The U.S. Food and Drug Administration (FDA) has approved oral combination of dextromethorphan HBr and bupropion HCl (AUVELITY, Axsome Therapeutics) for the treatment of agitation associated with dementia due to Alzheimer’s disease (AAD) in adults. The approved combination dextromethorphan-bupropion is an antidepressant that acts on NMDA and sigma-1 receptors. It received FDA Breakthrough Therapy designation and was reviewed under the Priority Review program. The drug is also approved for the treatment of major depressive disorder (MDD) in adults and has been used in more than 300,000 patients across clinical trials and real-world practice.
Alzheimer’s disease, the leading cause of dementia, affects more than 7 million individuals in the United States and is characterized by progressive, irreversible cognitive decline. Agitation is reported in up to 76% of patients and encompasses a spectrum of behaviors, including motor restlessness, pacing, and verbal or physical aggression. Among the behavioral and psychological symptoms of dementia, agitation is particularly persistent and complex, and is associated with increased caregiver distress and resource utilization.
Dextromethorphan (DXM) figure acts as a nonselective, noncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist. By blocking NMDA receptors, it increases downstream glutamate signaling, which in turn stimulates other glutamate receptors such as AMPA. Activation of AMPA receptors initiates intracellular pathways including mTORC1 and promotes the release of neurotrophic factors like BDNF, supporting synaptic protein production and increasing dendritic spine density. DXM also interacts with the serotonin transporter, potentially influencing serotonin levels, although its exact mechanism in agitation associated with dementia due to Alzheimer’s disease remains unclear.
Bupropion figure complements this activity by inhibiting CYP2D6, the primary enzyme responsible for metabolizing dextromethorphan, thereby significantly increasing DXM plasma concentrations and allowing for therapeutic central nervous system exposure. In addition, bupropion inhibits the reuptake of norepinephrine and dopamine, enhancing both noradrenergic and dopaminergic neurotransmission.
The FDA approval is supported by a comprehensive Phase 3 clinical program: the ADVANCE-1 and ACCORD-2 studies.
ADVANCE-1 was a 5-week, double-blind, parallel-group trial evaluating AUVELITY for agitation in Alzheimer’s disease, with patients randomized to AUVELITY, placebo, or bupropion monotherapy (the bupropion arm was terminated early for futility).
- Primary endpoint: Improvement in agitation symptoms measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score at Week 5 — AUVELITY was statistically significantly superior to placebo
- Key secondary endpoint: Response on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) — a statistically significantly greater proportion of AUVELITY-treated patients were rated as at least minimally improved vs. placebo
- Discontinuation due to adverse events: 1.3% for AUVELITY — identical to placebo
ACCORD-2 was a long-term, double-blind, randomized withdrawal trial in which known AUVELITY responders were re-randomized to continue AUVELITY or switch to placebo for up to 6 months.
- AUVELITY demonstrated a statistically significantly longer time to relapse of agitation symptoms (CMAI) vs. placebo
- AUVELITY is the only FDA-approved product to show statistically significant relapse prevention in a long-term controlled study in this population
In the ADVANCE-1 trial, the most common (incidence ≥5% for AUVELITY and more than twice as frequently as placebo) adverse reactions were dizziness and dyspepsia. In the study, 1.3% of patients discontinued AUVELITY due to an adverse event, the same rate as placebo.
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Medication Guides: Agents for Agitation
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