The Neurobiology of Depression: an Integrated Overview from Biological Theories to Clinical Evidence.

Depressive disorders are heterogeneous diseases, and the complexity of symptoms has led to the formulation of several aethiopathological hypotheses. This heterogeneity may account for the following open issues about antidepressant therapy: (i) antidepressants show a time lag between pharmacological effects, within hours from acute drug administration, and therapeutic effects, within two-four weeks of subchronic treatment; (ii) this latency interval is critical for the patient because of the possible further mood worsening that may result in suicide attempts for the seemingly ineffective therapy and for the apparent adverse effects; (iii) and only 60-70 % of treated patients successfully respond to therapy. In this review, the complexity of the biological theories that try to explain the molecular mechanisms of these diseases is considered, encompassing (i) the classic "monoaminergic hypothesis" alongside the updated hypothesis according to which long-term therapeutical action of antidepressants is mediated by intracellular signal transduction pathways and (ii) the hypothalamic-pituitary-adrenal axis involvement. Although these models have guided research efforts in the field for decades, they have not generated a compelling and conclusive model either for depression pathophysiology or for antidepressant drugs' action. So, other emerging theories are discussed: (iii) the alterations of neuroplasticity and neurotrophins in selective vulnerable cerebral areas; (iv) the involvement of inflammatory processes; (v) and the alterations in mitochondrial function and neuronal bioenergetics. The focus is put on the molecular and theoretical links between all these hypotheses, which are not mutually exclusive but otherwise tightly correlated, giving an integrated and comprehensive overview of the neurobiology of depressive disorders.