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Chronic pruritus is a common skin symptom with marked impact on quality of life. Adequate treatment can be challenging for clinicians, demanding the exploration of new treatment options such as oral antidepressants.To evaluate the use of oral antidepressants in chronic pruritus by a systematic overview of the available relevant literature.The PubMed, EMBASE, Cochrane, and Web of Science databases were searched. Studies providing original data on the efficacy of oral antidepressants in patients with chronic pruritus were included. We assessed the risk for bias by using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies.A total of 35 studies evaluating the oral use of fluoxetine, fluvoxamine, paroxetine, sertraline, amitriptyline, nortriptyline, doxepin, and mirtazapine were included. The majority of included articles showed a marked improvement of pruritus during treatment with oral antidepressants.Recommendations are mainly based on open-label trials, case series, and case reports.Oral antidepressants should be considered in patients with chronic pruritus that is unresponsive to topical treatment and oral antihistamines, particularly in patients with uremic pruritus, cholestatic pruritus, or paraneoplastic pruritus. More evidence based on randomized-controlled trials is required.