Integrating a Different Kind of Treatment Option into Schizophrenia Care: A Treating Physician’s Partnership-based Approach

Sponsored by Bristol Myers Squibb
Ike Nnawuchi, MD, was compensated for his time.

Dr. Ike Nnawuchi, medical director of MBI Health Services, shares his perspective and experience with treating individuals with schizophrenia.

Advancing Individualized Treatment Strategies in Schizophrenia Care

Schizophrenia is a complex, heterogeneous condition that continues to present meaningful challenges in clinical practice.¹ Patients may experience a spectrum of symptoms spanning positive symptoms, negative symptoms, and broader general psychopathology symptoms, including cognitive and emotional difficulties that can affect daily functioning.²

Together, these factors underscore the importance of individualized treatment approaches and ongoing clinical assessment.

In clinical practice, these considerations are well recognized. For Dr. Ike Nnawuchi, they inform an approach to care that begins with building a collaborative partnership with each patient. His treatment planning emphasizes comprehensive assessment, shared decision making, and clear education around available options, with the goal of aligning care to individual needs and circumstances.

A partnership model: listening before prescribing

When Dr. Nnawuchi meets a new patient, the first interaction is rarely about choosing a specific medication. It is about understanding the person and their context.

His evaluation routinely covers:

• Symptom profile: presence and severity of positive, negative, and general psychopathology symptoms.
• Functional impact: changes in work, school, relationships, and independent living.
• Treatment history: what medications have been tried and how and what benefits or side effects were seen.
• Adherence: what factors have led to patient successes or challenges in staying compliant on their past treatments.
• Support system: the roles of caregivers, family members, and community resources.

In Dr. Nnawuchi’s clinical experience, patient and caregiver discussions frequently encompass symptom experiences, treatment tolerability considerations, and the role of support systems in care. These are not abstract concepts, but real-world factors Dr. Nnawuchi regularly encounters as part of his routine clinical conversations, informing how he approaches individualized care planning.

Balancing symptom control, side effects, and daily life

In Dr. Nnawuchi’s practice, conversations about treatment planning are grounded in a structured, patient-centered approach that reflects common considerations in the long-term management of schizophrenia. Rather than focusing on any single outcome, these discussions are guided by ongoing clinical assessment and patient input, including in three broad areas:

• Current symptom experience. Clinicians routinely review the presence and impact of symptoms, including positive, negative, and general psychopathology symptoms, as part of regular follow-up and monitoring.
• Treatment tolerability. Potential side effects—such as metabolic changes, sedation, tremors, constipation, nausea, vomiting, or cognitive concerns—are discussed to understand how patients are experiencing their therapy and whether adjustments warrant consideration.
• Patient perspectives and priorities. Patients are encouraged to share how treatment fits into their daily routines and personal circumstances, recognizing that individual preferences and goals may evolve over time.

Dr. Nnawuchi emphasizes that these considerations are part of routine clinical conversations and are revisited over time. Treatment decisions are shaped through ongoing dialogue, clinical judgment, and patient input, recognizing that needs and preferences may change throughout the course of care.

Why explaining the clinical profile matters

To support these ongoing, patient‑centered discussions, healthcare professionals often consider the clinical profile of a treatment option as part of broader clinical education and shared decision‑making.

COBENFY is a twice-daily pill used to treat adults with schizophrenia. It is not known if COBENFY is safe and effective in children. Please see Important Safety Information and U.S. Full Prescribing Information, including Patient Information below.³

COBENFY is a combination of xanomeline, a muscarinic receptor agonist, and trospium chloride, a peripherally acting muscarinic antagonist. It is thought to exert its antipsychotic effects via preferential activation of M1 and M4 muscarinic receptors in the central nervous system and does not bind to dopamine D2 receptors.^4,5† Xanomeline binds to muscarinic receptors M1 to M5 with comparable affinity and exhibits higher agonist activity at the M1 and M4 receptors. Trospium chloride antagonizes the muscarinic receptors primarily in the peripheral tissues. The exact way COBENFY works is not fully understood.

From a clinical education standpoint, discussions with patients and caregivers about COBENFY often focus on two key areas, efficacy and safety. EMERGENT‑1 (N=182, phase 2), EMERGENT-2 (N=252, phase 3, and EMERGENT-3 (N=253, phase 3) were randomized, double‑blind, placebo‑controlled studies that assessed the safety and efficacy of COBENFY. The primary endpoint in all studies was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 5 vs. placebo. COBENFY was associated with statistically significant symptom improvement in the PANSS total score compared to placebo at 5 weeks across the EMERGENT Phase 3 pivotal trials. In the EMERGENT-2 and -3 trials, COBENFY-treated patients had a 9.6-point and 8.4-point greater reduction in PANSS total score when compared with placebo-treated patients, respectively (COBENFY, –21.2 vs. placebo, –11.6; 95% confidence interval [CI] –13.9, –5.2; P<0.0001; COBENFY, –20.6 vs. placebo, –12.2; 95% CI –12.4, –4.3; P<0.0001).^5,6 In the EMERGENT-1 trial (Phase 2), COBENFY-treated patients had an 11.6-point reducation in PANSS total score when compared to placebo-treated patients, respectively (COBENFY, -17.4 vs. placebo, -5.9; 95% CI, -16.1 to -7.1). EMERGENT-1 (N=182) was a randomized, double-blind, placebo-controlled, phase 2 study that assessed the safety and efficacy of COBENFY. The primary endpoint was the change from baseline in PANSS total score at Week 5 vs. placebo.⁴

As assessed by the PANSS total score in the pooled, mITT population, patients taking COBENFY had about a 2-times greater reduction in PANSS total score compared to placebo (-19.5 vs. -9.6) at Week 5.⁷ Endpoints in the pooled analysis were analyzed descriptively and are considered exploratory.⁸ Across all 3 short-term trials, 56% of patients achieved a clinically meaningful response with COBENFY,^5,6 as defined by a reduction from baseline in PANSS total score of at least 20% over 5 weeks.⁹

Safety considerations for COBENFY are outlined in the Prescribing Information and informed by data from its clinical trial program. The most common adverse reactions (≥5% and at least twice placebo) included nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.³ Additional adverse reactions include dry mouth, somnolence, vision blurred, salivary hypersecretion, orthostatic hypotension, cough and extrapyramidal symptoms (non-akathisia).³ COBENFY has warnings and precautions for: risk of urinary retention, risk of use in patients with hepatic impairment, risk of use with biliary disease, decreased gastrointestinal motility, risk of angioedema, risk of use in patients with narrow-angle glaucoma, increases in heart rate, anticholinergic adverse reactions in patients with renal impairment, and CNS effects.³ Please see U.S. Full Prescribing Information, including Patient Information.

For healthcare professionals, efficacy and safety together provide a foundational framework for clear, balanced education on treatment options and support individualized clinical decision-making.

From skepticism to engagement: the role of patience and education

One of Dr. Nnawuchi’s cases involved a patient with a history of aggression, multiple hospitalizations, and deep mistrust of medications.

“In the beginning, I wasn’t trying to convince the patient to try a different approach,” he recalls. “I was trying to show that I understood why he was reluctant and that I respected his prior experiences.”

Over time, he focused on:

• Establishing a nonjudgmental therapeutic alliance.
• Exploring the patient’s priorities throughout his journey.
• Educating the patient and his caregiver about the options available to him, including COBENFY and the associated benefits and risks.

Only after this groundwork and a discussion of the potential benefits and risks did the patient agree with the HCP’s recommendation to trial COBENFY, with structured follow-up and caregiver involvement. Through continued coordination of care and caregiver support, the patient has experienced an improvement in his overall schizophrenia symptoms. Individual responses will differ, and this experience cannot be generalized. However, for this patient, a non-D2 option was initiated as part of a comprehensive treatment plan with a trust-based partnership model, which proved to be a pivotal step.

Dr. Nnawuchi notes that patience matters. For patients who are medication wary, introducing a new therapy starts with clear, respectful conversations. Patients and care partners understandably approach switching cautiously, and providers play a key role in acknowledging and guiding that process.

Practical steps for integrating COBENFY into a comprehensive care plan

For psychiatrists and mental health clinicians considering COBENFY for their patient within a partnership-based model of care, Dr. Nnawuchi highlights several practical steps:

• Set shared goals: Define with patients and caregivers what overall symptom improvement would look like.
• Educate clearly: Discuss the COBENFY clinical profile, helping patients and caregivers understand what to expect with respect to efficacy and safety, and highlighting the unique, non–D2 mechanism of action in clear, accessible terms.
• Engage caregivers: Include caregivers in discussions about expectations, monitoring, and adherence, while maintaining patient autonomy and confidentiality.
• Plan for follow-up: Schedule early and regular visits to monitor clinical response, side effects, and functional outcomes, and to adjust treatment as needed.

“Schizophrenia is a long-term illness that demands long-term relationships,” Dr. Nnawuchi concludes. “Medication doesn’t replace the need for partnership—it makes that partnership even more important, because we are offering options. When patients feel heard and supported, they’re more willing to explore different approaches and to stay with us through the ups and downs of treatment.”

INDICATION

COBENFY^TM (xanomeline and trospium chloride) is indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

COBENFY is contraindicated in patients with:

• urinary retention
• moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment
• gastric retention
• history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride.
• Untreated narrow-angle glaucoma

WARNINGS AND PRECAUTIONS

Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention.

COBENFY is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment.

In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated.

Risk of Use in Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions.

COBENFY is contraindicated in patients with moderate or severe hepatic impairment. COBENFY is not recommended in patients with mild hepatic impairment.

Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment.

Risk of Use in Patients with Biliary Disease: In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.

COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated.

Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values.

Decreased Gastrointestinal Motility: COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride.

Risk of Use in Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring.

Increases in Heart Rate: COBENFY can increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY.

Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment.

Central Nervous System Effects: Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.

Most Common Adverse Reactions (≥5% and at least twice placebo): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.

Use in Specific Populations:

• Moderate or Severe Renal Impairment: Not recommended
• Mild Hepatic Impairment: Not recommended

Pregnancy and Lactation: There is a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medications, including COBENFY, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/.

There are no available data on COBENFY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Additionally, there are no data on the presence of xanomeline or trospium in human milk, the effects on the breastfed infant, or the effects on milk production. However, xanomeline and trospium are present in animal milk, suggesting they may also be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COBENFY and any potential adverse effects on the breastfed infant from COBENFY or the underlying maternal condition.

COBENFY (xanomeline and trospium chloride) is available in 50mg/20mg, 100mg/20mg, and 125mg/30mg capsules.

Please see U.S. Full Prescribing Information, including Patient Information

References

1. Owen, M. J., Sawa, A., & Mortensen, P. B. (2016). Schizophrenia. Lancet (London, England), 388(10039), 86–97. https://doi.org/10.1016/S0140-6736(15)01121-6
2. Treatment Advocacy Center. (2024). Schizophrenia Fact Sheet. Retrieved from https://www.treatmentadvocacycenter.org/reports_publications/schizophrenia-fact-sheet
3. COBENFY. Prescribing Information. Bristol-Myers Squibb Company; 2026.
4. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726.
5. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170.
6. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia. JAMA Psychiatry. 2024;81(8):749-756.
7. Kaul I, Correll CU, Sawchak S, et al. KarXT (xanomeline–trospium) demonstrates broad efficacy in people with schizophrenia across a wide range of demographic subgroups: pooled results from the 3 randomized, double-blind, placebo-controlled EMERGENT trials. Presented at: 2024 NEI Synapse; April 19-21, 2024; Las Vegas, NV.
8. Kaul I, Citrome L, Sawchak S, et al. Efficacy of KarXT (xanomeline–trospium) in schizophrenia: pooled results from the randomized, double-blind, placebo-controlled EMERGENT trials. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 9-12, 2023; Colorado Springs, CO.
9. Younis IR, Gopalakrishnan M, Mathis M, et al. Association of end point definition and randomized clinical trial duration in clinical trials of schizophrenia medications. JAMA Psychiatry. 2020;77(10):1064-1071.