In the present study, we revealed that FLX treatment for 5 weeks improved depression-like behavior in mice, decreased necroptosis-related protein levels, such as RIPK1/p-RIPK1, RIPK3/p-RIPK3, and MLKL/p-MLKL, and inhibited astrocyte necrosis, suggesting that FLX-mediated antidepressive effects may be partially associated with inhibiting RIPK1/RIPK3/MLKL-induced necroptosis of astrocytes. This evidence concerns the gene RIPK1 and major depressive disorder.