Can Donepezil Worsen Anxiety in Dementia Patients?
Donepezil can cause a transient initial increase in agitation (which may manifest as anxiety) in some dementia patients, but this typically subsides after a few weeks and does not represent a sustained worsening of anxiety symptoms. 1
Initial Agitation vs. Sustained Anxiety Worsening
The American Academy of Family Physicians explicitly notes that donepezil may cause an initial increase in agitation in some patients, but this typically subsides after a few weeks 1. This transient phenomenon should not be confused with sustained anxiety worsening. The guideline specifically lists anxiety as a side effect of rivastigmine (another cholinesterase inhibitor), but notably does not list sustained anxiety as a side effect of donepezil 2.
Evidence for Anxiety Improvement with Donepezil
The evidence actually suggests donepezil may improve rather than worsen anxiety in dementia patients:
- In responders to donepezil treatment, anxiety significantly improved after 12 weeks of treatment 3
- A 2017 trial demonstrated that mood disorders including anxiety were significantly decreased in patients treated with donepezil plus choline alphoscerate compared to those whose anxiety severity and frequency increased in the control group 4
- Behavioral disturbances overall, which can include anxiety symptoms, are reported at significantly lower rates in patients receiving donepezil compared to those not receiving treatment 5
Clinical Management of Initial Agitation
When initiating donepezil therapy 1, 6:
- Start with 5 mg once daily in the evening to minimize side effects 6
- Take with food to reduce gastrointestinal and potentially behavioral side effects 1, 6
- Counsel patients and caregivers that any initial agitation typically resolves within the first few weeks 1
- Increase to 10 mg daily after 4-6 weeks only if the initial dose is tolerated 6
Important Caveats
The distinction between initial transient agitation and sustained anxiety worsening is critical. While the cholinergic mechanism of donepezil can cause mild, transient side effects 1, the overall effect on neuropsychiatric symptoms including anxiety appears neutral to beneficial over time 3, 4, 7, 5. The Cochrane systematic review of 30 studies involving 8,257 participants found no difference between donepezil and placebo for behavioral symptoms measured by standardized scales at 26 weeks 7, suggesting that any initial agitation does not translate into sustained behavioral problems.
If anxiety or agitation persists beyond the first few weeks of treatment, consider other contributing factors such as disease progression, comorbid conditions, or environmental stressors rather than attributing it solely to donepezil 2.