Primary Care Companion for CNS Disorders
Academic Highlights

Clinical Pearls

Targeted Treatment of Agitation in Alzheimer’s Dementia: Prioritizing Function and Safety Over Sedation and Other Serious Harms

Pierre N. Tariot, MD (Chair); Leslie Citrome, MD, MPH; Carolyn K. Clevenger, DNP, GNP; W. Clay Jackson, MD, DipTh; C. Brendan Montano, MD; Amita Patel, MD; Anton P. Porsteinsson, MD; Marwan Sabbagh, MD

Why is an agitated patient with Alzheimer’s dementia my patient to manage?

Primary care is the front line, often the first and only point of intervention.

44–76%

of patients with Alzheimer’s dementia experience agitation during the illness

80%

of patients with dementia have a primary care clinician as predominant clinician

18–50mo

projected wait to see a dementia specialist; rural waits about 3× longer

~25%

of patients treated with psychotropic agents experience sedation

Longitudinal relationships position primary care to detect behavior change, start treatment, and monitor response, reserving referral for diagnostically complex or treatment-refractory cases.

Why not just sedate an agitated patient with Alzheimer’s dementia?

Sedation is not efficacy. Off-label sedating agents are not first-line and may cause harm.

Harms linked to sedating medications

up to 3.8×

Risk of falls

2.4×

Risk of hip fracture

+33%

Injurious falls, multiple fall-risk drugs

Quetiapine, benzodiazepines, trazodone, risperidone, citalopram, and nabilone are not approved for agitation in Alzheimer’s dementia. Many quiet patients through sedation, which the Centers for Medicare & Medicaid Services (CMS) defines as excessive sleeping, drowsiness, and withdrawal. Sedation is not efficacy.

Sedation also raises the risk of

Aspiration pneumoniaCognitive and functional declineReduced daytime alertness and engagement

What is driving agitated behavior?

A neurobiological imbalance: decreased prefrontal control and increased amygdala emotional drive.

Cause

Tau-mediated disruption of monoamine systems

NoradrenergicSerotonergicDopaminergic

Agitation

A sign the disease has reached emotional-control systems, not a change in character

Decreased executive control and increased emotional drive contribute to agitation in Alzheimer’s dementia. Adapted from Cummings et al. 2024. CNS Spectr. 29(5):316–325.

Targeted treatment acts on agitation-related circuitry. Select by receptor-binding profile, not drug class.

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Which medication, if any?

Favor an agent FDA-approved for agitation in Alzheimer’s dementia; safety profiles differ.

Approved agents were tested specifically in agitation in Alzheimer’s dementia, and the panel identified an FDA-approved indication as the clearest prescribing guide for primary care.
Off-label agents were adopted from other indications, with evidence limited by dose or end point.
Among agents with positive placebo-controlled data, effect sizes are modest and broadly comparable; safety profiles differ.
No head-to-head trials exist; weigh safety and preservation of alertness through shared decision-making.

Agent	FDA-approved for this indication	Positive placebo data	Key safety and tolerability notes
Approved agents
Brexpiprazole			Approved 2023. Somnolence 3% vs 1% placebo
Dextromethorphan–bupropion ER			Approved April 2026, after the panel met; pivotal trial data were not available for review. Somnolence 8% vs 4% placebo
Off-label · not first-line and may cause harm
Risperidone			Effect for aggression end point only; somnolence 37% vs 25% placebo
Citalopram			Effect only at 30 mg/day, above the 20 mg/day maximum for age ≥60; QTc; somnolence 52% vs 49% placebo
Nabilone			Sedation 45% vs 16% placebo
Quetiapine			Effect at 200 mg/day only; none at the 25–50 mg/day typically used; somnolence 9% vs 2% placebo
Benzodiazepines, trazodone, divalproex			No positive evidence. Benzodiazepines: falls, fractures, cognitive decline; divalproex: brain atrophy

YesLimited (dose or end point)No

All atypical antipsychotics carry a class boxed warning for mortality in elderly patients with dementia-related psychosis. Brexpiprazole’s warning has been modified; its labeled indication permits use for agitation in Alzheimer’s dementia whether or not psychosis is present.

How will I know it is working?

Measure at baseline and at every follow-up with a validated tool.

A validated instrument is recommended to assess baseline and to monitor treatment response

Screen

Agitation in Alzheimer’s Screener for Caregivers (AASC)

8 caregiver yes/no items aligned with International Psychogeriatric Association (IPA) criteria; about 1 minute

Baseline + every follow-up

Pittsburgh Agitation Scale (PAS)

Preferred for monitoring change over time

Full range

Neuropsychiatric Inventory Questionnaire (NPI-Q)

All neuropsychiatric symptoms; can be embedded in the electronic health record

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What do I rule out first to confirm agitation?

Reversible causes and delirium first.

Confirm International Psychogeriatric Association (IPA) agitation criteria are met, and exclude contributors before attributing agitation to Alzheimer’s dementia.

Delirium · always firstUrinary tract infectionPainMedication effects, including over-the-counter drugs and supplementsSensory impairmentEnvironmental triggers

What do I try first to manage an agitated patient?

Nonpharmacologic care, structured with DICE, for a suggested 2-week trial.

Agitated behavior is often an unmet need the patient can no longer name. Clinician coaches the caregiver through DICE; document what was tried, for how long, and the result.

DDescribe triggers and what calms

IInvestigate causes

CCreate a plan

EEvaluate whether it worked

When is medication warranted?

When any one of three conditions is met.

Consider medication when any one condition is met. Favor an agent FDA-approved for agitation in Alzheimer’s dementia and continue behavioral care alongside it.

Persists despite an adequate, documented nonpharmacologic trial

Immediate safety risk behavioral approaches cannot contain

Caregiver distress exceeds capacity for behavioral care

Does the setting change the plan?

Yes. Agitation management is setting-specific.

Acute / emergent

De-escalate: seated posture, lowered voice, less stimulation.
Any crisis medication is a bridge, not a permanent solution.

Community

Reframe without criticism.
Ask the caregiver, “What does a good day look like?”

Long-term care

Taper ineffective off-label agents.
Reassess every 1 to 2 weeks.
Document to CMS F605 standards.

Four outcomes define success in every setting

Safety

Alertness

Functional engagement

Caregiver well-being

Take-home

Measure agitation with a validated tool at baseline and follow-up
Rule out reversible causes, delirium first
Nonpharmacologic care first, structured with DICE
When medication is warranted, an FDA-approved agent is favored

Based on

Tariot PN, Citrome L, Clevenger CK, et al. Prim Care Companion CNS Disord. 2026;28(5):PCC.haadachi2603. Published September 22, 2026. doi.org/10.4088/PCC.haadachi2603

Sponsor

Meeting sponsored and editorial support funded by Otsuka America Pharmaceuticals Inc. and H. Lundbeck A/S; recommendations reflect the faculty’s independent perspectives. Faculty disclosures appear in the full article. This summary does not replace prescribing information.