“…Although the incidence of sex differences in MDD has been known for many years, even recent studies of brain circuitry and genes associated with mood dysregulation and MDD per se do not design studies to investigate sex effects nor incorporate even current sex-dependent knowledge into development of therapeutics. MDD is associated with abnormalities in stress response circuitry, i.e., brain circuitry regulating the hypothalamic pituitary adrenal (HPA) axis [23][24][25][26][27][28], including hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), anterior cingulate cortex (ACC), and ventromedial prefrontal and orbitofrontal cortices (vmPFC, OFC) [26,27,[29][30][31][32], areas that are among the most sexually dimorphic in the brain, i.e., areas that develop in sexdependent ways and function differently across the lifespan. HIPP, HYPO, AMYG, and PFC are dense in sex steroid and glucocorticoid receptors (GRs) [33][34][35] coupled with cytokine receptors [36][37][38][39], in particular, TNF-α, IL-1β, IL-6, the major co-activators of the HPA axis [36,37,40,41].…”