title: The role of GSK-3 in treatment-resistant depression and links with the pharmacological effects of lithium and ketamine: A review of the literature.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Inserm U1178, équipe « Dépression et antidépresseurs », CESP, université Paris-Sud, 94275 Le Kremlin-Bicêtre, France; Service de psychiatrie de l'adulte, centre hospitalier universitaire Bicêtre, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France. Electronic address: Jean-francois.costemale-lacoste@aphp.fr.
authors.forename: J F
authors.initials: JF
authors.lastname: Costemale-Lacoste
authors.affiliation: Inserm U1178, équipe « Dépression et antidépresseurs », CESP, université Paris-Sud, 94275 Le Kremlin-Bicêtre, France; EA3544, faculté de pharmacie, université Paris-Sud, 92296 Châtenay-Malabry, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Guilloux
authors.affiliation: Laboratoire de physiopathologie des maladies psychiatriques, centre de psychiatrie et neurosciences U894, université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre hospitalier Sainte-Anne, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Gaillard
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008094:Lithium / Q000494:pharmacology*; D019964:Mood Disorders / Q000188:drug therapy / Q000201:enzymology
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D007649:Ketamine; D008094:Lithium; D038362:Glycogen Synthase Kinase 3
keywords: Dépression résistante au traitement; GSK-3; Ketamine; Kétamine; Lithium; Treatment-resistant depression