PCC manifests as debilitating symptoms that impact multiple cognitive domains and negatively affect HRQoL. Targeting the mediators of HRQoL in PCC could potentially enhance patient-reported outcomes (PROs), providing a basis for therapeutic strategies aimed at enhancing overall quality of life.

Our objective was to investigate the effects of cognitive function on health-related quality of life (HRQoL) in individuals with post-COVID-19 condition (PCC). Additionally, we aimed to determine whether vortioxetine modulates the relationship between cognitive function and HRQoL.

Participants aged 18-65 years were randomized to receive either vortioxetine or placebo for 8 weeks. HRQoL was assessed using the World Health Organization Wellbeing Scale 5-item, while cognitive function was measured using the Digit Symbol Substitution Test and the Trail-Making Test A/B. Generalized estimating equations were used to model the relationship between cognition and HRQoL for each treatment group.

147 participants (75.5% females) were included. At baseline, there was a statistically significant positive association between WHO-5 scores and combined DSST z-scores (β = 0.090, 95% CI [0.051, 0.129], p < 0.001). Conversely, there were statistically significant negative associations with TMT-A (β = −0.007, 95% CI [-0.011, −0.003], p < 0.001) and TMT-B (β = −0.002, 95% CI [-0.003, 0.000], p = 0.024) scores. A significant interaction among treatment, time, and combined DSST z-scores on changes in overall WHO-5 total scores was observed (χ² = 15.481, p = 0.004). After adjusting for the type of cognitive test, a significant between-group difference was noted (mean change = 1.77, SEM = 0.868, p = 0.042), favoring vortioxetine.

Cognitive function is significantly associated with HRQoL in individuals with PCC, with better cognitive functioning correlating with improved HRQoL. Vortioxetine has demonstrated effectiveness in enhancing HRQoL by improving cognitive function, highlighting cognitive enhancement as a potential therapeutic target in PCC. Future studies should explore pro-cognitive therapeutic strategies.