ACCORD Trials: Efficacy and Safety of Dextromethorphan-Bupropion in Agitation

In "ACCORD Trials: Efficacy and Safety of Dextromethorphan-Bupropion in Agitation," the panel walks through the pivotal trial data behind a newer, non-antipsychotic agitation therapy.

The panel walks through the pivotal trial data behind one of the two on-label agents, dextromethorphan-bupropion, beginning with a five-week, placebo-controlled, multicenter short-term trial. Enrolled outpatients had a clinical Alzheimer's dementia diagnosis, mini-mental status scores between 10 and 24, and a reliable caregiver able to document frequency using the 29-item CMAI. Patients on SSRIs or with a seizure disorder were excluded given the therapy's antidepressant component. Statistical separation from placebo appeared as early as two weeks and was firmly established by five weeks, and a secondary endpoint, a modified global impression of change, showed improvement in 82% of patients.

A separate long-term study then enrolled patients who had completed the short-term trial into an open-label extension. After four weeks of titration, patients had to sustain a five-point CMAI improvement and a global impression of change of three or better for four consecutive weeks, a notably demanding bar, before being randomized to continued therapy or placebo. Remarkably, 71% of patients met that threshold, with average CMAI scores falling from roughly 71 at baseline, reflecting a highly agitated population, down to 44, a reduction of more than 30%. At six months, 92% of patients remained relapse-free. The most common side effects across both studies were dizziness and dyspepsia, and fewer than 2% of patients discontinued because of side effects.

The panel frames this data as reshaping when treatment should start: not necessarily earlier for its own sake, but at the clinically appropriate moment, rather than waiting for a crisis, since delayed treatment is linked to hospitalization and earlier death. Follow-up frequency after starting therapy is described as depending on disease stage, comorbidities, and family circumstances, ranging from monthly to every few weeks, often coordinated through nurse case managers using phone or virtual check-ins between formal visits.

The next episode in this series, "Safety, Dosing, and Drug Interactions for Dextromethorphan-Bupropion in Agitation," features the panel comparing safety data and detailing practical dosing for that same therapy.