The findings from our laboratory that inhibition of Cyclooxygenase-2 (COX-2)-mediated inflammation could suppress p38 MAPK activation in an animal model of depression (Song et al., 2018), suggest that, not only may oxidative stress promote neuronal injury to result in the development of depression, but that MAPK signaling may provide a bridge between stress stimuli and neuronal damage, thus revealing a potential pathophysiological mechanism for depression. Here, PTGS2 is linked to major depressive disorder.