FDA Approves First Non-Antipsychotic Treatment for Alzheimer Agitation

The US Food and Drug Administration (FDA) has approved dextromethorphan hydrobromide-bupropion hydrochloride (Auvelity), formerly AXS-05, for the treatment of agitation associated with dementia due to Alzheimer disease, adding a labeled option for a neuropsychiatric symptom that is common, difficult to manage, and associated with institutionalization and caregiver burden.^1,2

The product had previously been approved in 2022 for major depressive disorder in adults.³

“Agitation in patients with dementia due to Alzheimer’s disease is distressful, consequential, and challenging for patients, their caregivers and healthcare providers,” said George Grossberg, MD, Professor and Director of the Division of Geriatric Psychiatry at the Saint Louis University School of Medicine.¹ “[Dextromethorphan hydrobromide-bupropion hydrochloride] 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.”

Supporting Data for Auvelity in Alzheimer Dementia

According to the company, the approval was supported by 2 phase 3 studies, ADVANCE-1 and ACCORD-2. ADVANCE-1 was a 5-week, double-blind, parallel-group trial that randomized patients to dextromethorphan-bupropion, placebo, or bupropion alone; the bupropion arm was stopped early for futility. Axsome reported that dextromethorphan-bupropion was superior to placebo on the primary end point, change in Cohen-Mansfield Agitation Inventory total score at week 5, and on a key secondary end point, the modified Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change. Numerical efficacy results were not included in the press release.¹

The second study, ACCORD-2, used a randomized withdrawal design in patients described as responders to active treatment. During an up to 6-month double-blind phase, participants continued dextromethorphan-bupropion or were switched to placebo. Axsome said continued treatment significantly prolonged time to relapse of agitation symptoms compared with placebo, measured by the Cohen-Mansfield Agitation Inventory. Randomized withdrawal studies can help assess maintenance benefit, but they also enrich for responders and may not fully reflect outcomes in an unselected clinical population.

In ADVANCE-1, the most common adverse reactions occurring in at least 5% of treated patients and at more than twice the placebo rate were dizziness and dyspepsia, according to the company.¹

Discontinuation due to adverse events was reported as 1.3% in both the active-treatment and placebo groups. The prescribing information cited in the release also carries boxed warning language related to suicidal thoughts and behaviors associated with antidepressants, along with warnings about seizure risk, hypertension, serotonin syndrome, angle-closure glaucoma, and hyponatremia. Those risks may be particularly relevant in older adults with multimorbidity and polypharmacy.^1,3

“Importantly, [dextromethorphan hydrobromide-bupropion hydrochloride] showed a compelling safety and tolerability profile, with rates of discontinuation due to adverse events that were low and matched those of placebo. The approval of Auvelity is a significant advancement that provides patients and their caregivers with a much-needed treatment option for this debilitating condition.”

Agitation and Unmet Need in Alzheimer Disease

Agitation occurs in a substantial proportion of patients with Alzheimer disease and has been linked to faster cognitive and functional decline, greater caregiver distress, and earlier nursing home placement.^2,4

Nonpharmacologic strategies remain foundational, including evaluation for triggers such as pain, infection, environmental stressors, sleep disruption, or medication adverse effects.^4 When drug treatment is considered, clinicians have often relied on off-label use of antipsychotics, antidepressants, anticonvulsants, or sedative agents, each with important tolerability limitations in older adults.⁴

Dextromethorphan-bupropion combines an uncompetitive N-methyl-d-aspartate receptor antagonist and sigma-1 receptor agonist with bupropion, which inhibits CYP2D6 and increases dextromethorphan exposure. The exact mechanism by which the combination improves agitation in Alzheimer disease remains unclear. The product received Breakthrough Therapy designation and Priority Review for this supplemental application, according to Axsome.^1,3

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. GlobeNewswire. April 30, 2026. Accessed April 30, 2026. https://www.globenewswire.com/news-release/2026/04/30/3285345/33090/en/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.html

2. Alzheimer’s Association. 2025 Alzheimer’s disease facts and figures. Accessed April 30, 2026. https://www.alz.org/alzheimers-dementia/facts-figures

3. Axsome Therapeutics Announces FDA Approval of AUVELITY™, the First and Only Oral NMDA Receptor Antagonist for the Treatment of Major Depressive Disorder in Adults. Axsome Therapeutics. August 19, 2022. Accessed April 30, 2026. https://axsometherapeuticsinc.gcs-web.com/node/10466/pdf

4. Porsteinsson AP, Antonsdottir IM. An update on the advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother. 2017;18(6):611-620. doi:10.1080/14656566.2017.1308481