Background: Fatigue is among the most prevalent symptoms for people with multiple sclerosis (pwMS) and is significantly detrimental to mental health-related (mental) quality of life (QoL). We examined the role of depression and physical activity as mediators in the fatigue-QoL relationship in pwMS.

Methods: Using baseline cross-sectional data from an international cohort of 2,104 pwMS, characteristics of fatigue and mental QoL, measured by Fatigue Severity Scale and MSQOL-54 respectively, were assessed using linear and log-binomial regression. Structural Equation Models (SEM) were used to explore the mediating roles of depression and physical activity between fatigue and mental QoL.

Results: The median mental QoL score was 71.9/100. The mean fatigue score was 41.5/63, with 65.6% participants having clinically significant fatigue. In the SEM evaluating depression as a mediator of the fatigue-QoL relationship, mental QoL was 14.72 points lower (95% CI: -16.43 -13.01, p<0.001) in participants with clinically significant fatigue, of which depression accounted for 53.0% (-7.80, 95% CI: -9.03 -6.57, p<0.001). In the SEM evaluating physical activity as a mediator of the fatigue-QoL relationship, mental QoL was 10.89 points lower (95% CI: -12.47, -9.32, p<0.001) in participants with clinically significant fatigue, of which the indirect effect via physical activity accounted for only 4.4% (-0.48, 95% CI: -0.81, -0.14, p=0.005).

Conclusion: Depression accounted for the majority of the fatigue-mental QoL relationship when modelled as a mediator, while physical activity had only a minor role. Our findings may inform the development of treatments for reducing the impacts of fatigue and improving mental QoL in pwMS.