More than 3200 Caucasian outpatients with a major depressive episode (MDE) from real-life settings were herein analyzed for clinical response to tianeptine, a treatment initiated from 79.5% of the subjects, during 6–8 weeks follow-up, assessing polymorphisms targeting four genes involved in the HPA axis (NR3C1, FKPB5, CRHR1, and AVPR1B). Here, NR3C1 is linked to major depressive episode.