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The antidepressant effect and safety of non-intranasal esketamine: A systematic review

Sanne Y. Smith-Apeldoorn, Maurice Vischjager, Jolien K. E. Veraart, Jeanine Kamphuis, Marije Aan Het Rot, Robert A. Schoevers

Journal of Psychopharmacology May 1, 2022 DOI: 10.1177/02698811221084055 (opens in new tab)

Study at a glance

AI-extracted from the abstract
Characteristics Systematic review Open-label Peer reviewed
Population Patients with major depressive disorder, bipolar depression, and treatment-resistant depression
Intervention subcutaneous
Topics Esketamine Ketamine
Citations 26
Key findings Intravenous, subcutaneous, and possibly oral esketamine were reported to reduce depressive symptoms in most patients with major depressive disorder, bipolar depression, and severe treatment-resistant depression, with response to repeated administration persisting over treatment. Most patients tolerated esketamine well, though open-label data indicate marked psychotomimetic symptoms in exceptional cases. The authors caution that most included studies lacked control groups and had small sample sizes, limiting the quality of the results.

Abstract

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: = 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.

Comparable studies

Other systematic reviews and meta-analyses on esketamine, most cited first.

Study Year Design Participants
Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression 2020 Systematic review and meta-analysis n = 1,877
The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation 2020 Systematic review and meta-analysis n = 197
Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature 2021 Systematic review
Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal 2020 Systematic review and meta-analysis n = 774
Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder 2025 Systematic review and meta-analysis

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