CREB1 and major depressive disorder: Several researchers have examined the critical influence of second messenger/signal transduction cascades in the physiopathology and treatment of depression, e.g., cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, NFκB/Δfobs, mTOR, and eEF2K/CAMKIII, resulting in the second-messenger imbalance hypothesis (Wachtel, 1989, 1990; Niciu et al., 2013).