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Depression, the most frequent psychiatric disorder following ischaemic stroke, negatively affects survivals' functional outcome, response to rehabilitation and quality of life. Approximately, one-third of them are affected by post-stroke depression (PSD), making it a serious social and public health problem and anti-depressant preventive and curative therapies worth investigating. However, a two-way association between depression and stroke has been also established: stroke increases the risk of PSD, but depression is an independent risk factor for stroke.The pathophysiology of PSD is presumably multifactorial, involving a combination of various ischaemia-induced neurobiological dysfunctions in the context of psychosocial distress. The damage of frontal-basal ganglia brainstem pathway suggested alterations of monoaminergic neurotransmitter systems. Several lines of evidence point to a relationship between neuroinflammatory response to acute ischaemic stroke, stress activation of the hypothalamic-pituitary-adrenal (HPA) axis and the impairment of adaptive response (neurogenesis) within a background of altered energy metabolism (i.e. mitochondrial dysfunction).The complexity of PSD mechanisms makes its biologically-based prevention and treatment a difficult task. So far, especially the selective serotonin (5-hydroxytriptamine, 5-HT) reuptake inhibitors (SSRIs) have mainly proved to be clinically active in preventing and treating PSD, although their effects have not been demonstrated unequivocally and they may cause bleeding and intracerebral haemorrhage. Besides the primary pharmacological activity of SSRIs (i.e. the inhibition of neuronal 5-HT reuptake) there is evidence supporting their pleiotropic mechanisms of action: anti-inflammatory and enhanced neurogenesis through the up-regulation of neurotrophins, conceivably supported by the stimulation of mitochondrial energy metabolism.In the future, novel developments might point at anti-cytokine modulators which can improve symptoms of depression, especially in subjects affected by inflammation processes.This review will address the various areas of epidemiology, pathophysiology, preventive and therapeutic strategies for PSD. The activity of SSRIs in clinical trials, as well as their pharmacology, pharmacokinetics, safety and mechanisms of action, will be examined in detail. A final section will deal with the effect of depression as risk factor for stroke. The literature on PubMed from 1990 to 2017 was reviewed.