Volume 30, Issue 174, August 2026

Ketamine and esketamine for treatment-resistant depression: A systematic review of published studies

Julia Rogała^1♦, Kinga Polityńska¹, Dominika Ruszel¹, Martyna Sarzyńska¹, Klaudia Samuła¹, Emilia Goc¹, Katarzyna Markuszka¹, Sylwia Lepak¹, Zuzanna Irzyk¹, Mateusz Szabat²

¹Faculty of Medicine, Collegium Medicum, University of Rzeszów, Rzeszów, Poland
²Clinical Provincial Hospital No. 2, Rzeszów, Poland

^♦Corresponding author
Julia Rogała, Faculty of Medicine, Collegium Medicum, University of Rzeszów, Rzeszów, Poland

ABSTRACT

Treatment-resistant depression occurs in roughly one-third of individuals diagnosed with depression. Ketamine and esketamine have appeared as innovative antidepressant treatments that target the glutamatergic system and deliver promising therapeutic options for patients unresponsive to conventional monoaminergic antidepressants. This review delivers a complete analysis of the mechanisms of action, efficacy, clinical applications, and safety of ketamine and esketamine in the treatment of TRD. We conducted this literature review using the PubMed, Embase, and Cochrane databases through 2024 and included systematic reviews, randomized controlled trials, meta-analyses, clinical guidelines, and effectiveness studies. Both ketamine and esketamine demonstrate antidepressant effects. Clinical response rates in TRD patients range from 45% to 67%, which exceeds traditional antidepressant success in this population. Intravenous racemic ketamine (0.5 mg/kg) produces strong antidepressant effects within 24 hours. Intranasal esketamine (56–84 mg) given to patients twice a week is effective when combined with oral antidepressants. Studies suggest that both ketamine and esketamine may be useful in patients with treatment-resistant depression. The most frequently reported adverse effects are temporary dissociation, nausea, dizziness, and increased blood pressure. In most cases, these symptoms are mild and disappear on their own after a short time. Long-term observations point toward possible improvement in cognitive functioning, although the issue of abuse potential is still unclear and requires further research. Acting through glutamatergic pathways, both substances are capable of reducing depressive symptoms relatively quickly. Esketamine has obtained FDA approval together with REMS safety regulations, while intravenous ketamine continues to be administered as an offlabel therapy.

Keywords: treatment-resistant depression (TRD); ketamine; esketamine; glutamatergic system; rapid-acting antidepressants

Medical Science, 2026, 30, e142ms3863

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Published: 09 August 2026