastric reflux (6%), and diarrhea (6%). There were two treatment-emergent serious events in the Cobenfy group in EMERGENT-2 (both for suicidal ideation) and one in EMERGENT-3 (for gastroesophageal reflux disease). No significant differences were observed between Cobenfy and placebo groups in the emergence of extrapyramidal symptoms, weight gain, or somnolence.^23,24

Two extension trials in the EMERGENT series (EMERGENT-4 (NCT04659174) and EMERGENT-5 (NCT04820309)) have provided positive long-term safety data. Both were phase 3, open-label trials spanning 52 weeks, in which participants received a fixed dose of xanomeline (125 mg) and trospium chloride (30 mg) twice daily. Data from these trials, presented at the 2024 Psych Congress in Boston, USA, demonstrated sustained efficacy for positive and negative symptoms of schizophrenia at 52 weeks, with no new safety or tolerability concerns associated with Cobenfy.²⁵ These findings have not yet been published in a peer-reviewed journal.

In September 2024, based on the results of EMERGENT-2 and EMERGENT-3, the FDA approved Cobenfy for the treatment of schizophrenia in adults.²⁶ This medication does not carry a boxed warning, although it is contraindicated in individuals with urinary retention, moderate-to-severe hepatic impairment, gastric retention, or untreated narrow-angle glaucoma.²⁶ In a subsequent analysis,²⁷ data from EMERGENT-2 and EMERGENT-3 were pooled to examine the impact of Cobenfy on cognition in schizophrenia. The overall sample did not show statistically significant cognitive improvements after 5 weeks; however, in the cognitively impaired subgroup (N = 120), a notable proportion of participants demonstrated at least a 0.5 standard deviation improvement (39.2% vs. 19.2%) by the fifth week of treatment. These findings have prompted further investigation of Cobenfy for cognitive enhancement in other conditions, including dementia.

There is also a neurobiological rationale supporting Cobenfy’s potential use for BPSD and dementia. For decades, the pathological basis of AD has been associated with the loss of cholinergic neurons in the nucleus basalis of Meynert in the basal forebrain as well as decreased presynaptic acetylcholine in the hippocampus and cerebral cortex.²⁸ Acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine, and galantamine) have historically been used to slow cognitive decline via this pathway.²⁹ The proposed mechanism of xanomeline in AD is therefore to enhance cholinergic neurotransmission by targeting M1 muscarinic postsynaptic receptors in the cerebral cortex and hippocampus and M4 muscarinic receptors in the cortex, hippocampus, and striatum.^30,31 M1 activation is believed to influence cognition by promoting cortical network synchrony and enhancing synaptic plasticity in brain regions essential for cognitive processing.³² M4 activation is believed to reduce excessive excitatory drive in the hippocampus, thereby helping to maintain appropriate circuit function. Overall, Cobenfy is proposed to decrease behavioral disturbances and psychosis in both schizophrenia and AD through dopamine downregulation.³² Enhanced cholinergic signaling may additionally improve cognition, potentially reducing confusion and agitation.

Given this neurobiology, xanomeline—without trospium chloride—was originally developed in the 1990s to treat cognitive decline in AD.³¹ A 1997 double-blind, randomized controlled trial³¹ evaluated the effect of xanomeline on cognitive decline in a sample of 343 patients aged 60 years and older with mild-to-moderate AD. Participants treated with high-dose oral xanomeline (225 mg daily) for up to 6 months demonstrated a statistically significant improvement in cognitive ability compared with those treated with placebo, as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (P ≤ 0.05). The Clinician’s Interview-Based Impression of Change (CIBIC+) also showed a significant dose response (P = 0.005). Secondary analyses revealed a dose-dependent reduction in BPSD, including vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. However, more than half (52%) of the patients receiving high-dose xanomeline, compared with 35% in the placebo group, discontinued therapy due to procholinergic side effects.³¹ Given these high rates of dose-dependent discontinuation, the development of xanomeline for treating AD was halted.^23,31

With the addition of trospium chloride to mitigate the undesirable peripheral cholinergic effects, xanomeline (as part of Cobenfy) appears mechanistically suitable for further study in dementia. Notably, Cobenfy’s side effect profile may pose a lower risk of serious adverse events compared with current treatments for BPSD, such as antipsychotics. Unlike antipsychotics, Cobenfy has not been associated with metabolic effects, extrapyramidal symptoms, or QTc prolongation.²⁶ Nonetheless, long-term data—particularly in older adults—are needed to determine Cobenfy’s effect size and geriatric-specific safety profile.

Current trials on Cobenfy for BPSD

To date, no published clinical trials have evaluated Cobenfy for BPSD; however, two sets of trials are currently underway, both sponsored by Bristol Myers Squibb in collaboration with the former Karuna Therapeutics. The first set, ADEPT 1–5,^33–37 aims to evaluate Cobenfy for psychosis in AD, while the second set, ADAGIO 1–3,^38–40 investigates Cobenfy for agitation associated with AD. The ADEPT trials, with the exception of ADEPT-3, are phase 3, global, multisite, randomized, double-blind, placebo-controlled studies examining Cobenfy for dementia-related psychosis. ADEPT-3 is an open-label extension rollover study for participants completing ADEPT-1, ADEPT-2, or ADEPT-4.

ADEPT-1 (NCT05511363),³³ launched in August 2022, is a 38-week outpatient study with the primary objective of evaluating relapse prevention of psychosis in AD among patients receiving Cobenfy (up to 66.7/6.67 mg three times daily) versus placebo. Recruitment is ongoing, targeting 380 participants aged 55–90 years who meet the criteria for possible or probable AD of mild-to-severe severity (Mini-Mental State Exam score 8–22). Eligible participants are required to exhibit psychotic symptoms, as evidenced by the following: (a) a history of psychotic symptoms, as defined by IPA criteria, for at least 2 months prior to screening; (b) a score of ≥4 (moderate) on the Clinical Global Impressions-Severity (CGI-S) scale at screening and baseline; and (c) moderate-to-severe delusions or hallucinations on the NPI-Clinician (NPI-C). During the initial 12 weeks, participants receive single-blind Cobenfy titrated to the maximum dose (66.7/6.67 mg three times daily). Responders are then randomized to continue Cobenfy or switch to placebo for the 26-week double-blind phase.⁴¹ The primary outcome measure is time from randomization to relapse, while secondary outcomes focus on the safety and tolerability of Cobenfy.

ADEPT-2 (NCT06126224),³⁴ initiated in August 2023, is a 14-week, parallel-group study evaluating the safety and efficacy of Cobenfy for psychosis in AD. The projected enrollment is 400 participants, with inclusion criteria consistent with those of ADEPT-1. The primary outcome is the change from baseline to the end of treatment (up to 14 weeks) on the NPI-C Hallucinations and Delusions score. Secondary outcomes include changes from baseline on the CMAI and the CGI-S scale.

ADEPT-3 (NCT05980949),³⁵ initiated in July 2023, is an open-label study designed to assess the long-term safety and tolerability of Cobenfy in participants who complete ADEPT-1, ADEPT-2, or ADEPT-4. Participants will be followed from the initial dose through 14 days after the final dose, for a total duration of up to 54 weeks. The primary outcome is the incidence of treatment-emergent adverse events. The study plans to enroll approximately 600 participants.

ADEPT-4 (NCT06585787),³⁶ launched in September 2024, is a 14-week, parallel-group study evaluating the safety and efficacy of Cobenfy for psychosis in AD, similar to ADEPT-2. Recruitment is ongoing, targeting approximately 400 participants. Inclusion criteria differ slightly from previous ADEPT trials: participants must be aged 55–90 years, meet the 2024 National Institute on Aging–Alzheimer’s Association criteria for AD with biomarker confirmation, and have a history of psychotic symptoms (per IPA criteria) for at least 2 months prior to screening. The primary outcome is the change from baseline on the NPI-C Hallucinations and Delusions score.

ADEPT-5 (NCT06947941),³⁷ initiated in July 2025, is a 12-week, parallel-group study investigating the safety and efficacy of Cobenfy combined with enteric-coated xanomeline (KarX-EC) for psychosis in AD. Recruitment has not yet begun; the study plans to enroll over 1000 participants meeting criteria similar to those of ADEPT-4. Participants in the experimental group will receive Cobenfy plus KarX-EC on specified days. The primary outcome is the change from baseline on the NPI-C Hallucinations and Delusions score.

The ADAGIO trials, initiated in July 2025, are designed to evaluate the efficacy, safety, and tolerability of Cobenfy combined with KarX-EC for the treatment of agitation associated with AD. ADAGIO 1 (NCT07011732)³⁸ and ADAGIO 2 (NCT07011745)³⁹ are phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. Each trial aims to recruit approximately 350 participants aged 55–90 years who meet the 2024 Alzheimer’s Association criteria for AD, with confirmed AD pathology via amyloid positron emission tomography or cerebrospinal fluid biomarkers. Eligible participants are required to exhibit symptoms of agitation, as evidenced by the following: (a) a history of agitation, as per IPA criteria, for at least 2 weeks prior to screening; (b) a score of ≥4 related to agitation on the CGI-S scale at screening and baseline; (c) an NPI/NPI-NH Agitation/Aggression score of ≥4 at screening and baseline; and (d) weekly aggressive behaviors as documented by the CMAI-IPA. Participants assigned to the experimental group will receive Cobenfy plus KarX-EC on specified days, compared with the placebo group. The primary outcome is the mean change from baseline on the CMAI-IPA total score at week 14. ADAGIO-3 (NCT06937229)⁴⁰ is a phase 3, open-label extension study designed to evaluate long-term safety and tolerability, enrolling participants who complete ADAGIO-1 or ADAGIO-2 for up to 30 weeks.

Conclusions

In summary, the demand for safe and effective interventions for BPSD is expected to rise with the increasing prevalence of dementia. Current treatments, such as antipsychotics, are limited and carry significant risk in older adults. Cobenfy, a combination of the muscarinic agonist xanomeline and the peripheral muscarinic antagonist trospium chloride, represents a potentially promising new treatment. Although no completed trials of Cobenfy for BPSD currently exist, multiple studies are underway investigating its use for psychosis and agitation in AD. Data from these trials will help determine the efficacy and safety of Cobenfy in older adults with dementia and guide its clinical application.

Footnotes

Acknowledgments

None.

Author contributions

Julia Golden: Investigation; Writing–original draft; Writing–review & editing

Kayla Murphy: Investigation; Writing–original draft; Writing–review & editing

Rajesh Tampi: Conceptualization; Project administration; Supervision; Writing–review & editing.

Data availability statement

All data used for this manuscript were accessible through library resources.

Declaration of conflicting interests

The authors have no conflicts of interest to declare.

Funding

This work received no funding. The authors did not receive financial support for the research, authorship, or publication of this article.

ORCID iDs

Julia C Golden

Rajesh R Tampi

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