FDA Approves Dextromethorphan-Bupropion for Agitation Due to Alzheimer Disease

Axsome Therapeutics announced on April 30, 2026, that the FDA approved dextromethorphan-bupropion (Auvelity) for the treatment of agitation associated with dementia due to Alzheimer disease, marking a significant advance in the management of one of the most burdensome neuropsychiatric symptoms affecting this population.¹

“The approval of our first-in-class medication for agitation associated with Alzheimer’s disease marks an important milestone for the millions of patients living with Alzheimer’s disease, their families, and their caregivers,” Herriot Tabuteau, MD, chief executive officer of Axsome, said in a statement.

Alzheimer disease affects more than 7 million Americans and is the most common form of dementia. Agitation is among its most prevalent and debilitating manifestations, reported in up to 76% of patients.² Beyond its immediate burden on patients and caregivers, agitation has been associated with accelerated cognitive decline, increased mortality risk, and is a leading driver of placement in assisted living and long-term care facilities, all of which have significant implications for payers, health systems, and managed care stakeholders.

The treatment works by targeting the N-methyl-D-aspartate (NMDA) receptor and sigma-1 receptor through its dextromethorphan component, while bupropion acts as a CYP2D6 inhibitor to elevate dextromethorphan plasma concentrations.¹

Supporting Clinical Evidence

The approval was supported by a pair of phase 3 trials. ADVANCE-1 (NCT03226522), a 5-week double-blind, parallel-group study, demonstrated that dextromethorphan-bupropion was statistically significantly superior to placebo in reducing agitation symptoms, as measured by the Cohen-Mansfield Agitation Inventor total score at week 5. A significantly greater proportion of treated patients were also rated as at least minimally improved on the modified Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change (mADCS-CGIC) compared with placebo.

The long-term ACCORD-2 trial (NCT04947553), a randomized withdrawal design enrolling known dextromethorphan-bupropion responders, found that patients continuing on the therapy experienced a statistically significantly longer time to relapse of agitation symptoms compared with those switched to placebo. Notably, George Grossberg, MD, professor and director of the division of geriatric psychiatry at the Saint Louis University School of Medicine, stated “Auvelity is the only FDA-approved product to result in a statistically significantly longer time to relapse of agitation symptoms, compared to placebo, in a long-term study.”

Safety and Tolerability Profile

In the ADVANCE-1 trial, the most common adverse reactions occurring in at least 5% of dextromethorphan-bupropion–treated patients and at more than twice the rate of placebo were dizziness and dyspepsia. Discontinuation due to adverse events occurred in 1.3% of AUVELITY patients, which is the same rate as placebo discontinuation. Other adverse effects included seizures, hypertension, manic episodes, and serotonin syndrome.

Dextromethorphan-bupropion received FDA breakthrough therapy designation and was evaluated under priority review for this indication, reflecting the agency's recognition of its potential to address a serious unmet need. This is the second neuropsychiatric indication for the treatment, which was initially approved for major depressive disorder in adults in 2022. To date, the product has been administered to more than 300,000 patients across clinical and real-world settings.

References

1. 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, Inc. April 30, 2026. Accessed May 1, 2026. https://www.axsome.com
2. 2026 Alzheimer's disease facts and figures. Alzheimers Dement. 2026;22:e71345. Published April 21, 2026. doi:10.1002/alz.71345