Auvelity (Dextromethorphan-Bupropion) for Agitation and Aggression in Alzheimer’s Disease Dementia: Mechanism, Efficacy, Safety, and Clinical Considerations
Mridul Sarangal, Charmi Sarangal, Jay Vora, Karishma Soni
Psychopharmacology Bulletin September 17, 2026 DOI: 10.64719/pb.20773 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Measures | Cohen-Mansfield Agitation Inventory (CMAI) |
| Key findings | Argues that dextromethorphan-bupropion is a highly efficacious and safer alternative to atypical antipsychotics for Alzheimer's disease-associated agitation. The authors cite the ADVANCE-1 and ACCORD trials as showing rapid, statistically significant reductions in Cohen-Mansfield Agitation Inventory scores and a 3.6-fold lower risk of agitation relapse compared with placebo, while avoiding antipsychotic-associated sedation, cognitive blunting, and fall risk, though blood pressure and CYP2D6 interactions require monitoring. |
Abstract
Background: Agitation and aggression in Alzheimer’s disease (AD) are highly distressing behavioral symptoms traditionally managed with off-label atypical antipsychotics, despite boxed warnings for increased mortality in elderly patients. The emergence of Auvelity (dextromethorphan-bupropion) provides a critical, non-antipsychotic therapeutic alternative. Mechanism: This combination utilizes bupropion as a CYP2D6 inhibitor to achieve therapeutic central nervous system concentrations of dextromethorphan. Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, bypassing dopaminergic blockade to promote synaptic plasticity via glutamatergic and monoaminergic modulation. Efficacy: Key clinical trials (ADVANCE-1 and ACCORD) demonstrate that dextromethorphan-bupropion produces rapid, statistically significant reductions in Cohen-Mansfield Agitation Inventory (CMAI) scores. Furthermore, it offers robust long-term maintenance, demonstrating a 3.6-fold lower risk of agitation relapse compared to placebo. Safety: The combination therapy was generally well-tolerated in trials, successfully avoiding the sedation, cognitive blunting, and heightened fall risks characteristic of antipsychotics. Clinicians must, however, monitor for blood pressure changes and potential CYP2D6 drug-drug interactions.
Conclusion: Dextromethorphan-bupropion represents a highly efficacious, safer paradigm shift in the pharmacological management of AD-associated agitation, offering targeted symptom relief while minimizing the severe risks associated with standard antipsychotic use.