Suspected donepezil withdrawal syndrome in an older woman with Alzheimer disease of abrupt cessation: A case report

Table 1 Day-by-day clinical timeline from the pre-admission decline through 12-week follow-up

Day	Location	Donepezil/other medication	CAM/cognition	Key symptoms or events	Interpretation
-14 to -1	Home	Donepezil 10 mg/day; amlodipine 5 mg/day	HDS-R 16/30 previously; 8/30 at pre-admission review	Reduced spontaneous speech, withdrawal and increased prompting for ADLs	Pre-existing cognitive/functional decline
0	Nursing-home admission	Donepezil 10 mg/day stopped abruptly; amlodipine continued	No acute CAM assessment documented	Major environmental transition	Start of medication exposure change
1	Nursing home/home	No donepezil	Not documented	No detailed standardized assessment available	Early post-discontinuation period
2	Home	No donepezil	CAM-positive syndrome recognized over day 2-3	Acute agitation, verbal aggression, refusal to sit for meals, insomnia, new gait instability	48-hour temporal association
3	Emergency department	No donepezil	CAM positive; distractible, disorganized thinking	CT and routine laboratory work-up unremarkable; diagnosed clinically as delirium	Major infection/metabolic/structural causes not identified
4-6	Home	No donepezil	Not standardized	Persistent agitation and sleeplessness	Ongoing symptoms before rechallenge
7	Nursing-home review	Donepezil 5 mg/day restarted; quetiapine 125 mg PRN added	No standardized severity scale	Withdrawal suspected; quetiapine used almost daily during first week	Rechallenge, but confounded by rescue medication
8-11	Nursing home	Donepezil 5 mg/day; PRN quetiapine	Not standardized	Agitation and verbal aggression progressively decreased	Improvement during combined rechallenge/adaptation period
12	Nursing home	Donepezil 5 mg/day; quetiapine discontinued	Not standardized	Sleeping through the night	Early clinical improvement
21	Nursing home	Donepezil 5 mg/day	Not standardized	Eating independently and adapting to facility	Functional recovery
84	Nursing home	Donepezil 5 mg/day	No recurrence reported	12-week follow-up without recurrence	Longer-term follow-up

Days are grouped when separate daily documentation was unavailable, to avoid implying precision that was not supported by the retrospective record. CAM: Confusion assessment method; HDS-R: Hasegawa Dementia Scale-Revised; CT: Computed tomography; ADLs: Activities of Daily Living; PRN: Pro re nata.

Table 2 Structured clinical causality assessment for the suspected donepezil withdrawal syndrome

Domain	Evidence in the present case	Interpretation
Temporality	Donepezil 10 mg/day was stopped on day 0; acute agitation, insomnia, gait instability and CAM-positive delirium emerged on day 2-3	Strong temporal association, but not specific for withdrawal
Dechallenge	Symptoms began after the drug had already been stopped; therefore conventional dechallenge cannot be assessed	Not applicable to the usual Naranjo framework
Rechallenge	Donepezil 5 mg/day was restarted on day 7; agitation and verbal aggression decreased within 5 days	Supportive, but improvement overlapped with quetiapine use and environmental adaptation
Dose relationship	Improvement occurred after restarting at 5 mg/day rather than the previous 10 mg/day dose	Compatible with recovery after re-exposure, but not a validated dose-response finding
Alternative explanations	Pre-admission HDS-R decline, nursing-home relocation, occult pain, unrecorded OTC drugs/supplements, possible non-convulsive seizures, and concomitant quetiapine were not fully excluded	Causal certainty is limited
Objective evidence	CAM-positive delirium was documented; no plasma donepezil concentration or cholinergic biomarker was obtained	Supports the presence of delirium, but does not establish drug causality
Pharmacokinetic plausibility	Donepezil has a long terminal half-life of approximately 70 hours	A 48-hour onset does not require complete drug elimination; an early response to declining exposure is plausible but unproven
Overall assessment	The sequence is compatible with suspected donepezil withdrawal	Clinical causality remains uncertain; the term “suspected” is used to reflect a provisional clinical interpretation rather than a validated probability score

The Naranjo Adverse Drug Reaction Probability Scale was designed for adverse drug reactions rather than withdrawal phenomena. We therefore removed the previous numerical Naranjo score and present a structured clinical causality assessment instead. CAM: Confusion assessment method; HDS-R: Hasegawa Dementia Scale-Revised.

Table 3 Selected published reports of cognitive or behavioural deterioration after cholinesterase-inhibitor discontinuation, compared with the present case

Ref.	Age/sex	Drug/daily dose	Duration before stop	Onset after stop	Outcome after restart/withdrawal
Singh and Dudley[6]	77 male/79 female	Donepezil 10 mg/5 mg	Approximately 1 year/3 years	Within days	Improved within days after donepezil 5 mg
Bidzan and Bidzan[7]	62 female (Alzheimer disease)	Donepezil	Approximately 1 year	After discontinuation; delirium developed	Delirium resolved and mental state stabilized after restart
Greiman et al[8]	83 female (DLB)	Donepezil 10 mg; abrupt switch/discontinuation	Not clearly stated in report	Rapid cognitive/functional decline	Improved after restoration of cholinesterase-inhibitor therapy
Minett et al[9]	DLB/PDD; 19 patients	Donepezil up to 10 mg/day	20 week treatment; 6-week withdrawal	During withdrawal	Loss of cognitive treatment gains and behavioural deterioration; improvement after recommencement
Present case	89 female (Alzheimer disease)	Donepezil 10 mg	> 5 years	2 days	CAM-positive delirium/behavioural syndrome; improvement after 5 mg restart

DLB: Dementia with Lewy bodies; PDD: Parkinson disease dementia; CAM: Confusion assessment method.