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The role of GSK-3 in treatment-resistant depression and links with the pharmacological effects of lithium and ketamine: A review of the literature.

J F Costemale-Lacoste, J P Guilloux, R Gaillard

L'Encephale April 2016 DOI: 10.1016/j.encep.2016.02.003 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Peer reviewed
Interventions Lithium Ketamine
Topics Depression Ketamine Esketamine
Keywords Gsk-3 Kétamine Lithium
Key findings The authors argue that GSK-3β inhibition is involved in the antidepressant effects of lithium and ketamine, acting through mechanisms such as the PP2A/β-arrestin/AKT protein scaffold for lithium and p70S6K for ketamine. They report that GSK-3β inhibition appears effective and sufficient to improve mood in animal models, and that human evidence links antidepressant use to GSK-3β inhibition, supporting GSK-3β as a potential therapeutic target.

Abstract

Since the discovery of antidepressants, new treatments have emerged with fewer side effects but no greater efficacy. Glycogen synthase kinase 3 β (GSK-3β), a kinase known for its activity on glycogen synthesis, has in the last few years raised growing interest in biological psychiatry. Several efficient treatments in major depression have an inhibitory effect on this kinase, which could be targeted in new mood disorder treatments. The aim of this review is to summarize findings concerning the intracellular pharmacologic effects of GSK-3β inhibitors on mood. After a brief description of the intracellular transduction pathways implicated in both GSK-3β and mood disorders, we reviewed the results demonstrating GSK-3β involvement in the effects of lithium and ketamine. GSK-3β can be inhibited through several mechanisms such as serine phosphorylation or binding in a proteic scaffold and others. Its inhibition is implicated in numerous cellular pathways of interest involved in neuronal growth and architecture, cell survival, neurogenesis or synaptic plasticity. This inhibition appears to be both efficient and sufficient in improving mood in animal models. In human beings, several levels of evidence show GSK-3β inhibition with antidepressant use. Crucially, strong inhibition has been shown with lithium via the proteic scaffold PP2A/β-arrestin/AKT, and with the rapid antidepressant effect of ketamine via p70S6K. Our review focuses on mechanisms whereby the GSK-3β pathway has a part in the antidepressant effect of lithium and ketamine. This article highlights the importance of translational research from cell and animal models to the clinical setting in order to develop innovative therapeutic targets.

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

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