Effect of ketamine and esketamine on RNA expression and its relevance for depression: a systematic review.
C. Pisanu, R. Carvalho Silva, Mattia Meattini, Massimo Gennarelli, Bernhard T Baune, A. Squassina, A. Minelli
Pharmacological Research July 31, 2025 DOI: 10.1016/j.phrs.2025.107894 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Citations | 6 |
| Key findings | Ketamine and esketamine induce diverse transcriptional changes implicating neuroplastic, inflammatory, and metabolic pathways, but no consistent peripheral biomarkers emerged. |
Abstract
Treatment-resistant depression (TRD) remains a challenge in psychiatry, necessitating novel therapeutic strategies beyond traditional monoaminergic antidepressants. Ketamine and its S-enantiomer esketamine have demonstrated rapid and robust antidepressant effects in TRD, probably through mechanisms involving glutamatergic modulation, neuroplasticity, and anti-inflammatory properties. However, the molecular underpinnings of these effects are not yet understood. This systematic review aimed to synthesize evidence from human and in vitro studies evaluating transcriptional changes associated with ketamine and esketamine treatment, to identify potential biomarkers and clarify molecular pathways relevant to their antidepressant properties. A systematic search conducted on PubMed and Scopus identified 12 studies assessing RNA expression following ketamine or esketamine treatment in patients with unipolar or bipolar depression or in human-derived cell models. Eligibility and quality were evaluated using PRISMA guidelines and a modified version of Downs and Black checklist. Twelve studies met inclusion criteria, only one of which explored the effect of esketamine, while all others focused on racemic ketamine. Five studies examined peripheral blood gene expression in patients with TRD, while seven assessed mRNA changes in vitro using human-derived cells. Transcriptome and candidate gene expression studies revealed modulation of genes and pathways related to glutamatergic signaling (GRM2, GRIN2D), immune regulation (STAT3, CCL22, IL6), and neuroplasticity (IGF2). No consistent peripheral biomarkers emerged, but transcriptional profiling revealed dynamic molecular responses to ketamine and esketamine. Ketamine and esketamine induce diverse transcriptional changes implicating neuroplastic, inflammatory, and metabolic pathways. Transcriptomic profiling offers a promising approach for uncovering biomarkers and mechanisms of antidepressant response, warranting further multi-omics, large-scale studies.
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 3
- Differential effects of ketamine enantiomers on EEG parameters including the gamma-delta shift phenomenon. British Journal of Pharmacology June 1, 2026
- Esketamine alleviates the pain-depression dyad: insights from exploratory transcriptomic profiling and Wnt4-associated molecular alterations within the anterior cingulate cortex Frontiers in Pharmacology October 16, 2026
- Effects of sub-anesthetic doses of esketamine on immune function and postoperative negative emotions in acoustic neuroma patients: a randomized clinical trial. Annals of medicine July 3, 2026
Cites 10
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
- Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression Translational Psychiatry January 10, 2022
and 5 more in the library