Abstract Objective: The goal of this report is to develop a comprehensive model, which integrates psychosocial and neurobiological aspects, for better understanding the link between chronic stress and mood disorders. Method: A selective review of the relevant bibliography was conducted. The significant data were integrated with clinical and preclinical findings, particularly focusing on the effect of the hypothalamo-pituitary-adrenal (HPA) activity on the serotonergic neurotransmission in the CNS. Results: The reviewed data shows that chronic application of stress responses may lead to alterations in the regulation of the HPA system, and the resulting hypercortisolism may be reflected in various psychoneuroendocrinological processes, such as the observed...