Amygdala connectivity mediates the association between anxiety and depression in patients with major depressive disorder

Anxiety is the most frequently co-occurring symptom with depression and subsequently contributes to increased severity and treatment resistance in patients with major depressive disorder (MDD). However, little is known about how these two behaviors are linked or interact at the neural network level. Seventy-five unmedicated MDD patients and 42 cognitively normal (CN) subjects underwent resting-state functional magnetic resonance imaging (R-fMRI) and neuropsychological testing. Multivariate linear regression analysis was performed to investigate the neural substrates of anxiety and depression, as well as their interactive effects on the amygdala functional connectivity (AFC) network in MDD patients. In addition, mediation analysis was employed to explore whether intrinsic amygdala connectivity mediates the association between anxiety and depression in patients with MDD. We found that MDD patients suffered symptoms of severe anxiety and a widely reduced functional connectivity in the AFC network, especially in the frontoparietal system and medial temporal lobe. Furthermore, common and distinct neural circuits involving anxiety and depression were separately identified. Interactive analysis revealed that MDD patients with lower HAMA scores showed milder depressive symptoms and greater AFC strength, while those with higher HAMA scores showed more severe depressive symptoms and lower AFC strength. More importantly, mediation analysis suggested that amygdala connectivity strength mediated the relationship between anxiety and depression in MDD patients. These findings extend our understanding of the brain circuitry implicated in MDD patients with comorbid anxiety, and provide new insight into therapeutic targeting of the neural circuits involved in this comorbidity.