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After decades without substantial advances, multiple novel antidepressants show promise against treatment-resistant depression. Interestingly, many of these are anesthetics. The purpose of this review is to discuss the evidence for the antidepressant effects of ketamine, nitrous oxide, isoflurane and propofol and to consider potential clinical, administrative and research implications for anesthesiologists.Ketamine has acute, transient antidepressant and antisuicidal effects. Nitrous oxide has also shown antidepressant efficacy. There are converging preclinical and clinical data that isoflurane (and perhaps propofol), dosed to burst suppression, has relatively rapid, robust and durable antidepressant effects and lacks the adverse effects associated with electroconvulsive therapy (ECT).Several anesthetics show promise as novel antidepressants. Ketamine is the most well studied. Anesthetic-induced burst-suppression may provide an alternative to ECT that lacks adverse cognitive effects. Further study is necessary to better understand how these drugs work and how they might be used as effective antidepressant therapy.