There are generally 5 to 6 REEP genes in vertebrates, and two REEP genes in invertebrates [11–13] with each member responsible for different functions: REEP1 has been related to hereditary spastic paraplegia (HSP) protein, REEP2 can enhance the function of sweet taste receptors, REEP3 has been identified as a candidate gene for autism, REEP4 plays an important role in muscle and neural development, REEP5 positively correlates with major depression disorder (MDD), and REEP6 knockout causes necrosis of mouse retinal cells and lethality in zebrafish embryos [9–12,14–18]. Here, REEP5 is linked to major depressive disorder.