Low-Dose Aripiprazole for Long COVID Symptom Management: A Retrospective Observational Study

ABSTRACT Background Long COVID (1) is defined as the persistence of new or worsened symptoms for 3 or more months following acute SARS-CoV-2 infection, affecting multiple organ systems. Currently, there are no approved drugs for treating LC. We reported the effect of low-dose Aripiprazole (LDA) on the management of LC symptoms in a retrospective study. Methods A retrospective study was done using electronic health records from 50 adult patients from the Stanford LC clinic with a history of SARS-CoV-2 and subsequent LC who received LDA between 5/2021 and 10/2023. LDA was prescribed with dose titration (0.1-2.0 mg oral daily). The assessment include 29 symptoms, (ii) severity of each symptom on the Likert-scale 1 (mild) to 5 (very severe), and (iii) the Functional Status Scale (FSS) from asymptomatic (level I), symptomatic without limitations (level II), symptomatic with reduced daily activity (level III), symptomatic with a struggle to perform daily activities (level IV), or incapacitated and bedridden (level V). An improvement was defined as a reduction in the FSS ordinal scale (V, IV, III, II, and I) from higher to lower before and after exposure to LDA. A composite score of the severity of the seven most common symptoms (headache, fatigue, brain fog, unrefreshing sleep, sleep difficulty, post-exertional malaise, and lightheadedness) was calculated to assess the effect of LDA pre- and post-treatment, using Wilcoxon Signed-Rank Tests. Results Within the cohort of 50 patients, the median patient age was 46.5 years, 62% were female, and the mean body mass index (BMI) was 27.5 kg/m 2 . The median duration of symptoms was 566.5 days (range 153-1457). The FSS improved significantly from 3.78 to 3.28 (p = 0.001) after treatment with LDA. There were no statistically significant differences in reductions in symptom severity, symptom count, or composite scores across the seven selected symptoms. Symptom duration before treatment, and course of the illness before and after the aripiprazole period did not significantly affect treatment associated changes. The median dose of LDA was 1 mg. LDA was generally well tolerated in our study cohort (the most common side effects reported were headache in 3, restless leg in 1, and diarrhea in 1), with no severe adverse effects reported. Conclusion In our cohort study, LDA was associated with improved FSS. These retrospective observational results suggest that LDA warrants further investigation in a randomized controlled trial as a therapeutic option for LC. Exploring the mechanism of action for LDA in LC may also provide new insights into pathogenesis.