Genetic, Epigenetic, and Hormonal Regulation of Stress Phenotypes in Major Depressive Disorder: From Maladaptation to Resilience.

Major Depressive Disorder (MDD) is a complex psychiatric disorder with varied molecular mechanisms underlying its aetiology, diagnosis, and treatment. This review explores the crucial roles of stress, genetics, epigenetics, and hormones in shaping susceptibility and resilience to mood disorders. We discuss how acute stress can be beneficial, while prolonged stress disrupts brain function, leading to MDD. The review also highlights the significance of various animal models in understanding depression pathophysiology, including zebrafish, mice, and rats, which exhibit distinct sex differences in stress responses. Furthermore, we delve into the molecular bases of susceptible and resilient phenotypes, focusing on genetic aspects such as gene polymorphisms, mutations, and telomere length alterations. The review also examines epigenetic aspects including DNA methylation, histone acetylation and deacetylation, histone methylation and HMTs, and miRNA, which contribute to the development of MDD. Additionally, we explore the role of hormones such as estrogen, progesterone, and prolactin in modulating stress responses and influencing MDD susceptibility and resilience. Finally, we discuss the clinical implications of these findings, including recent clinical methods for determining MDD susceptibility and resiliency phenotypes. By consolidating the current knowledge and insights, this review aims to provide a comprehensive understanding of the molecular basis of susceptibility and resilience in mood disorders, contributing to the ongoing efforts in combating this debilitating disorder.