NeuroVoices: Gus Alva, MD, DFAPA, on Potential Impact of Newly Approved AXS-05 for Alzheimer Disease Agitation

Agitation remains one of the most challenging and burdensome neuropsychiatric symptoms associated with Alzheimer disease (AD), often contributing to accelerated cognitive decline, caregiver stress, institutionalization, and reduced quality of life. Despite its prevalence, treatment options for AD-related agitation have historically been limited, with brexpiprazole becoming the first FDA-approved therapy for the condition in 2023.

Recently, the FDA approved Axsome Therapeutics’ AXS-05 (dextromethorphan-bupropion), marketed as Auvelity, as a treatment for agitation associated with dementia due to AD, making it the second approved therapy specifically indicated for this symptom domain. The oral therapy combines dextromethorphan, an NMDA receptor antagonist and sigma-1 receptor agonist, with bupropion, which functions as a CYP2D6 inhibitor to increase dextromethorphan exposure. The approval was supported by data showing statistically significant improvements in agitation symptoms and prolonged time to relapse compared with placebo.

Just days before the FDA decision, NeurologyLive^® sat down with Gus Alva, MD, DFAPA, psychiatrist and medical director of ATP Clinical Research, to discuss the potential implications of an AXS-05 approval, the unmet need in AD agitation, and how clinicians should think about integrating newer therapies into practice. As part of a new iteration of NeuroVoices, Alva also reflected on the growing importance of collaboration between psychiatry and neurology in the care of patients with neurodegenerative disease.

NeurologyLive: If AXS-05 were to be approved for agitation associated with Alzheimer disease, what benefits or broader implications would that approval have for patients and clinicians?

Gus Alva, MD, DFAPA: First and foremost, unfortunately, agitation affects about 1 out of every 2 people living with Alzheimer disease, and regardless of the disease state in which the individual finds themselves, agitated symptomatology can be quite annoying not just for the patient, but also the caregiver, family member, or care partner involved with the individual.

How important is it to hear the FDA’s take on AXS-05? It’s enormous. As you mentioned, we currently have brexpiprazole as the first and only FDA-approved agent, but if another medication enters the space, that opens the door for a lot of potential benefit for many people. It underscores that treatment is not one-size-fits-all.

Brexpiprazole works, otherwise it would not have received FDA approval, and it has shown a relatively favorable safety and tolerability profile. But it is still an atypical antipsychotic, meaning it carries a boxed warning related to increased morbidity and mortality in elderly patients with dementia-related psychosis.

AXS-05 is different. It combines dextromethorphan and bupropion and works through a completely different mechanism than atypical antipsychotics. When you look at the safety and tolerability profile associated with dextromethorphan-bupropion, it’s also very favorable. The key question becomes whether we are able to meaningfully reduce agitation symptomatology, and the metrics being utilized are very similar to what was done with brexpiprazole.

I think it’s exciting because it underscores an important theme: our field continues to evolve. The neuropsychiatric space is fluid, not static, and it means we can continue to broker hope to individuals who often lack it. Sometimes patients may have drug-drug interactions or disease-related issues that limit treatment options. Having more than one FDA-approved therapy that has been well vetted for efficacy and safety is enormously important for clinicians caring for people with Alzheimer disease.

What clinical considerations should clinicians keep in mind if AXS-05 enters practice for patients with Alzheimer disease agitation?

It’s incumbent upon clinicians to understand the pros, cons, and alternatives associated with any treatment modality. One of the strengths of the FDA process is that therapies must demonstrate both efficacy and safety before broad exposure to patients.

It’s also important to understand the metrics we use to evaluate agitation. It’s one thing to use instruments like the Cohen-Mansfield Agitation Inventory, but in real-world practice agitation often manifests through repetitive questioning, repetitive behaviors, negative statements, or other actions that become distressing to caregivers. Those are the things that often drive families to seek additional therapies.

Ultimately, caregivers and care partners are often the people deciding whether treatment escalation is necessary. So, we want therapies that are effective, safe, and practical to use. I’m excited about the data we’ve seen so far and optimistic about the potential benefit this therapy could have for many individuals.

We know there are nearly 7 million Americans living with Alzheimer disease, and those numbers are only expected to rise. Alzheimer disease is not simply a memory disorder; it’s a functional disorder. As abilities erode, patients become increasingly dependent on others, and the behavioral symptoms become more prominent. The ABCs — activities of daily living, behavior, and cognition — all have to be factored into care.

We should always maximize nonpharmacologic interventions first, but there are times when the threshold is crossed and a pharmacologic intervention becomes necessary. At that point, clinicians need to understand how to use these therapies effectively and safely. Glutamate signaling is critically important because it influences learning, cognition, memory, mood, and many of the factors involved in Alzheimer disease progression.

Even with newer monoclonal antibodies, we are not curing Alzheimer disease. We may be slowing progression or buying additional functional time, but the neurodegenerative process continues. Because of that, it’s important that we address all facets of the disease as they evolve and continue to provide hope to caregivers and care partners.

How can psychiatry and neurology continue to collaborate more effectively in the care of neurodegenerative disease?

The collaborative process between psychiatry and neurology is really imperative. I’ve been working in this space for more than 30 years, and Jeff Cummings, who has been both a mentor and friend, used to call himself a behavioral neurologist while I called myself a neuropsychiatrist because we were essentially doing the same thing.

Historically, psychiatry and neurology have sometimes operated in parallel rather than together, even within industry-sponsored clinical research. I’ve worked on studies involving cholinesterase inhibitors, memantine, and numerous investigational therapies, and it was interesting how the psychiatry and neurology groups often did not communicate despite overlapping patient populations and goals.

In reality, we’ve always needed a collaborative approach, especially in disorders like Alzheimer disease and Parkinson disease where psychiatric and neurologic symptoms are deeply intertwined. I think we are evolving in that direction more now, particularly as biomarker-driven diagnosis and earlier disease identification become increasingly important.

We are at a better place today in terms of identifying biomarkers that may predict disease progression earlier in the continuum, including mild cognitive impairment, but there is still a tendency for many patients to be diagnosed far too late in the disease process. We need to continue evolving, improving, and fine-tuning how we approach these conditions, and psychiatry and neurology should absolutely be contributing in a unified manner toward those goals.

Transcript edited for clarity.