AXS-05 Approval for Agitation in Alzheimer Disease: Notes From John J. Miller, MD

Psychiatric Times' editor in chief, John J. Miller, MD, weighs in on the US Food and Drug Administration's (FDA) decision to approve AXS-05 for agitation in Alzheimer disease.¹

With the FDA's approval of AXS-05, this psychiatric pipeline update adds another medication option to treat agitation in dementia. Previously, the only approved drug for this indication was Rexulti (brexpiprazole). The novel agent, developed by Axsome, is a fixed combination of bupropion and dextromethorphan intended to treat the agitation element of Alzheimer dementia.

Approval from the FDA is based on data from the ADVANCE-1 and 2 and ACCORD-1 and 2 studies.² The ADVANCE-1 and ADVANCE-2 trials employed a 5-week, double-blind, active-controlled design in which patients with presumed Alzheimer disease and agitation were randomized to AXS-05, bupropion monotherapy at the equivalent dose contained in the combination agent, or placebo. AXS-05 demonstrated statistically significant superiority over both comparators. The ACCORD-1 and ACCORD-2 trials utilized an open-label run-in phase during which all participants received AXS-05, followed by blinded randomization to continued treatment or placebo, with time to relapse as the primary endpoint. Results showed "a significant prolongation of benefit and decreased agitation in the group with the AXS-05."

Miller situated the approval within its clinical context, characterizing agitation in Alzheimer disease as "a very challenging and highly unmet need," and emphasized that AXS-05 represents only the second FDA-approved agent for this indication.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Volunteer Consulting Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

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 disease. Press 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. Kuntz L. A review of data on AXS-05 for Alzheimer disease agitation in advance of next week's PDUFA date. Psychiatric Times. April 23, 2026. https://www.psychiatrictimes.com/view/a-review-of-data-on-axs-05-for-alzheimer-disease-agitation-in-advance-of-next-weeks-pdufa-date