Beyond the Diagnosis: It's Time We Talk About What Surrounds It

It started earlier this week with a conversation that had nothing to do with a patient.

A pharmaceutical representative visited my resident clinic to discuss a medication that had just received FDA approval — not for Alzheimer's disease itself, but for one of its most disruptive and distressing symptoms: agitation. And as I listened, something clicked that I have been meaning to write about for a while. We spend so much of our energy in this area — and correctly so — talking about disease-modifying therapies, biomarkers, genetic risk, and prevention. But for the millions of families living with dementia right now, today, the most pressing questions are often not about amyloid plaque accumulation. They are about what to do at 4 o'clock in the afternoon when a loved one becomes inconsolable. About the pacing. The accusations. The frightening moments of anger that bear no resemblance to the person they have known for decades.

Agitation affects an estimated 70 to 76% of people with Alzheimer's disease at some point in their illness. It is one of the leading drivers of caregiver burnout and one of the most common precipitants of nursing home placement. And until very recently, the medicine cabinet for addressing it was surprisingly empty.

Why This Has Been Such a Hard Problem to Treat

Before we talk about what is available, it is worth understanding why this has been so difficult.

Agitation in dementia is not a single phenomenon. It encompasses restlessness, irritability, verbal outbursts, repetitive questioning, pacing, physical aggression, and the problem many caregivers know as sundowning — a reliable worsening of behavioral symptoms in the late afternoon and evening that can transform the end of every day into a crisis. The underlying neurobiological drivers are still being worked out, but the leading theories implicate dysregulation of glutamate signaling, serotonin pathways, and the brain's stress response circuitry — all of which are disrupted by the progressive neurodegeneration of Alzheimer's.

For years, the clinical default was to reach for antipsychotic medications — quetiapine, risperidone, olanzapine — despite the fact that none of them carry FDA approval for this indication and all of them carry a black box warning in elderly patients with dementia-related psychosis, reflecting a documented increase in mortality risk with their use. They were not good options. They were the only options that most clinicians had.

The New Pharmacological Landscape

That has now changed meaningfully, with two FDA-approved medications arriving in the last two years.

Brexpiprazole (Rexulti) became the first FDA-approved treatment specifically for agitation associated with Alzheimer's disease in 2023. It is an atypical antipsychotic — though it works through a somewhat different receptor profile than older agents in that class, with partial agonism at dopamine D2 receptors and serotonin 5-HT1A receptors rather than full blockade. In its Phase 3 trials, brexpiprazole showed statistically significant reductions in agitation scores compared to placebo on the Cohen-Mansfield Agitation Inventory, the standard clinical measurement tool. It was a genuine advance — the first time the FDA had formally recognized agitation in Alzheimer's as a treatable indication — though clinical experts noted that the effect size was modest and roughly comparable to other antipsychotics used off-label. It still carries mortality risk warnings applicable to its class.

Dextromethorphan-bupropion (Auvelity) received FDA approval for Alzheimer's-related agitation on April 30, 2026, and it represents a meaningful departure from everything that came before it. This is the first non-antipsychotic treatment ever approved for this indication — and that distinction matters clinically.

Auvelity was originally approved in 2022 for major depressive disorder. The combination works through a completely different mechanism than antipsychotics: dextromethorphan acts on NMDA receptors and sigma-1 receptors — the same glutamate-related pathways implicated in agitation neurobiology — while bupropion serves primarily to increase dextromethorphan's bioavailability by inhibiting its metabolism. The FDA approval was supported by two Phase 3 trials. ADVANCE-1 demonstrated statistically significant improvement in agitation at five weeks compared to placebo. ACCORD-2, a randomized withdrawal design, found that patients who continued Auvelity experienced significantly lower relapse rates than those switched to placebo — 8.4% versus 28.6% — and a meaningfully longer time to symptom return.

Importantly, the tolerability profile appears favorable in a population where tolerability is everything. Discontinuation rates due to adverse events were low and comparable to placebo in long-term evaluation. The most common side effects were dizziness, headache, diarrhea, and somnolence. And unlike brexpiprazole and other antipsychotics, Auvelity does not appear to carry an increased mortality risk in elderly dementia patients — a critical distinction for this population.

It would be intellectually dishonest not to note that the clinical trial data has some complexity. ADVANCE-2, a subsequent five-week parallel-group trial, did not meet its primary endpoint, and some clinical experts have characterized the overall effect as mild to modest. These are fair observations. But mild to modest improvement in a condition with almost no safe alternatives — and no mortality signal — represents a meaningful clinical option, particularly for families who have been managing agitation with nothing or with medications that are genuinely dangerous.

What Medications Cannot Do Alone

Here is where I want to step back from the pharmacology entirely, because the evidence is unambiguous about something that gets too little attention in clinical practice: non-pharmacological interventions are not a consolation prize for families waiting on a prescription. They are first-line treatment, supported by a robust and consistent research literature.

A 2025 systematic review published in the International Journal of Emergency Medicine analyzed pharmacological and non-pharmacological interventions for dementia agitation and found that non-pharmacological approaches demonstrated promising results in reducing agitation — with the critical advantage of doing so without adverse effects. In a population where every medication carries tradeoffs, that is not a minor point.

The interventions with the strongest evidence base are more accessible than most families realize.

Music. This is the one I return to most often with families because the research is so consistent and the implementation is so simple. Individualized music — meaning music personally meaningful to the patient, from their own history — has been shown across multiple randomized controlled trials to reduce agitation, anxiety, and distress in people with dementia. A 2024 BMC Psychiatry study found that twenty minutes of individualized music listening every other day, delivered by family caregivers at home via a simple app, produced meaningful improvements in behavioral symptoms. The mechanism likely involves preserved emotional memory circuits — music reaches parts of the brain that dementia spares longer than almost anything else.

Structured routine and environmental modification. Agitation is frequently triggered by unmet needs — pain, hunger, overstimulation, disorientation, fear — that the person can no longer articulate. A predictable daily structure, reduced environmental noise and visual clutter, adequate lighting (particularly during the late afternoon sundowning window), and consistent caregiver presence dramatically reduce the frequency of agitation episodes in many patients. These are not soft interventions. They are evidence-based strategies that work.

Caregiver communication training. How a caregiver responds to an agitated patient either de-escalates or amplifies the episode. Validation therapy — meeting the patient in their emotional reality rather than correcting or redirecting — has demonstrated efficacy in reducing distress in multiple studies. Simple techniques: lower voice, slow approach, physical proximity, brief sentences, and asking rather than directing. These skills can be taught, practiced, and improved, and be genuinely transformative for families navigating these moments daily.

A Word About the People Behind the Care

I want to say something directly that does not make it into enough clinical conversations.

The families managing agitation at home — the spouses who have not slept through the night in months, the adult children managing their own jobs and children while fielding calls about a parent's evening episodes — are doing something that deserves explicit acknowledgment. Caregiver burnout is not a personal failing. It is the predictable result of a sustained, invisible, uncompensated labor that our healthcare system vastly under-resources.

Agitation is one of the primary drivers of caregiver exhaustion. It is personal in a way that other symptoms often are not — the anger is directed at people who love the patient most. Understanding that agitation is neurological, not intentional, is not just clinically useful. It is psychologically protective for the families living through it.

If you are a caregiver reading this and you are exhausted: that is not weakness. That is what happens when a human being tries to absorb what this disease puts on the people closest to it. The goal of everything discussed in this post — the medications, the music, the structured routines — is not only to help the patient. It is to make your days survivable as a caregiver.

Takeaways

Agitation affects up to 76% of people with Alzheimer's disease and is one of the leading causes of caregiver burnout and nursing home placement. It deserves the same clinical attention we give to cognitive symptoms.

Two FDA-approved medications now exist specifically for this indication. Brexpiprazole (Rexulti), approved in 2023, was the first. Dextromethorphan-bupropion (Auvelity), approved April 2026, is the first non-antipsychotic option — with a different mechanism, favorable tolerability, and no mortality signal.

Non-pharmacological interventions are first-line, not fallback. Individualized music, structured routine, environmental modification, and caregiver communication training have consistent evidence behind them and no adverse effects. They should be implemented before, alongside, and sometimes instead of medication.

Caregivers are the invisible infrastructure of dementia care. Supporting them — with information, with language, with validated strategies — is not ancillary to treatment. It is treatment.

Citations and References

FDA Press Release. FDA Approves First Non-Antipsychotic Drug to Treat Agitation Associated with Dementia. April 30, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-antipsychotic-drug-treat-agitation-associated-dementia

Psychiatric Times. FDA Approves Auvelity for Treatment of Agitation in Alzheimer Disease. May 2026. https://www.psychiatrictimes.com/view/fda-approves-auvelity-for-treatment-of-agitation-in-alzheimer-disease

Grossberg G, et al. Treatment of agitation in dementia — a systematic review. International Journal of Emergency Medicine. 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12105158/

Jakob E, et al. Randomized controlled trial of an individualized music intervention for people with dementia in the home care setting. BMC Psychiatry. 2024. https://doi.org/10.1186/s12888-024-05697-0

Kales HC, et al. Evidence-Based Nonpharmacological Practices to Address Behavioral and Psychological Symptoms of Dementia. The Gerontologist. 2019. https://doi.org/10.1093/geront/gny167