Highlights • Depressive disorders may represent an interactive matrix of reciprocally interactive pathophysiological mechanisms. • These biological mechanisms may reduce neuroplasticity and compromise the functional integrity of affect regulation neurocircuitry. • An R-Doc approach to depressive disorders is essential to understand each biological mechanism before understanding their interaction. • An overly reductionistic approach may miss the essence of the disorder, which likely lies in the complex interactions among various pathophysiological mechanisms, rather than in one mechanism in isolation. • An integrated view of the neurobiology of depression is only one hypothesis, and depressive disorders may represent several subsyndromes, or even numerous discrete disorders