FDA Approves First Non-Antipsychotic Drug for Alzheimer’s Agitation

The FDA expanded the indication for dextromethorphan hydrobromide and bupropion hydrochloride (Auvelity) extended-release tablets to treat agitation associated with Alzheimer’s disease dementia, the agency announced Thursday.

This decision marks the first approved treatment for Alzheimer’s dementia that is not an antipsychotic, the FDA said. The drug initially was approved to treat major depressive disorder in 2022.

“This approval represents a significant advancement in our ability to help patients and families dealing with one of the most challenging aspects of Alzheimer’s disease,” said FDA Commissioner Marty Makary, MD, MPH.

Agitation is common in people with Alzheimer’s dementia and can include excessive motor activity or verbal or physical aggression, affecting patients’ and caregivers’ quality of life, the agency noted.

“For too long, people living with Alzheimer’s disease agitation and their families have had limited options, and the options that existed came with significant risks,” Joanne Pike, DrPH, president and CEO of the Alzheimer’s Association, said in a statement.

“This approval gives patients, caregivers, and clinicians an important new tool — one that works through a different mechanism than antipsychotic medications and that can help address a symptom that profoundly affects quality of life for people living with Alzheimer’s and those who care for them,” Pike added.

The treatment is an oral N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor, drugmaker Axsome Therapeutics said. It works on the NMDA receptor and the sigma-1 receptor through its dextromethorphan component. The bupropion component increases blood levels of dextromethorphan by inhibiting CYP2D6, the company noted.

The drug showed efficacy in two randomized trials. The first was the 5-week randomized ADVANCE trial in which the drug was superior to placebo in improvements in Cohen-Mansfield Agitation Inventory scores. The second was the randomized ACCORD-2 withdrawal study of treatment responders that showed patients who continued the drug had a longer time to relapse compared with those who received placebo.

The most common side effects associated with the drug include dizziness, upset stomach, headache, diarrhea, drowsiness, dry mouth, sexual dysfunction, and uncontrolled sweating, the FDA said. The treatment can cause seizures, with risk increasing with dose. It can also cause elevated blood pressure and hypertension, and may activate mania or hypomania in susceptible patients.

The drug’s label includes a boxed warning highlighting increased risks of suicidal thoughts and behaviors in adolescents and young adults who use antidepressants. The FDA advised clinicians to monitor patients for signs of clinical worsening or the onset of suicidal thoughts and behaviors, especially during initial treatment.

Before starting therapy, clinicians should evaluate blood pressure, check for personal or family history of bipolar disorder, and determine whether patients are taking other medications that contain bupropion or dextromethorphan, the agency added.