FDA Approves Auvelity for Alzheimer’s Agitation

SILVER SPRING, Md. - The Food and Drug Administration approved Auvelity for agitation associated with dementia due to Alzheimer’s disease in adults, giving U.S. patients and caregivers the first FDA-approved option for the condition that is not an antipsychotic.

The agency said Thursday that the approval expands Auvelity’s use beyond major depressive disorder, the adult indication FDA first approved in 2022. The drug combines dextromethorphan hydrobromide and bupropion hydrochloride in extended-release tablets, according to FDA.

The decision matters because agitation is one of the most difficult symptoms families face as Alzheimer’s progresses. FDA described the condition as common and distressing, with excessive motor activity, verbal aggression, or physical aggression that can affect patients and caregivers.

What Happened

FDA said Auvelity is now approved to treat agitation associated with dementia due to Alzheimer’s disease in adults. The approval was granted to Axsome Therapeutics after FDA gave the application breakthrough therapy designation and priority review designation.

"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," FDA Commissioner Marty Makary said in the agency’s announcement. "With today’s action, patients and their families have access to an additional important treatment for complications of this devastating disease."

The approval does not make Auvelity an Alzheimer’s cure or a disease-modifying treatment. FDA framed the drug as a treatment for agitation tied to dementia due to Alzheimer’s disease, not for the underlying neurodegenerative disease itself.

Image: BruceBlaus, via Wikimedia Commons (CC BY-SA 4.0)

The National Institute on Aging says Alzheimer’s is the most common cause of dementia among older adults. "Estimates vary, but experts suggest that more than 6 million Americans, most of them age 65 or older, may have Alzheimer's," NIA says in its Alzheimer’s disease fact sheet.

That patient population makes even symptom-focused approvals consequential for U.S. families. Agitation can strain home care, complicate nursing-home treatment, and force clinicians to balance symptom control against medication risks, according to FDA’s description of the condition and the safety limits attached to Auvelity.

The Evidence Behind The Decision

FDA said the approval was supported by two randomized studies. The first, listed on ClinicalTrials.gov as NCT03226522, was a five-week, multi-center, randomized, double-blind, placebo-controlled Phase 2/3 study designed to assess AXS-05, the development name for Auvelity, in Alzheimer’s agitation.

ClinicalTrials.gov lists actual enrollment for NCT03226522 at 366 participants. FDA said the trial measured change from baseline to week five on the Cohen-Mansfield Agitation Inventory, a caregiver-reported survey used to assess the frequency of agitated behaviors in elderly patients.

According to FDA, Auvelity was significantly superior to placebo in Cohen-Mansfield Agitation Inventory score improvements in that study. The agency did not include detailed effect-size data in its announcement, so the approval should be described in FDA’s language rather than as a quantified clinical magnitude.

The second study, listed on ClinicalTrials.gov as NCT04947553, was a completed Phase 3 study of long-term safety and efficacy. ClinicalTrials.gov lists actual enrollment at 456 participants.

FDA said that study used a withdrawal design. Participants who reached a sustained clinical response to Auvelity were randomly assigned either to keep taking Auvelity or to switch to placebo, and the primary endpoint was time to relapse.

Participants who continued Auvelity had a significantly longer time to relapse of agitation symptoms than participants switched to placebo, according to FDA.

"Auvelity was found to be efficacious for treating agitation in Alzheimer’s disease in two randomized trials and now represents an additional option to address one of the most difficult sequelae of the disease, especially as it progresses," said Tracy Beth Hoeg, acting director of FDA’s Center for Drug Evaluation and Research. "We hope this approval will provide meaningful benefit to patients, their families, and caregivers."

The Safety Limits

FDA’s approval adds a new option, but the agency’s announcement also outlined risks clinicians will need to evaluate before prescribing the drug.

The most common side effects include dizziness, upset stomach, headache, diarrhea, drowsiness, dry mouth, sexual dysfunction, and uncontrolled sweating, according to FDA. The agency said Auvelity carries a boxed warning about increased risk of suicidal thoughts and behaviors in adolescents and young adults taking antidepressants.

Although the Alzheimer’s agitation indication is for adults with dementia due to Alzheimer’s disease, FDA said health care providers should monitor patients for clinical worsening and the emergence of suicidal thoughts and behaviors, especially during initial treatment.

FDA also said the medicine can cause seizures, with risk increasing with dose. The agency said Auvelity can cause elevated blood pressure and hypertension, and may activate mania or hypomania in susceptible patients.

Before starting Auvelity, FDA said health care providers should assess blood pressure, screen for a personal or family history of bipolar disorder, and determine whether patients are taking other medicines containing bupropion or dextromethorphan.

Those limits make the approval a clinical judgment call rather than a simple replacement for existing approaches. Families may see the first non-antipsychotic labeled option as an important development, while physicians still have to evaluate seizure risk, blood pressure, drug overlap, psychiatric history, and each patient’s dementia status.

What People Are Saying

"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," Makary said.

"Auvelity was found to be efficacious for treating agitation in Alzheimer’s disease in two randomized trials and now represents an additional option to address one of the most difficult sequelae of the disease, especially as it progresses," Hoeg said.

"Estimates vary, but experts suggest that more than 6 million Americans, most of them age 65 or older, may have Alzheimer's," the National Institute on Aging says.

The Big Picture

The approval gives clinicians a labeled non-antipsychotic option for a symptom that can dominate daily life for Alzheimer’s patients and their caregivers. FDA’s decision also shows how symptom control remains a major part of dementia care even as researchers continue studying treatments aimed at the underlying disease process.

For families, the next step is practical. The label creates another conversation to have with a physician, but FDA’s warnings mean the choice will depend on the patient’s full medical history, other medications, and the severity of agitation symptoms.