Donepezil for Fatigue and Psychological Symptoms in Post–COVID-19 Condition

Importance Fatigue is the most commonly reported symptom of post–COVID-19 condition (also known as long COVID) and impairs various functions. One of the underlying mechanisms may be intracerebral inflammation due to decreases in acetylcholine levels. Objective To examine the effects of donepezil hydrochloride, an acetylcholinesterase inhibitor, on post–COVID-19 fatigue and psychological symptoms. Design, Setting, and Participants A multicenter, double-blind randomized clinical trial was performed in Japan. Between December 14, 2022, and March 31, 2024, adult patients within 52 weeks of the onset of COVID-19 and with a global binary fatigue score of 4 or greater on the Chalder Fatigue Scale were randomized into a donepezil or a placebo group. Exposure The intervention was conducted during a 3-week period, with donepezil hydrochloride being administered at a dosage of 3 mg/d for the first week and then 5 mg/d for 2 weeks. Main Outcomes and Measures The primary outcome was a change in the Chalder Fatigue Scale score and the absolute score 3 weeks after the initiation of treatment. Other outcomes at 3 and 8 weeks, such as psychological symptoms and quality of life, were evaluated as secondary outcomes. Results A total of 120 eligible patients were enrolled and 10 withdrew or were lost to follow-up; therefore, 110 patients (55 in each group) were included in the efficacy analysis (64 [58%] female; mean [SD] age, 43 [12] years). No significant differences were observed in baseline characteristics between the 2 groups. The baseline-adjusted estimating treatment effect of donepezil, measured as the mean difference on Chalder Fatigue Scale scores at 3 weeks, was 0.34 (95% CI, −2.23 to 2.91), showing no significant effect of the intervention ( P = .79). Scores for the Hospital Anxiety and Depression Scale, Impact of Event Scale–Revised, EuroQol 5-Dimension 5-Level Version, Patient Health Questionnaire, and Daily Health Status at 3 and 8 weeks were similar. No serious adverse events occurred in either group. Conclusions and Relevance In this randomized clinical trial of donepezil to treat post–COVID-19 condition, the efficacy for fatigue and psychological symptoms was not confirmed in a general population. The development of effective therapeutics for post–COVID-19 symptoms is needed, and more clinical trials should be conducted in the future. Trial Registration Japan Registry of Clinical Trials Identifier: jRCT 2031220510