In leukocytes from unmedicated MDD subjects ↑ transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and Nrf2. 8 wk sertraline treatment was associated with ↓ in Ham-D scores and ↓ activity of Nrf2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor, NF-κB and (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment. Here, NFE2L2 is linked to major depressive disorder.