Special Guest Author: Billy Smith, MD
Blanca is a 75 yo woman with a history of mild Alzheimer’s Dementia (AD), hypertension, and hyperlipidemia. She lives at home with her husband, and her daughter lives across the street. She can attend to all of her Activities of Daily Living (ADLs), including bathing and dressing. She is no longer able to perform Instrumental Activities of Daily Living (IADLs) independently, such as managing the household and the finances.
Blanca has become progressively more irritable and anxious over the last several months. She fixates on the mail, specifically the bills that she used to manage for the family. She also frequently checks her jewelry box. If she is unable to find what she is looking for, she accuses her daughter of stealing it. When she is feeling particularly anxious or frustrated, she paces and wrings her hands. Reassurances from her family do not help, and these episodes can last hours.
Blanca’s family has worked hard to manage Blanca’s anxiety using behavioral strategies that were introduced in a previous PsychSnap and are described in detail by the Alzheimer’s Association (www.ALZ.org). They have simplified routines, created predictable daily schedules, minimized distractions in her environment (not leaving mail on the counter, keeping unfamiliar people out of the house), and involved Blanca in activities with low cognitive load, such as cleaning and folding clothes. Despite these efforts, Blanca continues to have periods of severe anxiety, and her family asks you what else can help.
What medications can be used to manage the neuropsychiatric symptoms of Alzheimer’s Disease (AD)?
Acetylcholinesterase Inhibitors for the neuropsychiatric symptoms of AD
Donepezil and other acetylcholinesterase inhibitors (AChEIs) delay cognitive decline by 6-12 months on average in patients with AD. AChEIs can also improve the neuropsychiatric symptoms of AD, including anxiety, depression, and irritability (Campbell 2008, Cummings 2016, Holmes 2004). As a class, acetylcholinesterase inhibitors reduce the behavioral and psychiatric symptoms of dementia with a small effect size of -0.10 compared to placebo (Campbell 2008). When patients stop taking AChEIs, the improvements in cognition and neuropsychiatric symptoms are lost (Cummings 2016).
Donepezil is the first line medication for managing mild-to-moderate anxiety or depression in patients with cognitive deficits from Alzheimer’s or Lewy Body Dementia, particularly when the mood change is related to distress from worsening cognition. If depression or anxiety is severe, with pronounced functional limitations due to mood, significant weight loss, or suicidal ideation, then SSRIs (see below) are the appropriate initial medication choice.
AChEIs are low risk medications and are generally well tolerated. The most common side effect is GI upset, which can improve over time and is mitigated by a slow titration. If there are intolerable GI side effects from donepezil, the transdermal rivastigmine patch may be preferred. Donepezil can also cause vivid dreams, which can be lessened with morning dosing. Potentially serious side effects from AChEIs include conduction abnormalities (prolonged QTc, bradycardia, AV block) and syncope. A baseline ECG should be completed prior to starting an AChEI to evaluate for conduction abnormalities, and can be repeated after the final dose is reached. Patients should monitor for dizziness or lightheadedness.
Back to Blanca
AChEIs like donepezil increase Acetylcholine (ACh), while anticholinergic medications do the opposite, commonly worsening cognition associated with AD. Before starting donepezil, you look carefully at Blanca’s medication list for any medications with anticholinergic side effects. She has been taking oxybutynin for an overactive bladder, and after learning that the medication hasn’t helped her urinary incontinence, you stop it. There is no change in Blanca’s cognition or mood symptoms two weeks after stopping oxybutynin.
You get a baseline ECG then recommend that Blanca start donepezil at a low dose, 2.5mg PO qAM, because GI side effects are common when patients start at donepezil 5mg. The donepezil dose is increased by 2.5mg q2-4 weeks up to 10mg qAM. An ECG completed when Blanca is taking donepezil 10mg shows a QTc in the 420s and a heart rate of 65. Her husband notes that Blanca had some subtle sharpening in her cognition and a significant reduction in her anxiety. She has no side effects.
Despite an initial improvement with donepezil, Blanca begins to have more frequent episodes of anxiety, agitation, and irritability over the following year. The family wonders if another medication change could be helpful, in addition to the behavioral interventions that they continue to use.
SSRIs for the neuropsychiatric symptoms of AD
SSRIs, specifically sertraline, citalopram, and escitalopram, have evidence for treating a spectrum of neuropsychiatric symptoms in AD. The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind trial comparing citalopram with placebo in patients (n=186) with probable Alzheimer disease and clinically significant agitation. Patients who received citalopram 30mg showed significant reductions at 9 weeks in delusions (odds ratio (OR) = 0.40), anxiety (OR = 0.43), and irritability/mood lability (OR = 0.38) compared with placebo (Leonpacher 2016). Due to the increased risk of QTc prolongation at moderate doses of citalopram (>20mg daily for adults over 60), neurologists and geriatric specialists generally start with escitalopram (the S-enantiomer of citalopram, which that has a lower risk of QTc prolongation).
Sertraline also treats depression associated with AD with an effect size of 0.82. Sertraline may be preferred over escitalopram if the patient has a history of major depressive disorder or has an extensive cardiac history (Zhang 2023). Sertraline can be started at 12.5-25mg daily and increased by 12.5-25mg increments every 2-4 weeks to a maximum dose of 200mg daily.
Back to Blanca
Blanca starts taking escitalopram 2.5mg qAM in addition to donepezil 10mg daily. She continues to take donepezil because she tolerated it well, and the family wants to avoid the possibility of a rapid decline in her cognition if she were to stop it. The escitalopram dose is increased by 2.5mg every 2 weeks to escitalopram 10mg daily. After a month at escitalopram 10mg, Blanca’s episodes of agitation are less frequent and less severe. Because geriatric patients have a higher risk of side effects from SSRIs than younger patients, including QTc prolongation and SIADH, you order a routine ECG and a serum sodium when she reaches her final dose of escitalopram 10mg daily.
Guest Author Billy Smith, MD is a geriatric psychiatrist and an assistant professor at UCSF.
Key Points
- Donepezil and other acetylcholinesterase inhibitors are the first-line medications used for cognitive and neuropsychiatric symptoms of Alzheimer’s Dementia, including mild-to-moderate anxiety, depression, irritability, and agitation.
- Escitalopram and sertraline can lessen the neuropsychiatric symptoms of Alzheimer’s Dementia and are the first-line medications for severe depression or anxiety associated with AD. They can also be added to donepezil if mild-to-moderate neuropsychiatric symptoms progress.
Related PsychSnaps:
How do you manage behavioral and psychological symptoms in a patient with dementia? Anna Chodos, Ashley Johnson, Anna Hines. July, 2023.
What caused low energy in a patient whose other depressive symptoms were improving with escitalopram? Emma Samelson-Jones, Dec 2022.
References:
Campbell, Noll, et al. “Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer’s disease: a meta-analysis.” Clinical Interventions in Aging 3.4 (2008): 719-728.
Cummings, Jeffrey, et al. “Role of donepezil in the management of neuropsychiatric symptoms in Alzheimer’s disease and dementia with Lewy bodies.” CNS neuroscience & therapeutics 22.3 (2016): 159-166.
Holmes, Clive, et al. “The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.” Neurology 63.2 (2004): 214-219.
Leonpacher, Anne K., et al. “Effects of citalopram on neuropsychiatric symptoms in Alzheimer’s dementia: evidence from the CitAD study.” American Journal of Psychiatry 173.5 (2016): 473-480.
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