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

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. Depuis la découverte des antidépresseurs, de nouveaux traitements ont vu le jour avec de moins en moins d’effets secondaires, mais sans amélioration de l’efficacité. La glycogène synthase kinase 3 β (GSK-3β), une kinase connue pour son activité sur la synthèse du glycogène, a au cours des dernières années soulevé un intérêt croissant en psychiatrie biologique. Plusieurs traitements efficaces dans la dépression majeure ont un effet inhibiteur sur cette kinase, qui pourrait être une cible dans de nouveaux traitements des troubles de l’humeur. Le but de cette revue de littérature est de résumer les preuves concernant les effets pharmacologiques intracellulaires d’inhibiteurs de GSK-3β sur l’humeur. Après une brève description, des voies de transduction intracellulaire im