Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis.
Ashok Seshadri, Larry J. Prokop, Balwinder Singh
Journal of Affective Disorders July 1, 2024 DOI: 10.1016/j.jad.2024.03.137 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Randomized Peer reviewed |
|---|---|
| Sample size | 12 |
| Population | Adults with treatment-resistant depression |
| Intervention | Intranasal esketamine |
| Dose | 0.2-0.5 mg/kg and >0.5 mg/kg for IV ketamine; 56-84 mg and 28 mg for IN esketamine |
| Topics | Depression Esketamine Ketamine |
| Keywords | Clinical trials Dose escalation Intranasal esketamine Intravenous ketamine Depression treatment Ketamine therapy Psychiatric research Mental health medicine |
| Citations | 50 |
| Key findings | Intravenous ketamine shows efficacy at doses as low as 0.2 mg/kg with no added benefit above 0.5 mg/kg, while intranasal esketamine is most effective at 56–84 mg. |
Abstract
Intravenous (IV) racemic ketamine and intranasal (IN) esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). This systematic review aims to evaluate the efficacy and safety of ketamine and esketamine at various dosages for depression. We included randomized controlled trials (RCTs) with parallel group dose comparison of ketamine and esketamine for depression/TRD. Ovid Medline, Embase, PsycINFO, Scopus and Cochrane databases were searched. Standardized mean differences were calculated using Hedges'-g to complete random effects meta-analysis. The efficacy outcomes were changes in depression outcomes for IV ketamine and IN esketamine respectively. Safety was assessed by reported adverse effects. A random effects meta-analysis of studies (n = 12) showed efficacy in reducing depression symptoms with IV ketamine (Hedges'g = 1.52 [0.98-2.22], Z = 4.23, p 0.2-0.5 mg/kg and > 0.5 mg/kg. Higher IV ketamine doses (>0.5 mg/kg) did not lead to greater treatment response. Esketamine doses of 56-84 mg were superior to 28 mg dose. Overall quality of evidence was low and limited by small number of studies. Publication bias was high. This meta-analysis suggests that IV ketamine may be efficacious at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, without demonstrable increased benefit at 1 mg/kg, based on a small number of studies. Efficacy for IN esketamine increases with doses above 28 mg with best response being found between 56 and 84 mg for reducing depressive symptoms.
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 33
- Innovative approaches in the treatment-resistant depression: exploring different therapeutic pathways. GeroScience March 25, 2025
- Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Therapeutic Advances in Psychopharmacology 2025
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals? Journal of Affective Disorders April 15, 2026
- Utilizing depression symptom-based phenotypes to explore ketamine treatment response in major depression: The Bio-K multicenter trial. Journal of Affective Disorders September 15, 2025
and 28 more in the library
Cites 16
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- 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 and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
and 11 more in the library