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Depressive disorders constitute a set of debilitating diseases with psychological, societal, economic and humanitarian consequences for millions of people worldwide. Scientists are beginning to understand the reciprocal communication between the brain and the rest of the body in the etiology of these diseases. In particular, scientists have noted a connection between depressive disorders, which are primarily seen as brain-based, and, insulin resistance (IR), a modifiable metabolic inflammatory state that is typically seen as peripheral. We highlight evidence showing how treating IR, with drugs or behavioral interventions, may ameliorate or possibly prevent, depressive disorders and their long-term consequences at various stages of the life course.This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’IR is a pathological proinflammatory state underlying neuropsychiatric and somatic diseases.IR is part of a cascade of allostatic load, which is mediated in the periphery and CNS.PPAR- γ receptors, glutamate, cortisol are among mediators of peripheral and central crosstalk underlying IR.