FDA Approves First Nonantipsychotic Treatment for Agitation Associated With Alzheimer Disease

The FDA has approved Auvelity (dextromethorphan HBr/bupropion HCl; Axsome Therapeutics) for the treatment of agitation associated with dementia due to Alzheimer disease (AD), marking a significant shift in how clinicians may approach one of the most challenging neuropsychiatric symptoms of the disease.^1,2

The approval makes Auvelity the first FDA-approved therapy for AD agitation with a mechanism targeting the NMDA and sigma-1 receptors, a distinction that sets it apart from brexpiprazole (Rexulti; Otsuka), the only other agent with an FDA indication for this condition. Brexpiprazole, an antipsychotic, gained FDA approval in 2023 for this indication and carries a boxed warning for increased mortality in older patients with dementia-related psychosis. Auvelity carries no such antipsychotic-class warning for the AD agitation indication.^3,4

A Prevalent and Undertreated Condition

Alzheimer disease is the most common form of dementia, affecting more than 7 million Americans. Agitation is reported in up to 76% of patients and can include symptoms ranging from pacing or restlessness to verbal and physical aggression. The condition is associated with significant consequences beyond behavioral disruption: Prior research has linked agitation in Alzheimer disease to accelerated cognitive decline, increased caregiver burden, earlier nursing home placement, and higher mortality.²

“Agitation is highly prevalent in patients with AD and among the most burdensome aspects of the disease for patients and families,” Jeffrey Cummings, MD, ScD, Joy Chambers-Gundy Professor of Brain Science at UNLV Kirk Kerkorian School of Medicine, said in a news release from Axsome Therapeutics. “The approval of Auvelity for this condition has the potential to play an important role in patient care for this challenging and impactful symptom of AD.”²

Despite its prevalence, pharmacologic options have historically been limited. Until brexpiprazole's 2023 approval, clinicians largely relied on off-label use of antipsychotics—a practice long shadowed by safety concerns in older dementia populations.⁴

Clinical Trial Evidence

The FDA approval is supported by a comprehensive clinical program that included the phase 3 ADVANCE (NCT03226522) and ACCORD-2 (NCT04947553) studies.^1,2,5,6

ADVANCE-1 was a 5-week, double-blind, parallel-group study in which patients were randomly assigned to Auvelity, placebo, or bupropion—the bupropion arm was terminated early for futility. Auvelity was statistically significantly superior to placebo in improving agitation symptoms, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score at week 5, the study's primary end point. On the key secondary end point of response on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, a statistically significantly greater proportion of patients treated with Auvelity were rated by clinicians as at least minimally improved compared with a placebo.^1,2

The long-term data came from ACCORD-2, a randomized withdrawal design. In ACCORD-2, patients who continued treatment with Auvelity experienced a statistically significantly longer time to relapse of agitation symptoms, measured by the CMAI, than patients who switched to placebo. The relapse prevention data were a key differentiator highlighted by clinical experts at the time of approval.^1,2

Safety and Tolerability

In the ADVANCE-1 trial, the most common adverse reactions—occurring in at least 5% of patients treated with Auvelity and more than twice as frequently as placebo—were dizziness and dyspepsia. Notably, only 1.3% of patients discontinued Auvelity due to an adverse event, a rate identical to placebo. Importantly, tolerability appeared favorable, supporting its use even in frail populations.^1-3

Pharmacists should be aware that Auvelity carries a boxed warning related to suicidal thoughts and behaviors, a class warning tied to its bupropion component and shared with antidepressant medications. Key contraindications include seizure disorders, active eating disorders, recent discontinuation of alcohol or benzodiazepines, and concurrent or recent use of monoamine oxidase inhibitors (MAOIs). Clinicians should also monitor for elevated blood pressure, manic episodes, and serotonin syndrome, particularly when used alongside serotonergic agents.^1,2

Implications for Pharmacy Practice

For the AD agitation indication, dosing begins with Auvelity 30 mg/105 mg once daily in the morning for 7 days, increasing to twice daily on day 8. On day 15, the dose may be increased to the maximum recommended dosage of 45 mg/105 mg twice daily based on tolerability. Auvelity should not be used on an as-needed basis for agitation episodes.²

For pharmacists, Auvelity's approval introduces a meaningful counseling opportunity. Unlike brexpiprazole, Auvelity does not carry an antipsychotic-class mortality warning, a distinction that may influence prescribing patterns, particularly for patients or caregivers who have previously been hesitant about antipsychotic use. However, the drug's interaction profile, including its CYP2D6 inhibition via bupropion and its contraindication with MAOIs, warrants careful medication reconciliation in a population that is frequently on complex polypharmacy regimens.

"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. "With [this] action, patients and their families have access to an additional important treatment for complications of this devastating disease."¹

REFERENCES

1. FDA approves first non-antipsychotic drug to treat agitation associated with dementia. News release. FDA. April 30, 2026. Accessed April 30, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-antipsychotic-drug-treat-agitation-associated-dementia?utm_medium=email&utm_source=govdelivery

2. Axsome Therapeutics announces FDA approval of AUVELITY (dextromethorphan HBr and bupropion HCl) for the treatment of agitation associated with dementia due to Alzheimer’s disease. News release. Axsome Therapeutics. April 30, 2026. Accessed April 30, 2026. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-fda-approval-auvelityr

3. Kuntz L. FDA approves Auvelity for treatment of agitation in Alzheimer disease. Psychiatric Times. April 30, 2026. Accessed April 30, 2026. https://www.psychiatrictimes.com/view/fda-approves-auvelity-for-treatment-of-agitation-in-alzheimer-disease

4. Meglio M. FDA approves AXS-05 as new treatment for Alzheimer disease agitation. NeurologyLive. April 30, 2026. Accessed April 30, 2026. https://www.neurologylive.com/view/fda-approves-axs-05-new-treatment-alzheimer-disease-agitation

5. Addressing dementia via agitation-centered evaluation (ADVANCE). ClinicalTrials.gov. Updated September 13, 2023. Accessed April 30, 2026. https://clinicaltrials.gov/study/NCT03226522

6. A study to assess the long-term safety and efficacy of AXS-05 in subjects with Alzheimer’s disease agitation (ACCORD-2). ClinicalTrials.gov. Updated December 8, 2025. Accessed April 30, 2026. https://clinicaltrials.gov/study/NCT04947553