Dementia Drug Doesn’t Help Long COVID Fatigue, Psychological Symptoms

Use of donepezil (Aricept), an acetylcholinesterase inhibitor, for 3 weeks failed to demonstrate efficacy in treating fatigue and psychological symptoms of long COVID in a randomized trial from Japan.

Mean Chalder Fatigue Score (CFS) — the study’s primary outcome measure — was no different in the donepezil group compared with the placebo group at 3 weeks (P=0.31). The results remained nonsignificant after adjustment for baseline CFS using a regression model as well.

Furthermore, there were no significant effects on a host of secondary outcomes, including on measures of anxiety and depression, quality of life, and health status, according to researchers led by Kensuke Nakamura, MD, PhD, of Yokohama City University Hospital in Japan, in JAMA Network Open.

“Fatigue is the most common symptom in post-COVID-19 condition, and in its severe form, it prevents those affected from returning to work,” Nakamura’s group noted. However, “there are no effective drugs currently available.”

Animal models had suggested that donepezil, used to stabilize dementia symptoms, may alleviate psychiatric symptoms and particularly depression by controlling inflammation, which suggested a possible role for some of the key symptoms of long COVID, the researchers noted.

Harlan Krumholz, MD, a cardiologist at Yale University in New Haven, Connecticut, who was not involved in the trial, said the findings underscore the challenges of identifying effective pharmacologic treatments for long COVID.

“We need to conduct many more of these types of studies, given that millions report having this condition, and as yet we have no evidence-based treatments,” Krumholz said. “The results reinforce the need for continued research into targeted therapies for long COVID, including trials with longer durations and alternative mechanisms of action. This is the time to implement rapid-cycle, highly efficient trial designs to produce the abundance of evidence needed to address the needs of these patients.”

Nakamura and colleagues’ exploratory phase II trial enrolled 120 adults within 52 weeks of the onset of COVID-19 who had a global binary fatigue score of 4 or greater on the CFS and assigned them to receive either donepezil or placebo. The intervention took place over a 3-week period, with donepezil hydrochloride administered at a dose of 3 mg/day during the first week, followed by 5 mg/day for the next 2 weeks.

Of the 110 patients who completed the trial (55 in each group), 64% were female, with a mean age of 45 years. No significant differences in baseline characteristics were observed between the treatment and placebo groups. Over a third had cough (35-42%) at the time of study inclusion, 25-38% had sputum, 5-13% fever, 11-25% taste disorder, and 33-36% had loss of appetite. The vast majority (85%) had received at least two doses of COVID vaccine.

The primary outcome of interest was a change in CFS (a 0-33 point scale where higher scores indicate greater severity) and the absolute score 3 weeks after the initiation of treatment.

From a baseline score of 22.3 in the donepezil group, CSF scores declined to 14.6 at 3 weeks and 12.6 at 8 weeks. In the placebo group, scores decline from 21.4 to 14.1 and 13.4, respectively.

Secondary outcomes included the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, EuroQol 5-Dimension 5-Level Version, Patient Health Questionnaire-9, and Daily Health Status at either 3 or 8 weeks.

Adverse events occurred in 36% of patients assigned to donepezil and 42% of those in the control group, none of which were severe.

Nakamura and colleagues acknowledged certain limitations of the work, including that it might have been underpowered to detect significant differences in the outcomes. A phase III trial “with a larger number of patients is needed, along with valid subgroup identification,” they said.

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