Conference Coverage

Dextromethorphan-Bupropion Delays Relapse of Agitation Symptoms in Patients Diagnosed With Probable Alzheimer Disease

Anthony Calabro, MA

Dextromethorphan-bupropion, an FDA-approved medication for treating major depressive disorder, significantly delayed the relapse of agitation symptoms among patients with probable Alzheimer disease (AD) and clinically meaningful agitation when compared with placebo, according to a study presented at the 16th Clinical Trials on Alzheimer Disease Conference in Boston, MA.

Researchers developed the Assessing Clinical Outcomes in Alzheimer’s Disease Agitation (ACCORD) study, a Phase 3, randomized, discontinuation, double-blind, placebo-controlled, multi-center trial, to evaluate efficacy and safety of dextromethorphan-bupropion in those with Alzheimer disease-related agitation.

Participants with a diagnosis of probable AD and clinically meaningful agitation were enrolled into a 9-week, open-label period of the trial (n = 178). During this time, they were treated with dextromethorphan-bupropion and monitored for sustained clinical response, which the researchers defined as a ≥ 30% improvement from baseline in two scores: the Cohen Mansfield Agitation Inventory (CMAI) total score and the Patient Global Impression of Change (PGI-C; score of ≤3). Improvements for both scores needed to be maintained for at least 4 consecutive weeks.

The participants who achieved the sustained clinical response during the open-label period were then randomly assigned (1:1) to continue treatment with either dextromethorphan-bupropion or placebo in a double-blind fashion for up to 26 weeks. Researchers continued treatment until either a relapse of agitation symptoms occurred, or the participants reached the end of the double-blind period, whichever occurred first. The primary endpoint in the study was the time from randomization to relapse of agitation. The key secondary endpoint was the percentage of participants who relapsed.

Of the 178 initial participants, 108 were randomly assigned to continue dextromethorphan-bupropion (n = 53) or switched to placebo (n = 55). The results indicated that dextromethorphan-bupropion substantially delayed the time to relapse of agitation symptoms compared with those taking a placebo, meeting the primary endpoint. The hazard ratio for the time to relapse was 0.275 (p = 0.014), indicating a 3.6-fold lower risk of relapse compared with placebo. Dextromethorphan-bupropion also met the key secondary endpoint of relapse incidence rate compared with placebo (7.5% vs 25.9%, respectively; p= 0.018).

In the double-blind period, the rates of adverse events were 28.3% for the dextromethorphan-bupropion group and 22.2% for the placebo group. There were no discontinuations because of adverse events in the dextromethorphan-bupropion group and 1.9% discontinuations for the placebo group.

“Treatment with [dextromethorphan-bupropion] substantially reduced the risk of relapse and was generally well-tolerated for participants who achieved sustained clinical response in the preceding open label treatment period,” the authors concluded. “These data support the continued development of [dextromethorphan-bupropion] as an efficacious and safe novel treatment for Alzheimer disease-related agitation.”


Cummings J, Grossberg G, Andersson C, Eglit G, Streicher C, Tabuteau H. 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. Study presented at: 16th Clinical Trials on Alzheimer Disease. October 24-27, 2023. Accessed March 1, 2024.