The best way to reduce agitation in Alzheimer’s disease is to start with non-drug approaches—specifically identifying and addressing underlying triggers—before considering medication. Expert consensus in 2025 treatment guidelines is clear: nonpharmacological strategies should be the first line of defense. This means investigating whether the person is experiencing pain, an undiagnosed infection, constipation, or environmental discomfort like being too hot or cold. For example, a patient who becomes agitated every afternoon might actually be responding to unmanaged arthritis pain that worsens as the day progresses, and treating that pain can resolve the behavioral symptoms entirely.
When non-drug approaches aren’t sufficient for severe cases, there is now an FDA-approved medication option. On May 11, 2023, brexpiprazole (Rexulti) became the first drug specifically approved to treat agitation in Alzheimer’s disease—a significant milestone given that agitation affects between 36.5% and 76% of Alzheimer’s patients depending on disease stage. However, this medication carries serious warnings and is reserved for situations where behavioral interventions have failed. This article explores the full spectrum of evidence-based approaches to managing agitation, from music therapy and personalized interventions to the latest pharmaceutical developments. We’ll examine what the research actually shows about effectiveness, the limitations of current treatments, and what’s coming through the drug development pipeline in 2025.
Table of Contents
- Why Is Agitation So Common in Alzheimer’s Patients?
- Non-Drug Interventions: What the Evidence Actually Shows
- The Role of Brexpiprazole: First FDA-Approved Treatment
- Identifying and Treating Underlying Causes
- What’s in the Drug Development Pipeline?
- Practical Strategies for Caregivers
- When Professional Help Becomes Essential
- Looking Ahead: Evolving Standards of Care
Why Is Agitation So Common in Alzheimer’s Patients?
Agitation in Alzheimer’s disease isn’t a personality flaw or a choice—it’s a neurological symptom reflecting changes in the brain combined with an inability to communicate needs effectively. Current data suggests that 60% of patients with mild cognitive impairment experience agitation, and that figure climbs to 76% among those with diagnosed Alzheimer’s disease. In 2023, approximately 5.23 million diagnosed cases of agitation linked to Alzheimer’s were documented in the United States alone. The high prevalence stems from multiple factors converging. Damage to brain regions that regulate emotion and impulse control makes patients more reactive to stimuli. Meanwhile, cognitive decline makes it increasingly difficult to express discomfort verbally.
A person who used to say “I have a headache” might now only be able to communicate that distress through restlessness, pacing, or verbal outbursts. This creates a fundamental challenge for caregivers: the agitation is often a symptom of something else entirely. Understanding this distinction matters because treatment approaches differ dramatically based on the underlying cause. Agitation triggered by an untreated urinary tract infection requires antibiotics, not sedation. Restlessness caused by boredom in someone used to an active lifestyle calls for engagement, not medication. The first step in any effective intervention is detective work.
Non-Drug Interventions: What the Evidence Actually Shows
Current treatment guidelines from 2025 recommend a multidisciplinary approach that prioritizes nonpharmacological strategies before turning to medication. Among these approaches, music therapy has accumulated some of the strongest evidence. A systematic review published in BMC Geriatrics in 2025 examined multiple studies including a randomized trial with 976 nursing home residents that found personalized music interventions significantly reduced verbally agitated behaviors. The practical advantage of music-based interventions is accessibility.
Personalized or familiar music listening can reduce agitation even without a therapist present—meaning family caregivers can implement this approach at home using playlists of songs meaningful to their loved one from earlier decades of life. Other interventions with demonstrated effectiveness include massage, touch therapy, and structured exercise programs, though availability and cost vary significantly. However, caregivers should understand a significant limitation: effects across studies were often temporary. Music might calm someone during and shortly after listening, but the benefit may not persist throughout the day. This means non-drug approaches often need to be repeated, scheduled strategically around high-agitation periods, and combined with other strategies rather than treated as one-time solutions.
The Role of Brexpiprazole: First FDA-Approved Treatment
Brexpiprazole (Rexulti) represents a genuine advancement—it’s the first medication the FDA has ever approved specifically for agitation in Alzheimer’s disease, receiving approval on May 11, 2023. Clinical trials demonstrated that patients achieved a 31% greater reduction from baseline in frequency of agitation symptoms compared to placebo over 12 weeks. For families dealing with severe, persistent agitation that hasn’t responded to behavioral interventions, this offers a new option. For example, consider a patient whose agitation has escalated to the point where they’re becoming physically combative with caregivers, unable to be redirected, and at risk of injuring themselves or others.
When music therapy, environmental modifications, and treatment of potential underlying causes have all been tried without adequate improvement, brexpiprazole provides a targeted pharmacological tool that didn’t exist before 2023. That said, this medication carries a Boxed Warning—the FDA’s most serious safety alert—stating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Common side effects include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances. This isn’t a medication to use casually or as a first resort; guidelines explicitly reserve pharmacological interventions for severe cases where other approaches have proven insufficient.
Identifying and Treating Underlying Causes
Before attributing agitation to Alzheimer’s itself, clinicians and caregivers must investigate whether something treatable is driving the behavior. The 2025 treatment guidelines specifically highlight several common culprits: pain, infections (particularly urinary tract infections, ear infections, and sinus infections), constipation, and temperature discomfort. A practical example illustrates why this matters: an 82-year-old woman with moderate Alzheimer’s begins having episodes of increased agitation and aggression in the late afternoon. Her family assumes this is “sundowning”—a common pattern in dementia—and requests medication.
However, a thorough evaluation reveals she has an impacted bowel. Once the constipation is resolved, the afternoon agitation episodes stop entirely. No psychiatric medication was ever needed. The challenge is that patients with advancing Alzheimer’s often cannot articulate what’s wrong. They can’t say “my ear hurts” or “I’m too warm.” Caregivers need to become detectives, checking for signs of infection, ensuring adequate hydration, monitoring bowel regularity, and observing whether agitation correlates with specific times, places, or activities that might provide clues to the underlying trigger.
What’s in the Drug Development Pipeline?
Research into new treatments for Alzheimer’s-related agitation is active and expanding. As of 2025, 138 novel drugs are under evaluation in 182 clinical trials—a 9% increase from 2024. This suggests growing pharmaceutical interest in addressing behavioral symptoms, not just cognitive decline. Two combination therapy approaches are receiving particular attention. Six trials are currently assessing combinations of dextromethorphan and CYP2D6 inhibitors for agitation.
Separately, four trials are evaluating xanomeline plus trospium combination therapy. The rationale behind combination approaches is that targeting multiple pathways simultaneously may provide better efficacy or tolerability than single-agent therapy. The limitation here is timing—drugs in clinical trials take years to reach patients, and most candidates fail somewhere in the development process. For families dealing with agitation today, brexpiprazole remains the only FDA-approved option specifically for this indication. However, the pipeline activity suggests that better pharmacological tools may eventually become available, potentially with improved safety profiles or effectiveness for different patient populations.
Practical Strategies for Caregivers
Managing agitation effectively requires caregivers to think systematically rather than reactively. This means documenting patterns—when does agitation occur? What preceded it? What made it better or worse?—to identify individual triggers. It also means building a toolkit of interventions that can be deployed flexibly depending on the situation. Comparing approaches helps clarify tradeoffs.
Music therapy is low-cost, safe, and can be implemented immediately, but effects may be temporary and it requires knowing what music the person finds meaningful. Exercise programs provide broader health benefits beyond agitation reduction, but require physical capability and supervision. Touch and massage can be calming but may be rejected by some patients who find physical contact distressing as their disease progresses. Medication provides more sustained effects but carries real risks including that Boxed Warning about increased mortality. The practical reality is that most families end up using multiple approaches in combination—environmental modifications to reduce overstimulation, music during high-risk periods, attention to physical comfort needs, and medication reserved for breakthrough episodes or when other approaches have genuinely been exhausted.
When Professional Help Becomes Essential
Not every family can manage severe agitation safely at home, and recognizing that threshold matters. When agitation escalates to physical aggression that puts the patient or caregivers at risk of injury, or when episodes become so frequent that they preclude basic caregiving activities, professional intervention is warranted. This might mean consulting a geriatric psychiatrist for medication management, evaluating whether the current living situation is sustainable, or considering specialized memory care facilities with trained staff.
An example: a spousal caregiver is being hit and scratched during care tasks multiple times daily. Despite implementing music therapy, treating an identified UTI, and optimizing pain management, the aggressive episodes continue. At this point, the caregiver’s safety and wellbeing must factor into decision-making alongside the patient’s needs. A geriatric psychiatrist might recommend trialing brexpiprazole, or the family might explore memory care settings where staff are trained in managing behavioral symptoms and can provide care in shifts.
Looking Ahead: Evolving Standards of Care
The landscape of agitation treatment in Alzheimer’s disease is changing more rapidly than at any point in the past several decades. The 2023 approval of brexpiprazole was genuinely novel—before that, clinicians were using medications off-label with limited evidence and significant risk. The 9% year-over-year growth in clinical trials focused on this area suggests continued investment in finding better solutions.
What’s likely to evolve is our understanding of which patients benefit most from which interventions. Future research may identify biomarkers or clinical characteristics that predict response to music therapy versus medication, allowing more personalized treatment planning. For now, the evidence supports starting with non-drug approaches, investigating underlying causes thoroughly, and reserving pharmacological treatment for severe cases where benefits outweigh the real risks involved.
