Agitation is a common Alzheimer’s disease symptom, manifesting as pacing and restlessness as well as verbal and physical aggression to family members and caregivers. The drugs used to quell these behaviors come with safety risks. An Axsome Therapeutics drug that works in a different way now has FDA approval for treating Alzheimer’s agitation, giving this product the opportunity to become a first-line treatment in this indication.
The drug, Auvelity, was initially approved in 2022 for major depressive order in adults. The FDA decision announced Thursday expands use of the twice-daily pill to treating agitation associated with dementia due to Alzheimer’s.
Auvelity has two main pharmaceutical ingredients, bupropion and dextromethorphan. This drug combination blocks the NMDA receptor and activates the sigma-1 receptor. How this mechanism of action treats depression was not fully understood at the time of Auvelity’s initial approval and it’s also unclear exactly how it treats agitation. Speaking during a Friday morning conference call, Axsome CEO Herriot Tabuteau said hitting the NMDA and sigma-1 receptors is believed to modulate the function of neurotransmitters implicated in Alzheimer’s.
Axsome’s FDA submission for Auvelity in the agitation indication was based on two Phase 3 studies. In the trial that tested Auvelity against a placebo, results showed the study drug led to statistically significant improvement measured by scale used to assess agitation related to cognitive impairment. In the second study, responders to Auvelity were randomly selected to either stay on the study drug or continue the trial on a placebo. These results showed those who continued on Auvelity showed a statistically significant longer time to relapse compared to those switched to placebo. The most common adverse effects reported in the trials included dizziness and indigestion.
Dr. Jeffrey Cummings, professor of brain sciences at the UNLV Kirk Kerkorian School of Medicine, said during the Axsome conference call that Alzheimer’s agitation can appear at any stage of the disease. When patients become agitated, they tend to remain agitation prone for about three years. Patients would receive a drug for agitation during these periods.
Off-label treatments for agitation include older anxiety and antipsychotic medications. Before Auvelity’s new approval, the only FDA-approved treatment for Alzheimer’s agitation was Rexulti from partners Lundbeck and Otsuka Pharmaceutical. This once-daily pill, which modulates serotonin and dopamine activity in the brain, was approved for Alzheimer’s agitation in 2023 following earlier approvals of the product in depression and schizophrenia. But Rexulti’s label carries a black box warning for a higher risk of death in elderly patients with dementia-related psychosis, a warning carried by other antipsychotic medications as well. Cummings said this warning discourages clinicians from prescribing Rexulti for Alzheimer’s agitation.
“I think Auvelity is likely to be the first choice for prescribers,” Cummings said. “There’s no medication which is going to work for every patient, so there’ll be room for other drugs on the market. I think Auvelity will do very well within the therapeutic landscape of this very large problem.”
Auvelity is not an antipsychotic medication, though its label carries a black box warning for suicidal thoughts, which came with the drug’s initial approval in depression. That warning is consistent with the labels of other depression drugs. Tabuteau noted that the new Auvelity approval did not come with an additional black box warning.
Axsome reported $507.1 million in 2025 sales for Auvelity, a 74% increase over the product’s sales in the prior year. That growth came in a crowded market of depression drugs. Alzheimer’s disease is smaller market, but it’s also less crowded. Cummings said selective serotonin reuptake inhibitors (SSRIs), a class of drugs prescribed for anxiety and depression, are widely used off label for Alzheimer’s agitation, and they work better in those with less agitation. But Cummings added that he thinks patients and prescribers will shift toward drugs that have shown efficacy in this indication.
Agitation gives Auvelity a new growth opportunity against much less competition. Lundbeck’s annual report says Rexulti’s share of the Alzheimer’s agitation market was 4.6% in 2025. That makes this market wide open for Auvelity, William Blair analyst Myles Minter said in a research note. The bank projects Auvelity peak sales could top $2.1 billion in the agitation indication alone. That figure could catch the attention of other companies.
“This is an even more attractive M&A candidate, in our view, as well for several big pharma players touting their neuroscience franchises as key growth drivers,” Minter said.
Photo by Axsome Therapeutics
