In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with Post-COVID-19 Condition (PCC), while accounting for the interaction of metabolic dysfunction, elevated inflammation, and body mass index (BMI).

Post-COVID-19 Condition, as defined by the World Health Organization (WHO), currently lacks regulatory-approved treatments and is characterized by persistent cognitive impairment and mood symptoms. Additional features include metabolic dysfunction, chronic inflammation, and the risks associated with elevated BMI. Cognitive impairment, which affects 22% of cases, significantly reduces quality of life and functional capacity. The high prevalence and debilitating nature of these cognitive symptoms, alongside the unclear neurobiological mechanisms and broader pathophysiology of PCC, highlight the urgent need for further research.

The 8-week randomized, double-blind, placebo-controlled trial was conducted among adults aged 18 and older in Canada with WHO-defined PCC symptoms. Participant recruitment began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, with 147 randomized in a 1:1 ratio to receive either vortioxetine (5–20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in Digit Symbol Substitution Test (DSST) scores from baseline to the endpoint.

Our findings showed significant effects for time (χ² = 7.771, p = 0.005), treatment (χ² = 7.583, p = 0.006), and the treatment x time x CRP x TG-HDL x BMI interaction (χ² = 11.967, p = 0.018) on cognitive function. Additionally, the between-group analysis demonstrated a significant improvement with vortioxetine at the endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047).

Overall, vortioxetine significantly improved cognitive deficits in individuals with baseline markers of metabolic dysfunction, elevated inflammation, and higher BMI at the endpoint compared to placebo.