Beyond Off-Label: How Auvelity's Approval Changes Agitation Management in Alzheimer Disease

Agitation is one of the most common and disruptive behavioral symptoms of Alzheimer disease, affecting patient safety, caregiver burden, and quality of life; however, for years, health care professionals have had to rely on off-label medications with limited evidence and meaningful risks in older adults.

In this interview with Pharmacy Times, Robert Leffler, RPh, BCSP, FASCP, president of the American Society of Consultant Pharmacists, discusses how the recent FDA approval of dextromethorphan/bupropion (Auvelity; Axsome Therapeutics), the first nonantipsychotic therapy indicated specifically for agitation associated with Alzheimer disease, marks a significant shift in the treatment landscape. Leffler walks through how agitation presents clinically, the safety considerations pharmacists weigh most heavily in this population, and what the timing and durability of treatment response mean for patients and caregivers. He also addresses the practical realities of access and affordability, and offers guidance on patient selection, counseling, and monitoring as pharmacists help integrate this new therapy into person-centered, evidence-based care.

Pharmacy Times: What is agitation associated with Alzheimer disease, how does it present clinically, and why is it such a challenging symptom for patients, caregivers, and health care providers?

Robert Leffler, RPh, BCSP, FASCP: Agitation associated with Alzheimer disease is one of the behavioral and psychological symptoms we commonly see. Clinically, I think about agitation in 4 broad categories: verbally aggressive, physically aggressive, verbally nonaggressive, and physically nonaggressive behaviors. The aggressive symptoms are often easier to recognize (eg, verbal outbursts, threatening language, or hitting), [and] the nonaggressive symptoms can be easier to miss, but they may include repetitive questioning, complaining, restlessness, pacing, or wandering.

It is important to note that agitation is not limited to advanced disease. Studies have shown that it can occur even in patients with mild Alzheimer disease. Because it presents in so many different ways, it does not look the same in every patient. That variability is one reason agitation is so challenging. The patient may be experiencing fear, confusion, pain, or frustration, but may not be able to express that clearly.

Caregivers are working to keep patients safe while also trying to manage disrupted sleep, emotional stress, and day-to-day care needs. At the same time, health care providers are trying to understand what is behind the behavior to rule out reversible causes and determine when medication is appropriate. So while cognitive decline is often the most visible feature of Alzheimer disease, agitation can become one of the symptoms that most affects quality of life, caregiver burden, and safety.

Pharmacy Times: Despite its prevalence in Alzheimer disease, agitation has historically been challenging to treat. What are some limitations of current pharmacologic approaches, particularly given that many therapies have traditionally been used off-label?

Leffler: Treatment has historically been difficult because, for many years, we did not have FDA-approved medications specifically indicated for agitation associated with Alzheimer disease. Clinicians often used antidepressants, anxiolytics, sedative hypnotics, anticonvulsants, or antipsychotics off-label in an effort to reduce symptoms. The challenge is that these approaches have varying levels of evidence, may not address the underlying drivers of agitation, and can introduce meaningful risks in older adults, including sedation, falls, cognitive worsening, drug interactions, and other adverse effects [AEs]. Having therapies specifically studied and approved for this indication gives clinicians more evidence-based options rather than relying primarily on extrapolation from other conditions.

Pharmacy Times: Dextromethorphan/bupropion is the first nonantipsychotic medication approved for agitation associated with Alzheimer disease. How significant is this milestone, and what does it represent for pharmacists caring for this patient population?

Leffler: This is a very significant milestone because it gives clinicians another medication specifically studied and approved for agitation associated with Alzheimer disease. For years, we relied heavily on off-label pharmacotherapies, [hoping] they would help while minimizing risk. Approval of medications specifically for this indication helps validate agitation as a distinct and important therapeutic target, not simply an unavoidable consequence of dementia.

For pharmacists, it adds another evidence-based option to consider and supports more individualized treatment decisions, especially when balancing potential benefits against risks such as sedation, falls, cognitive effects, cardiovascular concerns, and drug interactions.

Pharmacy Times: Safety is always a major consideration when treating older adults with Alzheimer disease. What safety factors do pharmacists weigh most carefully when evaluating therapies for agitation, and how might those considerations influence treatment selection?

Safety is always central when we are treating older adults with dementia. Pharmacists routinely evaluate fall risk, sedation, potential cognitive worsening, cardiovascular effects, sleep disruption, anticholinergic burden, renal and hepatic function, drug interactions, seizure risk, and overall polypharmacy. Those considerations influence whether a therapy is appropriate, how it should be dosed, what monitoring is needed, and whether nonpharmacologic strategies or alternative approaches should be prioritized. In this population, the safest choice is rarely based on efficacy alone—it depends on the patient’s comorbidities, current medication regimen, functional status, caregiver support, and goals of care.

Pharmacy Times: Clinical trial data for dextromethorphan/bupropion demonstrated improvements in agitation beginning around 5 weeks that were sustained over time. From a clinical standpoint, how meaningful is the timing and durability of response when managing these patients?

Leffler: Both timing and durability matter clinically. For caregivers, every week can feel significant when agitation is disrupting sleep, safety, or daily care. Improvement around 5 weeks gives us a realistic timeframe for setting expectations and assessing whether the therapy is beginning to help. Durability is just as important because agitation is rarely a short-term issue. If a therapy can provide sustained benefit over time, that helps clinicians and caregivers weigh the value of continuing treatment against monitoring needs, AE risk, treatment burden, and cost.

Pharmacy Times: Beyond clinical efficacy and safety, access and affordability often influence treatment decisions. What role do pharmacists play in helping patients and caregivers navigate formulary coverage, prior authorizations, and overall medication value?

Leffler: Pharmacists are often the resource patients and caregivers rely on when access becomes complicated. We can help assess formulary coverage, clarify prior authorization requirements, support documentation of medical necessity, connect patients with manufacturer support or patient assistance resources, evaluate therapeutic alternatives when coverage is limited, and communicate with prescribers and care teams about medication value. That role is especially important in Alzheimer disease because caregivers may already be managing a complex care plan, and delays or confusion around coverage can become a real barrier to timely treatment.

Pharmacy Times: Dextromethorphan/bupropion has been available previously for major depressive disorder, and it has now expanded into the Alzheimer disease space. How might pharmacists think differently about the medication when considering its role in agitation associated with Alzheimer disease vs its use in depression?

Leffler: The medication is the same, but the clinical goal is different. In major depressive disorder, we are focused on improving mood, depressive symptom severity, function, and overall quality of life. In agitation associated with Alzheimer disease, the goal is to reduce the frequency, severity, and distress associated with agitation episodes and improve day-to-day interactions among patients, caregivers, and the care team. Pharmacists also need to think differently about monitoring because patients with Alzheimer disease may be older, more medically complex, more likely to have polypharmacy, and less able to reliably report AEs or improvement.

Pharmacy Times: As pharmacists become more familiar with newly approved therapies, what guidance would you offer regarding patient selection, counseling, monitoring, and collaboration with caregivers and the broader health care team?

Leffler: The first step is to make sure the agitation is actually associated with Alzheimer disease and not another potentially reversible cause, such as pain, infection, constipation, environmental triggers, medication AEs, or unmet needs. Once those contributors have been considered, treatment decisions should be person-centered and aligned with the patient’s goals, function, safety, and overall quality of life.

Pharmacists can help by reviewing the medication profile, identifying interactions and high-risk medications, counseling caregivers on what improvement may look like, setting realistic expectations for onset of benefit, and recommending monitoring for effectiveness, AEs, falls, sleep changes, appetite, behavior patterns, and overall function. Collaboration with caregivers, prescribers, nursing staff, and the broader care team is essential because they often provide the most reliable day-to-day observations.

Pharmacy Times: Looking ahead, how do you think the treatment landscape for agitation associated with Alzheimer disease will evolve, and how will pharmacists ensure that patients receive safe, evidence-based care?

Leffler: We have entered a new phase in the treatment of agitation associated with Alzheimer disease. We are no longer relying only on off-label medications for symptom management; we now have therapies specifically studied and approved for this indication. I think the landscape will continue moving toward more targeted symptom management, better integration of nonpharmacologic and pharmacologic approaches, and a stronger focus on outcomes that matter to patients and caregivers.

Pharmacists will be critical in that evolution. As medication experts, we can evaluate emerging evidence, optimize treatment selection, prevent prescribing cascades, monitor outcomes, and help ensure these therapies are used safely and appropriately.