The Effect of Comorbid Major Depressive Disorder on Working Memory in Young Adults With ADHD and the Mediating Role of the DLPFC

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) and Major Depressive Disorder (MDD) both exhibit working memory (WM) impairments and frequently co-occur. However, the impact of comorbid MDD on WM in ADHD patients and the underlying mechanisms remain unclear. Methods: The study included 409 adults, comprising 125 ADHD patients comorbid with MDD (ADHD+MDD), 145 ADHD patients without MDD (ADHD-MDD), and 139 healthy controls. In addition, functional connectivities (FCs) with the region of interest—the dorsolateral prefrontal cortex (DLPFC)—were analyzed in a subsample to explore the potential underlying neural mechanism. Results: The WM scores of the ADHD+MDD group were higher than those of the ADHD-MDD group. In all ADHD patients, depression scores were positively correlated with the WM impairment scores and explained 3.6% of the variance in WM impairment. Mediation analysis detected a potential effect of ADHD diagnosis on WM impairment via depressive symptoms. WM-related FC was identified between the left DLPFC and the right supramarginal gyrus (FC[DLPFC/L - SMG/R]), which partially mediated the relationship between the co-morbid status of MDD and WM. Conclusions: MDD in adults with ADHD exacerbated WM impairment, which may be related to the FC alteration between the left DLPFC and the right supramarginal gyrus (SMG). This finding provides a scientific basis for a deeper understanding of the pathogenesis and brain biomarkers of ADHD+MDD patients.