New Medications for Agitation in Alzheimer's: Brexpiprazole and Auvelity Explained

Summary: Two FDA-approved medications now treat agitation in Alzheimer's disease specifically — brexpiprazole (Rexulti), approved May 2023, and Auvelity (dextromethorphan/bupropion), approved April 30, 2026. Both produce statistically significant but modest improvements in agitation severity, with differing side effect profiles. Non-pharmacological approaches remain first-line in nearly all cases.

Agitation is one of the most distressing symptoms of Alzheimer's disease — both for the person experiencing it and for the caregiver living with it. It is also one of the most common reasons for emergency department visits, psychiatric hospitalizations, and early placement in memory care facilities. For decades, physicians treated dementia-related agitation with medications borrowed from other conditions — antipsychotics designed for schizophrenia, antidepressants designed for depression, sometimes benzodiazepines despite their known risks in older adults. None of these were specifically approved for dementia agitation, and the safety profile was often imperfect.

Two newer prescription medications now have specific FDA attention for this indication: brexpiprazole (Rexulti) and Auvelity (a combination of dextromethorphan and bupropion). This article walks through what each does, the trial evidence, the side effect profile, and where they fit in the broader picture of agitation care. Content reflects the discussion of biological advances in Alzheimer's disease at the American Psychiatric Association 2026 Annual Meeting.

This is not a replacement for the conversation with the clinician managing your family member's care. It is meant to help you understand what's being offered and what questions to ask.

What dementia-related agitation actually is

Agitation in Alzheimer's is more than ordinary frustration. Clinically, it can include:

• Verbal aggression — yelling, cursing, repetitive vocalizations
• Physical aggression — hitting, pushing, biting, throwing objects
• Motor restlessness — pacing, repetitive movements, inability to sit
• Resistance to care — refusing bathing, dressing, eating, medications
• Property destruction
• Wandering with apparent purposeful intent

These behaviors are categorized clinically using tools like the Cohen-Mansfield Agitation Inventory (CMAI) — the scale used in the trials we'll discuss. The CMAI captures frequency and severity across multiple agitation behaviors, and changes in CMAI total score are how trial efficacy is typically measured.

Importantly, agitation in dementia is usually communicating something. Pain, infection, dehydration, constipation, sleep disruption, sensory deficits, medication side effects, fear, and unmet emotional needs are all common triggers. Our agitation and aggression symptom page covers this in more detail.

Why these medications exist

Until recently, every medication used for agitation in Alzheimer's was off-label — meaning not specifically approved for this use, even though doctors prescribed them. The most common were typical and atypical antipsychotics (haloperidol, risperidone, quetiapine, olanzapine), SSRIs (citalopram, sertraline), and sometimes anticonvulsants like valproate.

The problem: antipsychotics in older adults with dementia carry an FDA black box warning for increased mortality. The risks are real — strokes, falls, sudden cardiac events, and worsening cognition. Yet clinicians often had little choice when agitation was severe and non-medication approaches were not enough.

Brexpiprazole and Auvelity represent the first medications studied specifically for this indication, with trials enrolling patients with Alzheimer's-related agitation rather than psychiatric populations.

Brexpiprazole (Rexulti)

What it is

Brexpiprazole is an atypical antipsychotic originally approved for schizophrenia and as an adjunctive treatment for major depressive disorder. Its mechanism is complex — it acts on dopamine and serotonin receptors as a partial agonist. In 2023, the FDA approved brexpiprazole for the treatment of agitation associated with Alzheimer's disease, making it the first medication with this specific indication.

The pivotal trial

Study 331-14-213 randomized 345 patients with dementia of the Alzheimer's type and clinically significant agitation (CMAI Factor 1 aggressive agitation at baseline) in a 2:1 ratio to either brexpiprazole 2 mg or 3 mg per day, or placebo. Dosing was titrated gradually over the first month: 0.5 mg for the first week, 1 mg for the second week, 2 mg for the next two weeks, then either 2 mg or 3 mg for the remainder of the 12-week double-blind treatment period.

Results on the primary endpoint:

• Brexpiprazole: -22.6 point reduction in CMAI total score from baseline (LS mean, SE 1.08)
• Placebo: -17.3 point reduction (LS mean, SE 1.44)
• Treatment difference: -5.32 (95% CI -8.77 to -1.87), p=0.0026

The Clinical Global Impression-Severity (CGI-S) scale, a secondary outcome measuring overall agitation severity, also favored brexpiprazole (-1.22 vs -0.93 on placebo, p=0.0055).

What the numbers mean in practice

A 5-point treatment difference on the CMAI is statistically significant and clinically detectable, though not dramatic. Patients on brexpiprazole continued to experience some agitation; the medication reduced its severity and frequency rather than eliminating it. Most of the improvement appeared by week 6-8, with continued benefit through week 12.

Side effects and safety

In the 12-week trial:

• Any adverse event: 44% of brexpiprazole patients vs 32% of placebo patients
• Serious adverse events: 2.7% brexpiprazole vs 2.6% placebo
• Discontinuation due to adverse events: 5.3% brexpiprazole (1.4% on 2 mg, 7.2% on 3 mg) vs 4.3% placebo
• Patient deaths: 1 death in the 3 mg brexpiprazole group, 0 in the 2 mg group, 0 in placebo

The death occurred 51 days from the first dose and 24 days from the last dose, in a patient with events of heart failure, pneumonia, and cachexia. Autopsy revealed cerebral and coronary atherosclerosis. Investigators and the manufacturer concluded the death was unrelated to brexpiprazole, though as with any single death event, families and clinicians should weigh this in context.

The black box warning

Like all antipsychotics, brexpiprazole carries the FDA black box warning for increased mortality in elderly patients with dementia-related psychosis. This warning has been in place for all atypical antipsychotics since 2005 and reflects population-level data showing modestly increased risk of death from cardiovascular events and infections in elderly dementia patients treated with this class.

The warning does not preclude using these medications — sometimes the alternative (uncontrolled severe agitation, danger to self or others, exhaustion of caregivers) carries its own risk. But families should be informed that this warning applies.

Cost and practical issues

Brexpiprazole is a branded medication with no current generic equivalent. Cost varies significantly by insurance, with cash prices often exceeding $1,000 per month at standard retail pharmacies. Insurance prior authorization is typically required.

Auvelity (dextromethorphan and bupropion)

What it is

Auvelity is a fixed-dose combination of dextromethorphan (the cough-suppressant compound also used in some psychiatric indications for its NMDA-modulating effects) and bupropion (an antidepressant that also acts as a CYP2D6 inhibitor, slowing the breakdown of dextromethorphan to maintain therapeutic levels).

Originally approved by the FDA for major depressive disorder, Auvelity has been studied specifically for agitation in Alzheimer's disease. Its mechanism in this indication is believed to involve NMDA receptor modulation and effects on noradrenergic and dopaminergic pathways, though the exact mechanism for agitation reduction is still being characterized.

The ADVANCE-1 trial

ADVANCE-1 was a Phase 2/3 randomized, double-blind, placebo-controlled study evaluating Auvelity (45 mg dextromethorphan / 105 mg bupropion twice daily) in patients with Alzheimer's-related agitation. After screening, 366 patients were randomized across three arms:

• Auvelity (AXS-05): n=152
• Bupropion alone (105 mg BID): n=49
• Placebo: n=158

The bupropion-alone arm served to demonstrate that the dextromethorphan component contributes to the effect.

Primary endpoint — change in CMAI total score at Week 5:

• Auvelity: -14.9 points
• Bupropion alone: -8.0 points
• Placebo: -11.6 points

Auvelity demonstrated statistical superiority to both placebo (p=0.010) and bupropion alone (p value less than 0.001), confirming that the combination's effect is greater than either component would produce on its own at standard doses.

The ACCORD-2 trial

ACCORD-2 was a Phase 3 randomized withdrawal study designed to demonstrate maintenance of effect. Eligible patients were 65-90 years old with probable Alzheimer's disease, agitation symptoms, MMSE between 10 and 24, and NPI-AA score ≥4. After at least 8 weeks of open-label Auvelity treatment, responders were randomized 1:1 to continue Auvelity (n=83) or switch to placebo (n=84) for up to 24 weeks of double-blind follow-up.

Primary endpoint — time to relapse of AD agitation:

• Hazard ratio: 0.276 (Auvelity vs placebo)
• This translates to a 3.6-fold lower risk of relapse with continued Auvelity treatment
• Two-sided p-value from log-rank test: 0.001

In plain language: patients who responded to Auvelity and then continued treatment were much less likely to have their agitation return than those who responded and were then switched to placebo. The trial therefore supports both initial response and ongoing prevention of relapse.

Side effects and safety

ACCORD-2 safety data:

• Treatment-emergent adverse events: 29.3% Auvelity vs 32.1% placebo
• Serious TEAEs: 0% Auvelity vs 2.4% placebo
• Discontinuation due to TEAEs: 0% Auvelity vs 1.2% placebo
• TEAEs in ≥3% of Auvelity patients: anemia (3.7%), headache (3.7%), hyperkalemia (3.7%), somnolence (3.7%)
• Falls: 2 patients on Auvelity (2.4%), only 1 deemed related
• Cognitive decline (measured by MMSE): not observed
• Sedation: not observed
• Deaths: none in either group

This is a notably favorable safety profile compared to typical antipsychotics in this population. The absence of significant sedation and the lack of measurable cognitive decline are particularly important — sedation has historically been one of the main reasons antipsychotics worsen quality of life in patients with dementia.

It should be noted that Auvelity, like all medications in this population, has not yet accumulated the decades of post-marketing safety data that allow us to fully characterize rare adverse events. Longer follow-up and broader real-world experience will continue to refine the safety picture.

Comparing brexpiprazole and Auvelity

Without head-to-head trials, comparisons are indirect. Key differences worth understanding:

Mechanism

• Brexpiprazole: Dopamine and serotonin receptor modulation (atypical antipsychotic class)
• Auvelity: NMDA receptor modulation plus noradrenergic/dopaminergic effects (not in the antipsychotic class)

Effect size

The trials used different durations and patient populations, so direct numerical comparison is imperfect. Both show a treatment effect over placebo that is statistically significant and clinically detectable, though neither produces dramatic improvement.

Side effect profile

• Brexpiprazole: Carries the antipsychotic class black-box warning; sedation, motor side effects (extrapyramidal symptoms), metabolic effects, and the small but documented mortality signal are concerns
• Auvelity: More favorable side effect profile in the trials so far; no observed sedation, no measurable cognitive decline; longer-term safety still being accumulated

Practical considerations

• Cost: Both are branded; insurance coverage varies; both typically require prior authorization
• Dosing: Brexpiprazole is titrated slowly; Auvelity has a fixed-dose schedule
• Drug interactions: Both interact with several common medications; clinician review is required

Who might be appropriate for each

These are general considerations — the actual prescribing decision belongs to the clinician treating the patient:

• Brexpiprazole may be considered when: agitation has a psychotic feature (hallucinations, delusions); the patient has previously tolerated other antipsychotics; the family understands and accepts the antipsychotic class risks
• Auvelity may be considered when: agitation is the primary feature without prominent psychosis; sedation needs to be avoided; the patient is on medications that limit antipsychotic options; the family prefers to avoid an antipsychotic if possible

In either case, the medication should not be the first intervention.

Why non-medication approaches come first

The clearest message from the APA 2026 talk was that non-pharmacological interventions are the first-line treatment for agitation in Alzheimer's disease in nearly all cases. This is also what the American Psychiatric Association's clinical guidelines reflect.

The reasons:

• Most agitation has a treatable underlying cause — pain, infection, urinary tract infection (notoriously presenting as agitation in older adults), constipation, dehydration, sleep disruption, sensory deficits (uncorrected vision or hearing loss), medication side effects, or unmet emotional needs
• Environmental and communication interventions often work — reducing overstimulation, maintaining consistent routines, using calm and simple communication, validating emotions without arguing about facts
• Medications carry real risks in older adults with dementia, even the newer ones
• Caregiver support is often as important as the patient's medication

The DICE framework

A widely used systematic approach is the DICE framework, developed by Kales, Lyketsos, and Gitlin:

• D — Describe: The caregiver describes the behavior in detail — context, who is present, what happened just before, what helped, what made it worse, and the degree of distress to patient and caregiver
• I — Investigate: The clinician investigates possible causes — medication side effects, pain, functional limitations, medical conditions, psychiatric comorbidity, sleep, sensory issues, caregiver factors, environment
• C — Create: The provider, caregiver, and team collaborate to create and implement a treatment plan — addressing physical problems, behavioral interventions, caregiver education, communication strategies, meaningful activities, environmental adjustments
• E — Evaluate: The clinician evaluates whether the interventions are working and adjusts as needed

This framework should generally be applied before medication is added, except when imminent harm to the patient or others requires faster pharmacological intervention.

Our caring for someone with dementia at home post covers many of the practical strategies that fall under the C step.

Medications that are NOT first-line for agitation

It is worth saying out loud which medications are commonly used but should generally be avoided or used cautiously in this population:

• Benzodiazepines (lorazepam, diazepam, alprazolam, clonazepam) — worsen cognition, increase fall risk, and can cause paradoxical agitation. Avoid as standing therapy.
• First-generation antipsychotics (haloperidol) — particularly risky in Lewy body dementia and Parkinson's disease dementia; even in pure Alzheimer's, generally considered worse-tolerated than atypicals
• Anticholinergic medications — worsen cognition, may precipitate or worsen agitation
• Sedating antihistamines (diphenhydramine) — both anticholinergic and sedating; particularly problematic in older adults

The Beers Criteria, published by the American Geriatrics Society and updated regularly, lists medications that are potentially inappropriate in older adults. Many medications historically used for agitation appear on this list.

What to ask the clinician

If a clinician is considering one of these medications for a family member with Alzheimer's-related agitation, productive questions include:

• Have we tried non-pharmacological approaches first? What specifically has been tried?
• Have we ruled out treatable contributors? Pain, infection (especially UTI), constipation, sleep disturbance, medication side effects, sensory issues
• Why this specific medication for this specific patient? What are the alternatives?
• What are the realistic goals? Complete resolution is uncommon — what reduction in agitation would constitute success?
• What side effects should we watch for? What should prompt us to call?
• For brexpiprazole specifically: How does the antipsychotic class mortality warning apply here? What's the plan if side effects occur?
• For Auvelity specifically: What's known about longer-term use? How will we know if it's working?
• How will we measure response? Often this is the CMAI or simple caregiver ratings of frequency and severity
• What's the plan if it doesn't work? Discontinuation criteria, alternative medications, escalation pathway
• What's the plan if it does work? Duration of treatment, plan to taper or continue indefinitely

A note for caregivers

If your family member is experiencing agitation severe enough that medication is being considered, you are not alone. This stage of dementia is exhausting in a way that's hard to describe to people who haven't been through it. Several things worth knowing:

The medications discussed here are imperfect. Both produce statistically meaningful but modest improvements. They are not cures for agitation. Realistic expectations help.

The non-medication strategies matter even when medications are added. Medications work better when underlying triggers are addressed and the environment supports the patient.

Caregiver support is part of the treatment. The APA 2026 presenters were explicit about this: in their case examples, treating the caregiver's own depression and exhaustion was often as important as treating the patient's symptoms. See our posts on caregiver burnout and anticipatory grief.

Sometimes the right answer is more help, not more medication. Adult day programs, in-home aides, respite care, and eventually memory care placement are sometimes more effective at reducing agitation (and protecting both patient and caregiver) than any pharmacological intervention. Our memory care vs nursing home post covers this transition.

Severe agitation is sometimes a medical emergency. If a patient is at imminent risk of harming themselves or someone else, an urgent psychiatric evaluation (often in an emergency department or geriatric psychiatry inpatient unit) is appropriate. This is not failure on your part — it is using the right level of care.

Closing

Brexpiprazole and Auvelity represent meaningful progress — two medications studied specifically for the agitation that has been the most distressing dimension of Alzheimer's disease for many families. They are not cures. They work modestly, in combination with non-pharmacological care, and they carry side effects that families should understand.

The bigger picture is that agitation in Alzheimer's is treatable. With a careful clinician, attention to non-pharmacological strategies first, and judicious medication when those are not enough, most patients can be helped. Both the patient and the caregiver deserve that effort.

If your family member's agitation is severe and you are not getting adequate help, ask for a referral to a geriatric psychiatrist or behavioral neurologist. These specialists do this work daily and often have approaches the general internist or family doctor may not be familiar with.

Related reading

• Dementia Medications: What Actually Helps, Explained
• Caring for Someone With Dementia at Home
• Alzheimer's Disease: A Complete Guide for Patients and Families
• Caregiver Burnout in Dementia
• Memory Care vs Nursing Home vs Assisted Living
• Lecanemab and Donanemab: A Patient's Guide

Related symptoms

• Agitation and aggression in dementia
• Mood and personality changes
• Paranoia and false beliefs in dementia
• Sleep changes in dementia
• Refusing help

References

• Anderson AA, Aga VM. Biological Advances in Alzheimer's Disease. Annual Meeting of the American Psychiatric Association, San Francisco, May 20, 2026.
• Aga VM. Brexpiprazole for the Treatment of Agitation in Alzheimer's Disease Dementia: Clinical Uncertainties and the Path Forward. American Journal of Geriatric Psychiatry. 2025;33(3):322-329.
• Lee D, Slomkowski M, Hefting N, et al. Pivotal Phase 3 trial of brexpiprazole for agitation associated with Alzheimer's disease (Study 331-14-213).
• Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. (background on dextromethorphan in AD agitation)
• ADVANCE-1 (Addressing Dementia via Agitation-Centered Evaluation 1; NCT03226522). Phase 2/3 trial of AXS-05 in Alzheimer's-related agitation.
• ACCORD-2 (NCT04947553). Phase 3 randomized withdrawal study of AXS-05 in Alzheimer's-related agitation.
• Kales HC, Gitlin LN, Lykestos CG. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. Journal of the American Geriatrics Society. 2014;62(4):762-769.
• American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.

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Disclosure: Dr. Shimada is the founder of Tokei Health. This article is informational and is not a substitute for individual medical advice from your own clinician. The data and presentation summary here reflect content presented by Drs. Allan A. Anderson and Vimal M. Aga at the American Psychiatric Association 2026 Annual Meeting, with additional context from cited published sources. Verify drug approval status and prescribing information with current FDA labeling.