A cytokine imbalance and altered reactivity of the HPA axis to a second stressor—along with normal basal levels of corticosterone, TNF, and IL-1β—are consistent with the “two-hit theory” of depression development, according to which exposure to environmental stress at an early age enhances behavioral and hormonal responses to an additional stressor in adolescence and adulthood (Calcia et al., 2016; Reshetnikov et al., 2021). This evidence concerns the gene IL1B and major depressive disorder.