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There is a clear clinical need for a better understanding of the biological underpinnings of major depressive disorder (MDD), allowing for the development of a treatment that is targeted to pathophysiology. Recent data indicate a role for the endogenous opioidergic system in MDD. This article reviews the roles and physiological interactions of the endogenous opioidergic system in the pathophysiology and heterogeneity of MDD. Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mitochondrial function,