Translational control by ketamine and its implications for comorbid cognitive deficits in depressive disorders
Vern Lewis, Brandon Rodrigue, Emma J. Arsenault, Molly Zhang, Fatimeh-Frouh Taghavi-Abkuh, W. Silva, Mysa Myers, E. Matta-Camacho, Argel Aguilar-Valles
Journal of Neurochemistry June 9, 2022 DOI: 10.1111/jnc.15652 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Measures | forced swim test, novelty suppressed feeding test |
| Topics | Depression Esketamine Ketamine |
| Key findings | The authors argue that ketamine's rapid antidepressant effects depend on activation of neuronal mRNA translation through the mTORC1 effector pathways 4E-BP1/2 and eEF2K, which mediate synaptic plasticity and antidepressant-like behaviors in rodents. They contend that preclinical data implicate these translation pathways in mood symptoms of major depressive disorder, while noting it remains unclear whether ketamine's pro-cognitive effects engage the same pathways or are consistently observed in treatment-resistant patients. |
Abstract
Ketamine has shown antidepressant effects in patients with major depressive disorder (MDD) resistant to first‐line treatments and approved for use in this patient population. Ketamine induces several forms of synaptic plasticity, which are proposed to underlie its antidepressant effects. However, the molecular mechanism of action directly responsible for ketamine's antidepressant effects remains under active investigation. It was recently demonstrated that the effectors of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, namely, eukaryotic initiation factor 4E (eIF4E) binding proteins 1 and 2 (4E‐BP1 and 4E‐BP2), are central in mediating ketamine‐induced synaptic plasticity and behavioural antidepressant‐like effect. 4E‐BPs are a family of messenger ribonucleic acid (mRNA) translation repressors inactivated by mTORC1. We observed that their expression in inhibitory interneurons mediates ketamine's effects in the forced swim and novelty suppressed feeding tests and the long‐lasting inhibition of GABAergic neurotransmission in the hippocampus. In addition, another effector pathway that regulates translation elongation downstream of mTORC1, the eukaryotic elongation factor 2 kinase (eEF2K), has been implicated in ketamine's behavioural effects. We will discuss how ketamine's rapid antidepressant effect depends on the activation of neuronal mRNA translation through 4E‐BP1/2 and eEF2K. Furthermore, given that these pathways also regulate cognitive functions, we will discuss the evidence of ketamine's effect on cognitive function in MDD. Overall, the data accrued from pre‐clinical research have implicated the mRNA translation pathways in treating mood symptoms of MDD. However, it is yet unclear whether the pro‐cognitive potential of subanesthetic ketamine in rodents also engages these pathways and whether such an effect is consistently observed in the treatment‐resistant MDD population.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 4
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- Long-Term Cognitive Outcomes of Esketamine Nasal Spray in Treatment-Resistant Depression: A Preliminary Report. Pharmaceuticals January 27, 2025
- Sex differences in placebo and antidepressant response to intranasal esketamine for treatment-resistant depression Molecular Psychiatry February 18, 2026
- Network Pharmacology Reveals the Potential Mechanism of Ketamine in Improving Cognitive Impairment in Patients With Depression. Alpha psychiatry August 2026
Cites 30
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
and 25 more in the library