In unmedicated participants with MDD, fatigue is significantly associated with depression severity but not sleep duration, sleep efficiency, or anterior cingulate cortex GABA+/Glx concentrations.
Key Findings
Results
Depression severity was significantly associated with fatigue in unmedicated MDD participants and had a significant mediation effect on the relationship between sleep duration and fatigue.
Sample consisted of N=76 unmedicated participants with MDD (median age: 23.5±14.2 years)
Depression severity mediated the relationship between sleep duration and fatigue
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
Multivariable logistic regression models with fatigue as the dependent variable were used to evaluate mediation effects
Results
No significant direct relationship was observed between sleep duration or sleep efficiency and fatigue in MDD participants.
Both sleep duration and sleep efficiency were examined as main predictors in separate analyses
The Wilcoxon rank sum or Kruskal-Wallis test was used to examine marginal differences in continuous variables between levels of fatigue
Bayes Factor hypothesis testing was used to examine the strength of evidence for null findings
The lack of direct association held for both sleep duration and sleep efficiency as predictors
Results
Anterior cingulate cortex GABA+ and Glx concentrations were not significantly associated with fatigue and did not mediate the effects of sleep on fatigue.
1H-MRS was acquired in the anterior cingulate cortex (ACC) of unmedicated MDD participants
GABA+ and Glx (combination of glutamate and glutamine) concentrations were quantified from an average co-edited difference spectrum
Preprocessing used Gannet and spectral fitting used TARQUIN
Neither GABA+ nor Glx showed a significant relationship with fatigue in marginal or mediation analyses
Methods
The study design used Magnetic Resonance Spectroscopy (1H-MRS) to quantify neurochemical concentrations in unmedicated MDD participants alongside sleep and depression questionnaires.
N=76 unmedicated participants with MDD were enrolled
Median age was 23.5±14.2 years, representing a relatively young population
Participants completed sleep and depression questionnaires in addition to neuroimaging
Mediation analyses used multivariable logistic regression with fatigue as the dependent variable
Separate analyses were conducted with sleep duration and sleep efficiency as the main predictor variable
Conclusions
The authors conclude that interventions targeting depression severity in MDD may be beneficial in reducing fatigue.
The results suggest that fatigue in this relatively young MDD population is driven by depression severity rather than sleep parameters or ACC neurochemistry
The indirect pathway from sleep to fatigue operated through depression severity, not through GABA+ or Glx
Authors suggest 'interventions to improve depression in MDD may be beneficial in reducing the debilitating effects of fatigue'
What This Means
This research suggests that in people with major depressive disorder (MDD) who are not taking medication, feeling fatigued is more closely tied to how severe their depression is than to how long or how well they sleep. The study examined 76 relatively young unmedicated adults with MDD, measuring brain chemistry in a region called the anterior cingulate cortex using MRI spectroscopy, and having participants report on their sleep and depression symptoms. The findings showed that while getting more sleep was associated with slightly lower odds of daily fatigue, this relationship worked indirectly through improvements in depression severity rather than through sleep itself or brain chemistry markers.
The study also found that two brain chemicals in the anterior cingulate cortex — GABA and glutamate/glutamine (Glx) — were not linked to fatigue and did not explain how sleep might affect fatigue. This suggests that at least in this brain region and in this relatively young population, these neurochemicals do not play a detectable role in the fatigue experienced during depression.
This research suggests that clinicians and researchers focusing on reducing fatigue in people with depression may want to prioritize treatments that address depression itself, rather than focusing primarily on improving sleep quantity or efficiency. The finding that the sleep-fatigue link is largely explained by depression severity implies that fatigue in MDD may be a symptom of the disorder rather than a downstream consequence of disrupted sleep.
Batheja S, Yang J, Liao Y, Wengler K, He X, Ali F, et al.. (2026). Fatigue in major depression is linked to depression severity, not sleep duration or anterior cingulate cortex neurochemistry.. Journal of affective disorders. https://doi.org/10.1016/j.jad.2025.121076