Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review

Salahudeen, Mohammed S; Wright, Cameron M; Peterson, Gregory M

doi:10.1177/2042098620937899

Cited by 72Treatment of Major DepressionElectroconvulsive Therapy StudiesTryptophan and brain disorders

Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review

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Salahudeen, Mohammed S, Wright, Cameron M, Peterson, Gregory M·2020·Therapeutic Advances in Drug Safety

DOI 10.1177/2042098620937899PMC PMC7383653

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Abstract

This narrative review aims to provide an overview of the current literature on the pharmacology, safety, efficacy and tolerability of intranasal esketamine, the S-enantiomer of ketamine, for the treatment of treatment-resistant depression (TRD). A literature search using Medline, Embase, PsycINFO and Cochrane Central was conducted (January 2000 to July 2019). Product information and www.clinicaltrials.gov were also reviewed. The literature search was limited to human studies published in English. Phase I, II, and III studies of intranasal esketamine for TRD were reviewed. About a third of patients with major depressive disorder fail to achieve remission despite treatment with multiple antidepressants. This article examines the trials that led to the approval of esketamine in the United States, as well as other recent studies of esketamine for TRD. The findings from limited phase III trials illustrate that intranasal esketamine is effective and safe in reducing depressive symptoms and achieving clinical response in patients with TRD. The optimum duration and frequency of use are not fully understood. Although the nasal spray is a convenient dosage form, its use in practice may be limited by cost and administrative regulation. While it may prove beneficial to many patients who suffer from TRD, further long-term data are required, along with comparative trials with the R-isomer (arketamine). In the interim, care and monitoring should be exercised in its use in clinical practice. Plain language summary: Esketamine: new therapy for severe depression Intranasal esketamine, the S-enantiomer of ketamine, was recently approved in the United States for the treatment of treatment-resistant depression (TRD). The findings from limited clinical trials indicate that intranasal esketamine is effective and safe in patients with TRD, although the optimum dose, duration and frequency of use are not fully understood. Its use in practice may be limited by cost and administrative regulation, and further long-term data are required.

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The action of esketamine on AMPA receptors may ultimately improve neural plasticity and synaptogenesis through signaling pathways resulting in enhanced BDNF production.
“Furthermore, the action of esketamine on AMPA receptors may ultimately improve neural plasticity and synaptogenesis through signaling pathways resulting in enhanced BDNF production [62].”
From The Impact of BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 Genetic Polymorphisms in Antidepressant Treatment Response Phenotypes (2023) · cites this paper as [62]

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Westenhöfer, S., Ehrt‐Schäfer, Y., Provaznikova, B., Prinz, S., Spies, M., Akhmetova, L., Nadesalingam, N., Strickler, E., Krähenmann, R., Seifritz, E., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10250654/v1
Efficacy and safety of perioperative esketamine for postoperative depressive symptoms in breast cancer patients: a meta-analysis
Ji, R., Shi, X., Liu, X. Q., Xiao, H., Sun, X., Yu, S., Dong, G., Zheng, C., & Ji, F. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1806943

Esketamine: A Novel Option for Treatment-Resistant Depression
Bozymski, K. M., Crouse, E. L. B., Titus-Lay, E. N., Ott, C. A., Nofziger, J. L., & Kirkwood, C. K. (2019) · Annals of Pharmacotherapy · doi:10.1177/1060028019892644 · Cited by 82 · see citing works
Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review
Sapkota, A., Khurshid, H., Qureshi, I. A., Jahan, N., Went, T. R., Sultan, W., & Alfonso, M. (2021) · Cureus · doi:10.7759/cureus.17352 · Cited by 45 · see citing works
Intranasal esketamine: A novel drug for treatment-resistant depression
Khorassani, F., & Talreja, O. (2020) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/zxaa191 · Cited by 19 · see citing works
Intranasal esketamine in treatment-resistant depression: a profile of its use
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The role of intranasal esketamine in treatment-resistant depression
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Authors: Salahudeen, M. S., Wright, C. M., & Peterson, G. M.
Affiliations: University of Tasmania (AU)
Corresponding author: Peterson, Gregory M
ORCID: Salahudeen, Mohammed S
Wright, Cameron M
Peterson, Gregory M
Venue: Therapeutic Advances in Drug Safety
Publisher: SAGE Publications
Published: 2020-01
Volume: 11
Pages: 2042098620937899-2042098620937899
ISSN: 2042-0986 (ISSN-L)
2042-0994
DOI: 10.1177/2042098620937899
PMC: PMC7383653
OpenAlex: W3044729970
Cited by: 72
References: 80
Citations by year: 2026: 8 · 2025: 11 · 2024: 18 · 2023: 14 · 2022: 12 · 2021: 8 · 2020: 1
FWCI: 1.15
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (unspecified)
Locations: Therapeutic Advances in Drug Safety (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
UTAS Research Repository (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: esketamine, treatment-resistant depression, major depressive disorder, intranasal administration, ketamine enantiomers, drug safety, drug efficacy, tolerability, drug approval, dose optimization, long-term outcomes

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Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review

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