Esketamine for treatment‑resistant depression: A review of clinical evidence (Review)

Abstract

Treatment-resistant depression (TRD) is a challenge for psychiatrists, even after more than seven decades since the first antidepressants were used in clinical practice. Non-monoaminergic-based drugs with antidepressant properties have been developed, but to date, only esketamine and brexanolone have been approved for TRD and postpartum depression, respectively. A narrative review on the efficacy and safety of esketamine in the main categories of depressive disorders has been conducted through four electronic databases (Pubmed, Cochrane, EMBASE and Clarivate/Web of Science) The primary objective of the present review was to find evidence that may support the usefulness of esketamine for patients diagnosed with TRD as well as data about its potential adverse effects in the short and long term. A total of 14 papers were reviewed, and their results support the recommendation of esketamine for treatment of TRD as an add-on to antidepressants, but more data is needed in order to assess its long-term efficacy and safety. It must also be mentioned that there have been a few trials which did not report a significant effect on the severity of depressive symptoms with esketamine in TRD, therefore, caution is indicated for patients initiated on this adjuvant agent. There has been insufficient data to formulate specific guidelines about esketamine administration because evidence about favorable or negative prognostic factors of this treatment has been lacking, and the duration of its administration has not been unanimously accepted. Novel directions for research have been identified, especially in the case of patients with TRD and substance use disorders, geriatric or bipolar depression or in major depression with psychotic features.

Keywords: esketamine; ketamine; major depressive disorder; psychotic depression; tolerability; treatment-resistant depression.

Figure 1

Mechanisms of action of esketamine, based on data from preclinical and clinical studies. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; Glu, glutamate; HC, hippocampus; NMDA, N-methyl-D-aspartate; PFC, prefrontal cortex.