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6 Longer and more frequent depressive episodes appear to increase vulnerability to further relapses, 7 facilitating an accelerating and progressive illness course associated with functional decline. In progressive illness, outcomes 1, 2, 3 and treatment efficacy 4, 5 are inversely correlated with earlier disease onset and increased number and length of depressive episodes. Evidence-based novel treatments informed by this knowledge are discussed.Īlthough some patients with major depressive disorder (MDD) suffer from only one depressive episode, many display characteristics of a progressive illness. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness.