Major Depressive Disorder (MDD) is characterized by increased stress sensitivity. Emerging findings in healthy adults suggest that stress responses within limbic/striatal-prefrontal regions are moderated by sex and unfold over time. Thus, we hypothesized that stress response abnormalities in MDD might be affected by sex and stress exposure time. The Montreal Imaging Stress Task was administered to 124 unmedicated patients with first-episode MDD (76 females) and 243 healthy controls (HC; 137 females) during functional magnetic resonance imaging (fMRI). Based on prior studies, amygdala, hippocampus, medial orbitofrontal cortex (mOFC), nucleus accumbens (NAc) and dorsolateral prefrontal cortex (dlPFC) were selected as a priori regions of interest. In a complementary approach, we probed the effects of stress on the frontoparietal network (FPN) and a network including the amygdala, NAc and anterior cingulate cortex (ACC). Across groups, males exhibited higher dlPFC activity and right FPN amplitude than females. Relative to female HCs, the female MDD group had less deactivation in limbic/striatal regions (amygdala, NAc, hippocampus, Amygdala-NAc-ACC network). Furthermore, unlike female HCs, the female MDD group failed to show a significant increase of deactivation over stress exposure time in the amygdala, mOFC and NAc. Our findings confirm the importance of considering sex differences when investigating neural stress responses. Case-control differences in neural stress responses observed in females (but not males) provide insights into sex differences in the etiology and pathophysiology of depression. The failure to deactivate limbic/NAc regions in depressed females point to dysfunction of adaptive stress responses over stress exposure time.
© 2021. The Author(s).