FDA Approves Auvelity for Treatment of Agitation in Alzheimer Disease

The US Food and Drug Administration has approved Axsome Therapeutics’ oral dextromethorphan-bupropion (Auvelity, formerly known as AXS-05) for the treatment of agitation associated with Alzheimer disease (AD).¹

Auvelity is a first-in-class treatment for AD agitation which targets the N-methyl D-aspartate (NMDA) and sigma-1 receptors.

“The approval of our first-in-class medication for agitation associated with Alzheimer disease marks an important milestone for the millions of patients living with Alzheimer disease, their families, and their caregivers. We are very pleased to deliver to clinicians and patients a new, effective, FDA-approved treatment option, with a distinct mechanism of action, for this debilitating and critically underserved condition,” said Herriot Tabuteau, MD, the chief executive officer of Axsome. “Alzheimer disease agitation is the second neuropsychiatric indication for which Auvelity has received FDA Breakthrough Therapy designation, and been granted FDA Priority Review and approval, underscoring Axsome’s pioneering work in neuroscience and our dedication to people living with serious brain health conditions.”

Up to 70% of individuals with AD experience agitation, an issue that leads to increased caregiver burden and mortality.²

“Agitation is highly prevalent in patients with Alzheimer disease and among the most burdensome aspects of the disease for patients and families. Alzheimer disease agitation is associated with accelerated cognitive decline, placement in assisted living and long-term care facilities, and increased mortality risk,” said Jeffrey Cummings, MD, ScD, Chambers-Grundy Professor of Brain Sciences, UNLV Kirk Kerkorian School of Medicine. “Treatment for agitation associated with Alzheimer disease dementia has been a critical unmet medical need. 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 Alzheimer disease.”

Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, the Psychiatric Times geriatric psychiatry Section Editor, said in an exclusive interview, “I think it’s very welcome that, with this serious illness, we have another class of medication being approved to treat agitation.”

The Journey to Approval

Investigators evaluated the efficacy and safety of AXS-05 for agitation associated with AD in several phase 3 studies, including ACCORD-2 and ADVANCE-2. Both trials were double-blind and placebo-controlled in design, and included 167 and 408 participants, respectively.

In ACCORD-2, participants completed an open-label treatment period followed by a 26-week, double-blind, placebo-controlled randomized withdrawal phase. AXS-05 achieved its primary end point, showing a statistically significant delay in time to relapse of agitation compared with placebo, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score (HR, 0.275; P = .001). AXS-05 also met its key secondary end point, with only 8.4% of AXS-05 treated participants experiencing relapse vs 28.6% of those receiving placebo (P = .001).

In ADVANCE-2, investigators randomly assigned 408 participants to receive either AXS-05 or placebo for 5 weeks. Although the trial did not meet its primary end point of change in CMAI total score (mean reduction: 13.8 points with AXS-05 vs 12.6 with placebo), AXS-05 did achieve numerical improvements across primary and secondary measures. ADVANCE-2 was the only study amongst the 4 pivotal trials of AXS-05 (ADVANCE-1, ADVANCE-2, ACCORD-1, and ACCORD-2) that did not meet its primary endpoint.³

AXS-05 was granted breakthrough therapy designation by the FDA for agitation in Alzheimer disease on June 26, 2020.⁴ Axsome ultimately submitted an sNDA to the FDA for AXS-05 for the treatment of agitation associated with Alzheimer disease on November 4, 2025.⁵

Final Thoughts

George Grossberg, MD, the professor and director of the Division of Geriatric Psychiatry at the Saint Louis University School of Medicine, said, “Agitation in patients with dementia due to Alzheimer disease is distressful, consequential, and challenging for patients, their caregivers and healthcare providers. 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. Importantly, Auvelity 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.”

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. April 30, 2026. Accessed April 30, 2026. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-fda-approval-auvelityr

2. Cummings J, Grossberg G, Streicher C, et al. Efficacy and safety Of AXS-05 in agitation associated with Alzheimer’s disease: results from ACCORD, a phase 3, double-blind, placebo-controlled, relapse prevention trial (PL5.004). Neurology. 2024;102(7 suppl):5194.

3. Marco M. Supplemental new drug application submitted for AXS-05 as treatment for Alzheimer disease agitation. Neurology Live. November 7, 2025. Accessed April 30, 2026. https://www.neurologylive.com/view/supplemental-new-drug-application-submitted-axs-05-treatment-alzheimer-disease-agitation

4. Axsome Therapeutics receives FDA breakthrough therapy designation for AXS-05 for the treatment of Alzheimer’s disease agitation. News release. June 26, 2020. Accessed April 30, 2026. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-receives-fda-breakthrough-therapy-0?field_nir_news_date_value%5Bmin%5D=

5. Kuntz L. sNDA submitted for AXS-05 for the treatment of Alzheimer disease agitation. Psychiatric Times. November 4, 2025. https://www.psychiatrictimes.com/view/snda-submitted-for-axs-05-for-the-treatment-of-alzheimer-disease-agitation