From Approval to Practice: Auvelity's Place in Alzheimer Disease Agitation Care

In this excerpt from the second episode of Mind the Meds, host Erica Marini, PharmD, and guest Millad Sobhanian, PharmD, a clinical pharmacy specialist in neurology at the University of Maryland, discuss dextromethorphan/bupropion (Auvelity; Axsome Therapeutics), which was newly approved on April 30, 2026, for agitation associated with dementia due to Alzheimer disease. This approval marked the treatment's second FDA-approved indication. The 2 unpack how its N-methyl-D-aspartate (NMDA) receptor antagonism targets the excessive glutamatergic activity linked to behavioral and psychological symptoms of dementia, weigh its modest Cohen-Mansfield Agitation Inventory (CMAI) efficacy data compared with brexpiprazole (Rexulti; Otsuka Pharmaceutical), and flag key safety considerations.

Erica Marini, PharmD: So, a few things to discuss here in the Alzheimer space. We're first going to discuss a new medication for agitation, specifically in Alzheimer [disease]. So, a little bit of context here…agitation is really one of the most common and clinically significant neuropsychiatric symptoms in Alzheimer disease, affecting up to 60% of patients over the course of the illness, and unfortunately, prevalence increases alongside disease severity, which is not the line on the graph we like to see, but when I say agitation—because often a caregiver might not describe certain things as agitation—I want to make sure we're talking the umbrella of symptoms…like inappropriate verbal, vocal, or motor activity, including restlessness, pacing, shouting, hitting, kicking, and actively resisting care. So, because this gets more prevalent as the disease gets more severe and is linked to things like earlier admission to nursing homes, it's really important to address this now.

Our current treatment model has a large focus on nonpharmacologic interventions. These are first-line, and this is probably not going to be a big spoiler to anyone, but that's really not going to change, even with [Auvelity] approved. But different types of therapies—like touch therapy and music therapy—tailored programs for the patient and caregiver education and skills training. We really move on to our pharmacologic therapy when these things have failed, or behavior poses a danger to either the patient or to others like their caregivers. So, for a while, as far as pharmacologic therapy, we relied on off-label options, which is…not uncommon in neuro and any other areas where you practice medicine, but in this space we're looking at mostly atypical antipsychotics and things like selective serotonin reuptake inhibitors (SSRIs), citalopram (Celexa; Forest Laboratories) specifically having the most data in other agitation states we might think of [benzodiazepines], maybe even as an initial therapy, but generally try to avoid in this population for obvious safety reasons, and all of these off-label options really are still used today as they can be accessed very easily.

But in 2023 we got our first FDA-approved therapy, a brand name Rexulti, or brexpiprazole, which is an atypical antipsychotic, and is marketed as, essentially, a “better tolerated aripiprazole.” Now, Millad, what are things that you think about when considering using pharmacologic therapy? Some of these available treatments in an Alzheimer patient.

Millad Sobhanian: Yeah, that's a great question. As you said, these are not therapies that we should be reaching for first line. These patients have to go through the systemic approach and the stepwise approach of nonpharmacologic intervention. If we've gotten to the point where the symptoms are severe and they're not really responding to those other interventions, then we can reach for some of these therapies, like, our antipsychotics and benzodiazepines.

When you look at antipsychotics, of course, we can't ignore the kind of glaring black box wording of increased mortality risk in patients with dementia, and particularly that's the population that we're working with. If you're looking at the data and the outcomes, I think you know the biggest reasons for mortality…sudden cardiac death, heart failure, [and] infections including pneumonia being the most common. So, kind of looking at your patient, looking at their past medical history and determining if they have any of these potentially underlying causes like heart failure or arrhythmias, or something that you want to be extremely careful with, including these therapies and starting these therapies for these patients. I think—and I'm not sure if in your practice you see this too—but with brexpiprazole, we do have to be, I think we're a little bit more [likely] to use this therapy because it has the on-label indication, but we do need to be aware and mindful that it's still an atypical antipsychotic, and so we can't ignore the potential risk of increased mortality. So, we do tend to reserve these therapies after everything else has failed, but those are some of the things that we keep in mind. Is that how we follow the appropriate standard in terms of getting the monotherapy that they need safely?

Marini: Yeah, absolutely. I love the way that you're thinking about that.

And so exciting, because Auvelity is our new agent in the game. It was approved just on April 30 of this year to treat agitation associated with dementia due to Alzheimer disease, that's its on-label indication. This is actually the second approved indication for this agent. It's been around originally since August of 2022 when it was approved for major depressive disorder, so it's been around a little while, but a new indication, a new labeled indication. This is actually a combination product, and at its maintenance dosing, it has dextromethorphan 45 mg and bupropion 105 mg, and it's a twice a day medication.

What I think might be surprising to some is that the rationale for its use in Alzheimer agitation is really focused on the dextromethorphan component, the bupropion here is really being used as for its CYP2D6 inhibition to increase and sustain the dextromethorphan levels…in other indications like depression, bupropion probably does play an active role, but not so much here.

Now, dextromethorphan, in its role, is an uncompetitive antagonist of the NMDA receptor, and this is the main mechanism where it could be helpful in Alzheimer agitation, because there is excessive glutamatergic stimulation at this receptor in Alzheimer [disease], which has been directly linked to behavioral and psychological symptoms of dementia, and so a lot of promise when this drug was getting developed…this does offer a novel mechanism from what we've been using off-label or on-label with Rexulti in the past.

I think that most pharmacy folks are familiar with these 2 products, both things that have been around for a long time. But can you give us Millad—what I call kind of the package insert rundown for this new drug—highlights on like [adverse] effects (AEs), drug interactions, things we should know before we recommend this drug specifically in [a patient with Alzheimer disease agitation].

Sobhanian: Yeah…you talking about the interaction and sort of that leveraging of the inhibition that you get with the substrate and the inhibitor, you know, the substrate being destructive, dextromethorphan, the inhibitor being bupropion. So, I think that's a good place to start. You think of our antidepressants, you know, like fluoxetine, some of our SSRIs. So, if your patient's already taking one of those medications, you may want to be mindful of their dosage, and you may consider a dose adjustment there. You mentioned NMDA antagonisms is the primary mode of action for the dextromethorphan component. Another therapy that we use for symptomatic management of Alzheimer disease is memantine (Namenda; Merz Pharmaceuticals, Forest Laboratories), which is also an NMDA receptor antagonist. So, using the 2 in concert, you may see [and] still maintain a therapeutic benefit, but you may push a patient over a little bit more into “too much” [of] an NMDA antagonist, which can result in certain AEs like dizziness and headache, and the like.

Other considerations from a tolerability and safety standpoint, bupropion is not typically the first medication that I think of starting in an elderly patient. It's an SDNRI, so selective dopamine or norepinephrine reuptake inhibitor. So, those are, you know, these sort of catecholamines, they have the sympathetic effects. Tachycardia, hypertension is, of course, a concerning risk factor, especially if patients are already have some underlying hypertension and arrhythmia to begin with, you know, cardiovascular history is another consideration. And, of course, bupropion, I think all pharmacists are really going to be like, “Oh, seizure history, that's the number one thing [to be aware of],” so it can lower seizure threshold, the doses that are used…100 to 200 mg a day, depending on where they are in the titration. Those typically aren't the ones that we worry about in terms of seizure history. Usually, if you look at the [older] outcome data, 300 to 400 mg a day of bupropion seems to be the dose associated, so we may not be getting to that point, but still, in an elderly patient, use caution there.

And renal impairment. If their kidneys don't work, they can't clear the medication, so you need to either adjust or avoid, depending on their EGFR, and the cut-offs are listed pretty clearly in the labeling. So, I think those are the big things that I would consider with this therapy as it comes to market.

Marini: I love how you stressed the idea of kind of additive AEs, because I feel like—especially with a combination product—everyone, including pharmacists, can fall into a trend of calling a combination product by its brand name instead of by the generic components, and where you have a drug like this…you could easily see a patient already on bupropion, you could easily see a patient requesting to get some dextromethorphan from the pharmacy for a cough, or you can easily see someone already on a memantine, and so it's going to be really important, I think, as this comes to use to really review patients' medication list and make sure there's none of that kind of additive stuff happening. So, I love that you brought that up.

Now, as far as efficacy, which we have to look at, of course, and we don't have a ton of time, but they had a study that took a look at the difference between active drug and placebo in CMAI, which is an appropriate end point. This is a primary end point that's been used in a lot of validated studies as far as Alzheimer agitation, but it was a relatively short trial at 5 weeks, and, like I said, we only really have time for a top-line review of the results.

They did show a reduction of 14.9 points on the CMAI scale in the treated group versus an 11.6-point drop in the placebo group. So, a least squares mean difference of 3.3 points. You know, as an obviously indirect comparison, but I always feel like I need to compare things in my mind. We did have a longer 12-week studies in our other approved drug, brexpiprazole, 2 or 3 milligrams, so there's a little difference in dosing based on these studies, but that did show a least squares mean change of 3.8 to 5.3 points compared to placebo, depending on the study you looked at and the dose. In clinical context, as another indirect comparison, a 2024 study showed that a meaningful within-patient change in CMAI is somewhere between 15 to 25 points, so you know we have a mean difference from placebo of 3.3, maybe up to 5.3 and Rexulti, where a meaningful within patient change is somewhere between 15 to 25 points. This is…it’s such a touchy area, because agitation is something that is sometimes subjective, and sometimes you want to do anything you can.

So, I have conflicting thoughts on this. Millad, what are your thoughts?

Sobhanian: I’m right there with you. I think this is really why we really want to make sure that we're looking at all of the tools in our tool belts, right? Relying on those nonpharmacologic interventions first, educating the caregivers and the provider to identify [and] recognize what agitation looks like, and then is this because of some other reason? Are they hungry? Is there a change in their schedule or routine? Do they have a [urinary tract infection] that needs to be treated?

These medications shouldn't be what we reach for first, because, as you rightfully pointed out, the outcomes aren't particularly robust. But it's something, right? And if we've gone through all of the treatment options, and know there are risks that we've already mentioned, like the risk of mortality with the antipsychotics, and even though brexpiprazole was not necessarily included in that analysis, it's still an atypical antipsychotic, so we can't ignore the risk that's there. And I mentioned, you know, the cardiovascular risk with the bupropion component of this combination product…

So, I think, you know…it just reinforces that idea [that] we should look at what we have first, and then work our way through the list, really.

REFERENCE

Marini E, Sobhanian M, McGovern G. Mind the Meds: Alzheimer Updates, Stroke Breakthroughs, and the Case for Early Treatment. Pharmacy Times. June 4, 2026. Accessed June 17, 2026. https://www.pharmacytimes.com/view/alzheimer-updates-stroke-breakthroughs-and-the-case-for-early-treatment