Background
Behavioral and psychological symptoms of dementia (BPSD) include agitation, depression, anxiety, delusions, sleep disturbances, and “sundowning.”1,2 Other Fast Facts cover delirium management (#1, #60, #397) and general dementia care (#150, #174, #388, #455). This Fast Facts reviews the evidence for the pharmacological management of BPSD.
Treatment of BPSD
Non-pharmacologic treatments and environmental modifications are the first line (see Fast Fact #498). Pharmacotherapy is reserved for refractory cases or when there is imminent risk of harm to the patient or others.
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While there are medications designed to slow down the neurodegenerative process of dementia (see Fast Fact #174), there are few FDA-indicated medications to treat BPSD. Supporting evidence for these pharmacotherapies is limited and must be weighed carefully.
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Evidence-Based Pharmacotherapies
Melatonin: May prevent BPSD via indirect benefits with sleep onset and duration.
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Case reports suggest melatonin and its prescription derivative (ramelteon) can improve agitation and sundowning behavior from BPSD.4,5 See Fast Fact #306. Dose: 3–10 mg by mouth at night.
Trazodone: May reduce agitation and insomnia; usual onset of effect 30–60 minutes.6,7 Limited evidence, but reasonable first choice for acute irritability and agitation in Alzheimer’s dementia (AD) and mixed dementia.
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Adverse effects: sedation and orthostatic hypotension. Dose: 25 mg multiple times daily as needed or 25–100 mg at nighttime. Maximum daily dose: 300 mg/day.
Brexpiprazole: FDA-approved at 2 mg/day for AD agitation, with some effect on day 1, and peak effect at 12 weeks.9,10 Black box warning for an associated increase in mortality when used to treat dementia-related psychosis and/or suicidal thoughts. Adverse effects: headaches, dizziness, and seizures.
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Dose: 0.5–3 mg/day.
Pimavanserin: FDA-approved for Parkinson’s disease (PD) hallucinations and delusions with promising preliminary results for AD agitation and aggression.
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Mechanism of action thought to be due to inverse agonism on serotonin receptors. Effects are seen within one week with further improvement after four weeks. Black box warning: similar to other antipsychotics.
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Adverse effects: agitation, insomnia, and falls.
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Usual dose: 34 mg/day.
Selective serotonin reuptake inhibitors (SSRIs): Reduce anxiety, irritability, and delusions in dementia. A meta-analysis showed that they are well tolerated and they decrease agitation, care burden, and depressive symptoms in patients with dementia.12–15
Citalopram and escitalopram have few P450 interactions, but if QTc or cardiac concerns, consider sertraline.14–16
SSRIs can take weeks to have an impact on symptoms and may require dose titrations. See Fast Facts #309.
Pharmacotherapies with Lower Levels of Evidence
Dextromethorphan combinations: Dextromethorphan-quinidine (usual dose 20 mg/10 mg daily) is approved for pseudobulbar affect disorder and has been prescribed to treat inappropriate emotional lability in patients with dementia. One randomized phase-2 study showed significant reductions in agitation compared with placebo for non-delirious patients with dementia; however, significant safety concerns were raised in this study.
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Cost, potential to incite delirium (on the Beers list), and concerns in patients with severe liver and renal impairment also limit its use.
Cholinesterase inhibitors (AchEIs): Mixed evidence but may delay dopamine-mediated BPSD (psychosis, delusions) in AD, Lewy Body Dementia, and PD Dementia.18,19 Well tolerated; monitor for syncope, bradycardia, and GI disturbances. Due to delayed onset of action, AchEIs are not ideal in situations of imminent risk of harm. Donepezil: 5–10 mg/day (also available as ODT and patch); Galantamine: 4–24 mg/day; Rivastigmine: 1.5–6 mg BID (also available as patch).
Cannabinoids: An evolving field of research with benefits in reducing BPSD symptoms using THC/CBD-based oral medications seen in some studies. Outside of the United States, nabilone, a synthetic THC analog, may be available, one small, controlled study suggest that it may reduce BPSD at doses of 1-2 mg/day after 2 weeks.9,20,21
Pharmacotherapies Generally Reserved to Treat Imminent Risk of Harm to Self or Other When Prognosis is Very Limited and/or Goals of Care Comfort in Focus
Antipsychotics:12,18 Black box warning for increased mortality, cerebrovascular events, and pneumonia in elderly dementia patients. Beware of QT prolongation. Higher mortality and neurologic morbidity with older agents (e.g., haloperidol).
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Use quetiapine or aripiprazole for Lewy Body Dementia or PD dementia. Starting Dose: risperidone: 0.25 mg PRN; Quetiapine: 25 mg PRN; Aripiprazole: 2 mg PRN; Olanzapine: 2.5–5 mg PRN; haloperidol: 0.5 mg PRN.
Anticonvulsants: Valproic acid, carbamazepine, oxcarbazepine, and gabapentin. No robust supporting data for BPSD, though nighttime gabapentin is prescribed for insomnia, agitation, and other BPSD symptoms often. Elevated risk for cognitive decline, mortality, and drug interactions.
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Benzodiazepines: Risks (dizziness, impaired coordination, delirium, paradoxical agitation) often outweigh benefits unless symptoms are refractory, sedative effects are needed, and/or prognosis is a few weeks or less.17,22–24
