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

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.