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In 2000, John Krystal’s group at Yale discovered that a single sub-anaesthetic dose of intravenous ketamine provided several days of symptomatic relief in a small group of depressed patients. This effect has been widely confirmed and has led recently to the licensing of intranasal esketamine for the treatment of patients with refractory depressive illness. In this talk we will describe the development of ketamine as an antidepressant, discuss the possible mechanisms involved in its action, and appraise the likely utility of ketamine and esketamine for clinical use in the NHS.