Fatigue in major depression is linked to depression severity, not sleep duration or anterior cingulate cortex neurochemistry

In major depressive disorder (MDD), it is unclear whether fatigue is a result of poor sleep or depression, and its biological basis is unknown. To explore this, Magnetic Resonance Spectroscopy (¹H-MRS) in the anterior cingulate cortex (ACC) was acquired in unmedicated participants with MDD (N = 76). Gamma-aminobutyric acid (GABA+) and Glx (combination of glutamate and glutamine) concentrations were quantified from an average co-edited difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Participants (median age: 23.5±14.2 years) completed sleep and depression questionnaires. The Wilcoxon rank sum or Kruskal-Wallis test was used to examine the marginal difference in continuous variables between levels of fatigue. Mediation effects of depression severity, GABA+, and Glx concentrations on the relationship between sleep duration and fatigue were evaluated using multivariable logistic regression models with fatigue as the dependent variable. Bayes Factor hypothesis testing examined the strength of evidence. Separate analyses were repeated with sleep efficiency as the main predictor. No significant relationship was observed between sleep duration/efficiency or GABA+/Glx and fatigue. Depression severity was significantly associated with fatigue and had a significant mediation effect on the relationship between sleep duration and fatigue. Specifically, for every additional hour of sleep, the odds of feeling fatigued nearly every day decreased by 11 % via an indirect mediating effect of decreased depression severity. GABA+/Glx did not mediate the effects of sleep on fatigue. The results suggest that, in this relatively young population, interventions to improve depression in MDD may be beneficial in reducing the debilitating effects of fatigue.