FDA Approves First Nonantipsychotic Treatment of Agitation From Dementia

The FDA recently expanded the approved use of dextromethorphan hydrobromide and bupropion hydrochloride (Auvelity) extended-release tablets to include the treatment of agitation associated with dementia due to Alzheimer disease (AD) in adults. This decision, announced on April 30, 2026, introduces the first nonantipsychotic treatment specifically indicated for a condition that has historically relied on off-label medications with significant safety risks.^1,2

"This approval represents a significant advancement in our ability to help patients and families dealing with one of the most challenging aspects of Alzheimer's disease," FDA Commissioner Marty Makary, MD, MPH, said in a news release.¹ "With today’s action, patients and their families have access to an additional important treatment for complications of this devastating disease."

For pharmacists managing complex geriatric regimens, this approval offers a novel therapeutic pathway for one of the most challenging aspects of AD care, characterized by excessive motor activity and verbal or physical aggression. Although Auvelity was initially approved in 2022 for major depressive disorder, its entry into the dementia space addresses a critical gap where approximately 30% to 50% of patients experience distressing agitation.^1,3

About The Approval

The clinical efficacy of Auvelity was established through 2 randomized trials that demonstrated significant improvements over placebo. In a 5-week trial, participants receiving the drug showed a superior reduction in the Cohen-Mansfield Agitation Inventory (CMAI) total score, which measures the frequency of agitated behaviors based on caregiver reports.¹

A second withdrawal study further confirmed these findings, revealing that patients who continued Auvelity treatment had a significantly longer time to relapse compared to those switched to a placebo. These results are particularly relevant given that traditional antipsychotics, such as risperidone, are often limited to short-term use and carry a black box warning due to an increased risk of stroke and death in elderly patients.^1,4

"Auvelity was found to be efficacious for treating agitation in Alzheimer disease in 2 randomized trials and now represents an additional option to address one of the most difficult sequelae of the disease, especially as it progresses,” Tracy Beth Hoeg, MD, PhD, acting director of the FDA’s Center for Drug Evaluation and Research, said in the news release.¹ "We hope this approval will provide meaningful benefit to patients, their families, and caregivers."

From a pharmacological perspective, Auvelity utilizes a multimodal mechanism involving N-methyl-D-aspartate receptor antagonism and sigma-1 receptor agonism. The dextromethorphan component acts as the primary antagonist at the ionotropic glutamate receptor, while the bupropion component serves as a potent CYP2D6 inhibitor. By competitively inhibiting this major biotransformation pathway, bupropion significantly elevates and maintains dextromethorphan blood levels, allowing for the therapeutic modulation of glutamatergic excitotoxicity. This mechanism of action closely resembles that of memantine, a long-standing treatment for moderate-to-severe AD, though Auvelity’s unique combination with bupropion offers a distinct clinical profile for managing behavioral symptoms.²

The Pharmacist’s Role in AD Care

Pharmacists must be vigilant regarding the safety profile and potential drug-drug interactions associated with this new indication. Auvelity carries a boxed warning regarding the increased risk of suicidal thoughts and behaviors, a concern inherited from its antidepressant components.¹

Common adverse effects identified in trials include dizziness, headache, somnolence, and gastrointestinal distress. Furthermore, the medication is known to be proconvulsant, with a seizure risk that increases with the dose, and it may also cause elevated blood pressure or hypertension.

Clinical monitoring is essential, particularly for patients with a personal or family history of bipolar disorder, as the drug may activate mania or hypomania in susceptible individuals. Before initiating therapy, health care providers should assess blood pressure and confirm if patients are already taking other medications containing bupropion or dextromethorphan to avoid toxicity.

As the population of Americans over 65 years is projected to reach 88 million by 2050, the availability of an FDA-approved, nonantipsychotic option provides a vital tool for pharmacists to improve the quality of life for both patients and their caregivers. Although nonpharmacological, person-centered care remains the recommended first-line intervention, Auvelity now represents a validated pharmacological option when behavioral changes compromise safety.²

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REFERENCES

1. FDA approves first non-antipsychotic drug to treat agitation associated with dementia. News release. FDA. April 30, 2026. Accessed May 4, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-antipsychotic-drug-treat-agitation-associated-dementia

2. Lepkowsky CM. Auvelity as a potential treatment for Alzheimer’s disease. Medical Research Archives. doi:https://doi.org/10.18103/mra.v10i10.3206.

3. Carrarini C, Russo M, Dono F, et al. Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions. Front Neurol. 2021;12:644317. Published 2021 Apr 16. doi:10.3389/fneur.2021.644317

4. Alzheimer’s Society. Antipsychotics and other drug approaches in dementia care. Accessed May 4, 2026. https://www.alzheimers.org.uk/about-dementia/treatments/dementia-medication/antipsychotic-drugs