, Volume 205, Issue 3, pp 419–429 | Cite as

Early effects of mood stabilizers on the Akt/GSK-3β signaling pathway and on cell survival and proliferation

  • Jean-Michel Aubry
  • Michèle Schwald
  • Eladia Ballmann
  • Félicien Karege
Original Investigation



Lithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed.


We evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3β axis, this pathway was explored for other drugs.

Materials and methods

The SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3β mRNA and protein were assessed for the seven drugs as well.


Lithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3β phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3β, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3β axis.


Valproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3β axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis.


Mood stabilizers SH-SY5Y cell proliferation Neuroprotection Akt–GSK-3β Signaling axis 



The authors thank Mrs Pascale Marin for her technical support. All the experiments complied with the current laws of Switzerland.


  1. Aubry JM, Ferrero F, Schaad N (2007) Pharmachotherapy of bipolar disorders. J Wiley (ed.), ChesterGoogle Scholar
  2. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347PubMedCrossRefGoogle Scholar
  3. Bowden CL, Brugger AM, Swann AC, Calabresse JR, Janicak PG (1994) Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study group. J Am Med Association 271:918–924CrossRefGoogle Scholar
  4. Bowden CL (1996) Dosing strategies and time course of response to antimanic drugs. J Clin Psychiatry 57(Suppl 13):4–9PubMedGoogle Scholar
  5. Brambilla P, Barale F, Soares JC (2003) Atypical antipsychotics and mood stabilization in bipolar disorder. Psychopharmacology 166:315–332PubMedGoogle Scholar
  6. Brunet A, Datta SR, Greenberg M (2001) Transcription-dependent and –independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11:297–305Google Scholar
  7. Calabrese JR, Huffman RF, White RL, Edwards S et al (2008) Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord 2008(10):323–333CrossRefGoogle Scholar
  8. Chen G, Hasanat KA, Bebchuk JM, Moore GJ, Glitz D, Manji HK (1999) Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosomatic Med 61:599–617Google Scholar
  9. Chuang DM (2005) The Antiapoptotic Actions of Mood Stabilizers: Molecular Mechanisms and Therapeutic Potentials. Annals of New York Academy of Science 1053:195–204CrossRefGoogle Scholar
  10. Ciapparelli A, Dell'Osso L, Pini S, Chiavacci MC, Fenzi M, Cassano GB (2000) Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24-month naturalistic study. J Clin Psychiatry 61:329–334Google Scholar
  11. Ciapparelli A, Dell'Osso L, Bandettini di Poggio A, Carmassi C, Cecconi D, Cassano GB (2003) Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder or psychotic bipolar disorder: a naturalistic 48-month follow-up study. J Clin Psychiatry 64:451–458CrossRefGoogle Scholar
  12. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995). Inhibition of glycogen synthase kinase-3 by insulin-mediated Protein kinase B. Nature 378:785–789Google Scholar
  13. De Sarno P, Li X, Jope RS (2002) Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium. Neurpharmacology 43:1158–1164CrossRefGoogle Scholar
  14. Di Daniel E, Mudge AW, Maycox PR (2005) Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons. Bipolar Disorder 7:33–41CrossRefGoogle Scholar
  15. Dwyer DS, Lu X-H, Freeman AM (2003) Neuronal glucose metabolism and schizophrenia: therapeutic prospects? Expert Rev Neurotherapeutics 3:29–40CrossRefGoogle Scholar
  16. Gelenberg AJ, Hopkins HS (1996) Antipsychotics in bipolar disorder. J Clin Psychiatry 57(Suppl 9):49–52PubMedGoogle Scholar
  17. Gould TD, Quiroz JA, Sing J, Zarate CA, Manji HK (2004) Emerging experimental therapeutics for bipolar disorder; insights from the molecular and cellular actions of current mood stabilzers. Mol Psychiatry 9:734–755PubMedCrossRefGoogle Scholar
  18. Grimes RS, Jope CA (2001) The multifaceted roles of glycogen synthase kinase 3β in cellular signalling. Progr Neurobiology 65:391–426CrossRefGoogle Scholar
  19. Gurvich N, Klein PS (2002) Lithium and Valproic acid: parallels and contrasts in diverse signaling contexts. Pharmacol Ther 96:45–66PubMedCrossRefGoogle Scholar
  20. Hajduch E, Litherland GJ, Hundal HS (2001) Protein kinase B (PKB/Akt)—a key regulator of glucose transport? FEBS Lett 492:199–203PubMedCrossRefGoogle Scholar
  21. Harwood AJ, Agam G (2003) Search for common mechanism for mood stabilizers as plasticity enhancers in the treatment of neuropsychiatric disorders. J Clin Psychiatry 64(Suppl 5):179–189Google Scholar
  22. Heiser P, Enning F, Krieg J-C, Vedder H (2007) Effects of haloperidol, clozapine and olanzapine on the survival of human neuronal and immune cells in vitro. J Psychopharmacol 21:851–856PubMedCrossRefGoogle Scholar
  23. Hsiung SC, Adlersberg M, Arango V, Mann JJ, Tamir H, Liu KP (2003) Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J Neurochem 87:162–194CrossRefGoogle Scholar
  24. Jope RS, Williams MB (1994) Lithium and brain signal transduction systems. Bioch Pharmacology 47:429–441CrossRefGoogle Scholar
  25. Jope RS, Johnson GVW (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95–102PubMedCrossRefGoogle Scholar
  26. Jope RS, Bijur GN (2002) Mood stabilizers, glycogen synthase kinase-3beta and cell survival. Mol Psychiatry 7(Suppl 1):S35–S45PubMedCrossRefGoogle Scholar
  27. Kahle PJ, Maas JW (1997) Use of CellTiter 96 reagents in semi automatic assay of neuronal survival. Neural Notes 3:12–14Google Scholar
  28. Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS (2004) The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett 560:11–119CrossRefGoogle Scholar
  29. Karege F, Perroud N, Burkhardt S, Schwald M, Ballmann E, La Harpe R, Malafosse A (2007) Alteration in Kinase activity but not in protein levels of kinase B and glycogen synthase kinase-3β in ventral prefrontal cortex of depressed suicide victims. Biol Psychiatry 61:240–245PubMedCrossRefGoogle Scholar
  30. Kim NR, Park SW, Lee JG, Kim YH (2008) Protective effects of olanzapine and haloperidol on serum withdrawal-induced apoptosis in SH-SY5Y cells. Prog Neuro-Psychopharmacol Biol Psychiatry 32:633–642CrossRefGoogle Scholar
  31. Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. PNAS USA 93:8455–8459PubMedCrossRefGoogle Scholar
  32. Kornhuber J, Schulz A, Wiltfang J et al (1999) Persistance of haloperidol in human brain tissue. Am J Psychiatry 156:885–890PubMedGoogle Scholar
  33. Kozlovsky N, Amar S, Belmaker TH, Agam G (2006) Psychoptropic drugs affect ser9-phosphorylated GSK-3β protein levels in rident frontal cortex. Int J Neuropsychopharmacol 9:337–342PubMedCrossRefGoogle Scholar
  34. Lawlor M, Alessi D (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Science 114:2903–2910PubMedGoogle Scholar
  35. Lesort M, Greendorfer A, Stockmeier C, Johnson GV, Jope RS (1999) Glycogen synthase kinase-3beta, beta-catenin, and tau in postmortem bipolar brain. J Neural Transm 106:1217–1222PubMedCrossRefGoogle Scholar
  36. Li R, El-Mallahk RS (2000) A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblatoma cells: caspase-3 dependency. Neurosci Lett 294:147–150PubMedCrossRefGoogle Scholar
  37. Li X, Bijur GN, Jope RS (2002) Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disorder 4:137–144CrossRefGoogle Scholar
  38. Li X, Zhu W, Roh MS, Friedman AB, Rosborough K, Jope RS (2004) In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. Neuropsychopharmacology 29:1426-31Google Scholar
  39. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(delta-delta) Ct method. Methods 25(4):412–408CrossRefGoogle Scholar
  40. Lu X-H, Bradley RJ, Dwyer DS (2004) Olanzapine produces trophic effects in vitro and stimulates phopshotylation of Akt/PKB, ERK1/2 and the mitogen-activated protein kinase p38. Brain Research 1011:58–68PubMedCrossRefGoogle Scholar
  41. Manji HK, Moora GJ, Chen G (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 46:949–940Google Scholar
  42. Manji HK, Duman RS (2001) Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 35:5–49PubMedGoogle Scholar
  43. Moore GJ, Bebchuk JM, Wids IB, Chen G, Manji HK (2000) Lithium-induced increase in human brain grey matter. Lancet 356:1241–1242PubMedCrossRefGoogle Scholar
  44. Olesen OV, Linnet K (1999) Olanzapine serum concentration in psychiatric patients given standard doses: the influence of comediacation. Ther Drug Monit 21:87–90PubMedCrossRefGoogle Scholar
  45. Pandey GN, Dwivedi Y, Rizavi HS et al (2009) GSK-3β gene expression in human postmortem brain: regional distribution, effects of age and suicide. Neurochem Res 34:274–285PubMedCrossRefGoogle Scholar
  46. Perry PJ, Bever KA, Arndt S, Combs MD (1998) Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biol Psychiatry 44:733–738PubMedCrossRefGoogle Scholar
  47. Robertson MD, McMullin MM (2000) Olanzapine concentrations in clinical serum and postmortem blood specimens–when does therapeutic become toxic? J Forensic Sci 45:418–421PubMedGoogle Scholar
  48. Roh M-S, Seo MS, Kim Y et al (2007) Haloperidol and clozapine differently regulate signals upstream of glycogen synthase kinase-3 in the rat frontal cortex. Exp Mol Med 39:353–360PubMedGoogle Scholar
  49. Sheline YI (2003) Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 54:338–352PubMedCrossRefGoogle Scholar
  50. Shin SY, Choi BH, Ko J, Kim SH, Kim YS, Lee YH (2006) Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca ± 2/calmodulin in PTEN-negative U-87MG human glioblastoma cells. Cell Signalling 18:1876–1886PubMedCrossRefGoogle Scholar
  51. Simhandl C, Denk E, Thau K (1993) The comparative efficacy of carbamazepine low and high serum level and lithium carbonate in the prophylaxis of affective disorders. J Affect Disord 28(4):221–231PubMedCrossRefGoogle Scholar
  52. Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signaling in intact cells. Curr Biol. 6:1664–1668PubMedCrossRefGoogle Scholar
  53. Tsai SJ, Liou YJ, Hong CJ, Yu YW, Chen TJ (2008) Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder. Pharmacogenomics J 8:384–390PubMedCrossRefGoogle Scholar
  54. Xie X, Hagan RM (1998) Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 38:119–130PubMedCrossRefGoogle Scholar
  55. Yatham LN, Goldstein JM, Vieta E et al (2005) Atypical antipsychotics in Bipolar depression: potential mechanisms of action. J Clin Psychiatry 66:40–48PubMedGoogle Scholar
  56. Yatham LN, Kennedy SH, O'Donovan C, Parikh SV, MacQueen G, McIntyre RS, Sharma V, Beaulieu S (2006) Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disorder 8:721–739CrossRefGoogle Scholar
  57. Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X (2005) A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438:873–877Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Jean-Michel Aubry
    • 2
  • Michèle Schwald
    • 1
  • Eladia Ballmann
    • 1
  • Félicien Karege
    • 1
  1. 1.Department of Medical GeneticsGeneva University Hospitals and Geneva UniversityChêne-BourgSwitzerland
  2. 2.Department of Psychiatry, Bipolar ProgramGeneva University Hospitals and University of GenevaGenevaSwitzerland

Personalised recommendations