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Background: The introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine. While the intranasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression. Aims: To systematically review the literature on non-intranasal esketamine for depression in terms of its antidepressant effect and safety. Methods: We searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021. Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression. We selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression. Results: We identified four randomized controlled trials (RCTs) on intravenous esketamine and 15 open-label studies on intravenous ( n = 80), subcutaneous ( n = 73), and oral ( n = 5) esketamine. We found intravenous, subcutaneous, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with major depressive disorder, bipolar depression, and (severe) treatment-resistant depression. Clinical response to repeated administration of esketamine persisted over the course of treatment. Esketamine was well tolerated by most patients, but open-label data indicate marked psychotomimetic symptoms in exceptional cases. The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low to moderate. Conclusions: Intravenous, subcutaneous, and possibly oral esketamine may offer an effective and safe addition to the depression treatment armamentarium. However, as most included studies lacked a control group and had small sample sizes, the quality of our results is limited. Different types and formulations of ketamine remain to be compared directly.

Item does not contain fulltext Ketamine has rapid yet often transient antidepressant effects in patients with treatment-resistant depression. Different strategies have been proposed to prolong these effects. Maintenance ketamine treatment appears promising, but little is known about its efficacy, safety, and tolerability in depression. We searched Pubmed, Embase, and the Cochrane Library and identified three randomised controlled trials, eight open-label trials, and 30 case series and reports on maintenance ketamine treatment. We found intravenous, intranasal, oral, and possibly intramuscular and subcutaneous maintenance ketamine treatment to be effective in sustaining antidepressant effect in treatment-resistant depression. Tachyphylaxis, cognitive impairment, addiction, and serious renal and urinary problems seem uncommon. Despite the methodological limitations, we conclude that from a clinical view, maintenance ketamine treatment seems to be of therapeutic potential. We recommend both controlled and naturalistic studies with long-term follow-up and sufficient power to determine the position of maintenance ketamine treatment within routine clinical practice. 15 p.