The Efficacy and Safety of Intranasal Formulations of Ketamine and Esketamine for the Treatment of Major Depressive Disorder: A Systematic Review
Ludivine Boudieu, Myriam Mennetrier, Pierre-Michel Llorca, Ludovic Samalin
Pharmaceutics December 22, 2023 DOI: 10.3390/pharmaceutics15122773 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Patients with major depressive disorder, including those with treatment-resistant depression or active suicidal ideation |
| Topics | Depression Esketamine Ketamine |
| Keywords | Intranasal formulation |
| Citations | 22 |
| Key findings | Intranasal esketamine has stronger evidence of efficacy than intranasal ketamine for major depressive disorder, with both providing rapid antidepressant action within hours. |
Abstract
Ketamine and its enantiomers represent an innovative glutamatergic agent as a treatment for individuals with treatment-resistant depression (TRD) and major depressive disorder (MDD) with suicidal ideation and behavior. Intranasal (IN) formulations could allow for quick onset of action on depressive symptoms as well as a reduction in side effects by bypassing the blood–brain barrier compared with administration via the intravenous route. The aim of this review was to provide an up-to-date analysis of the data on the efficacy and safety of IN ketamine and IN esketamine for the treatment of MDD. A systematic review following PRISMA guidelines was conducted. Databases (PubMed, Embase, MEDLINE, PsycINFO, and Google Scholar) were searched to capture articles about IN ketamine or IN esketamine for MDD. This systematic review highlighted the interest in IN routes of ketamine and esketamine for MDD patients with TRD or active suicidal ideation. They provide a rapid onset of antidepressant action within the first hours after administration. Nevertheless, the evidence of efficacy is stronger for IN esketamine than for IN ketamine in MDD patients. The safety profile appears to be acceptable for IN esketamine but requires further studies, and a more accurate IN delivery device is required for ketamine.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, 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 |
| 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 | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |
Citations in the library
Cited by 12
- Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry March 1, 2025
- Antidepressant effects of esketamine via the BDNF/AKT/mTOR pathway in mice with postpartum depression and their offspring. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 8, 2024
- Comparative safety of prescribed Esketamine and ketamine in relation to renal and urinary disorders: A pharmacovigilance perspective. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 10, 2025
- A Real-World Study on the Use, Effectiveness, and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression: INTEGRATE Study. Advances in Therapy May 1, 2025
- Ketamine and Esketamine in Psychiatry: A Comparative Review Emphasizing Neuroplasticity and Clinical Applications Psychoactives June 23, 2025
and 7 more in the library
Cites 28
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
and 23 more in the library