J Appl Biomed 3:25-35, 2005 | DOI: 10.32725/jab.2005.003

How does lithium mediate its therapeutic effects?

Anna Strunecká1,*, Jiří Patočka2,3, Milan ©árek4
1 Department of Physiology and Developmental Physiology, Faculty of Sciences, Charles University in Praha, Czech Republic
2 Department of Toxicology, Military Medical Academy, Hradec Králové, Czech Republic
3 Faculty of Health and Social Studies, University of South Bohemia in České Budějovice, Czech Republic
4 Psychiatric Department, First Faculty of Medicine, Charles University in Praha, Czech Republic

For the psychiatrist, lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. The molecular mechanisms underlying its therapeutic actions have not yet been fully explained. The effects of lithium on a number of enzymes and biological processes have been studied. Inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) have been suggested as the relevant intracellular targets for lithium action. The discovery of the role of GSK-3, the Wnt signalling system, and the anti-apoptotic factor Bcl-2 has led to the suggestion that there could be a therapeutic use for lithium in neurodegenerative disorders, such as Alzheimer's disease.

Keywords: bipolar disorder; Alzheimer's disease; inositol monophosphatase; glycogen synthase kinase-3; programmed cell death

Received: October 15, 2004; Revised: November 8, 2004; Published: March 31, 2005  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Strunecká A, Patočka J, ©árek M. How does lithium mediate its therapeutic effects? J Appl Biomed. 2005;3(1):25-35. doi: 10.32725/jab.2005.003.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Alda M., Grof P., Grof E. et al.: Mode of inheritance in families of patients with lithium-responsive affective disorders. Acta Psychiatr. Scand. 90: 304-310, 1994. Go to original source... Go to PubMed...
    2. Alda M., Grof E., Cavazzoniet P. al.: Autosomal recessive inheritance of affective disorders in families of responders to lithium prophylaxis? J. Affect. Disord. 44: 153-157, 1997. Go to original source... Go to PubMed...
    3. Allison J.H. and. Stewart M.A.: Reduced brain inositol in lithium-treated rats. Nature 33: 267-268, 1971. Go to original source...
    4. Atack J.R.: Inositol monophosphatase inhibitors: a novel treatment for bipolar disorder? Biol. Psychiatry 37: 761-763, 1995. Go to original source... Go to PubMed...
    5. Avissar S., Schreiber G., Danon A., Belmaker R.H.: Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature 331: 440-442, 1988. Go to original source... Go to PubMed...
    6. Bauer M., Forsthoff A., Baethge C. et al.: Lithium augmentation therapy in refractory depression-Update 2002. Eur. Arch. Clin. Neurosci. 253: 132-139, 2003. Go to original source...
    7. Berridge M.J., Downes C.P., Hanley M.R.: Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem. J. 206: 587-595, 1982. Go to original source... Go to PubMed...
    8. Berridge M.J., Downes C.P., Hanley M.R.: Neural and developmental actions of lithium: a unifying hypothesis. Cell 59: 411-419, 1989. Go to original source... Go to PubMed...
    9. Berridge M.J. and Irvine R.F.: Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315-321, 1984. Go to original source... Go to PubMed...
    10. Berry G.T., Buccafusca R., Greer J.J., Eccleston E..: Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain. Mol. Genet. Metab. 82: 87-92, 2004. Go to original source... Go to PubMed...
    11. Bhat R.V., Budd Haeberlein S.L., Avila J.: Glycogen synthase kinase 3: a drug target for CNS therapies. J. Neurochem. 89: 1313-1317, 2004. Go to original source... Go to PubMed...
    12. Bone R., Springer J.P., Atack J.R.: Structure of inositol monophosphatase the putative target of lithium therapy. Proc. Natl. Acad. Sci. USA 89: 10031-10035, 1992. Go to original source... Go to PubMed...
    13. Bone R., Frank L., Springer J.P., Atack J.R.: Structural studies of metal binding by inositol monophosphatase. Biochemistry 33: 9468-9476, 1994. Go to original source... Go to PubMed...
    14. Bunney W.E.. Pert A, Rosenblatt J., Pert C. B., Gallaper D.: Mode of action of lithium. Some biological considerations. Arch. Gen. Psychiatry 36: 898-901, 1979. Go to original source... Go to PubMed...
    15. Cade J.: Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 2: 349- 352, 1949. Go to original source... Go to PubMed...
    16. Cadigan K.M. and Nusse R.: Wnt signaling: a common theme in signal development. Genes Dev 11: 3286-3305, 1997. Go to original source... Go to PubMed...
    17. Chen D.F., Schneider G.E., Martinou J.C., Tonegawa S.: Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 385: 434-439, 1997. Go to original source... Go to PubMed...
    18. Dajani R., Fraser E., Roe S.M. et al.: Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105: 721-732, 2001. Go to original source... Go to PubMed...
    19. Davis J.M. and Fann W.E.: Lithium. Ann. Rev. Pharmacol. 11: 285-302, 1971. Go to original source... Go to PubMed...
    20. De Ferrari G.V., Chacon M.A., Barria M.I. et al.: Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol. Psychiatry. 8: 195-208, 2003. Go to original source... Go to PubMed...
    21. Dehpour A.R., Emamian E.S., Ahmadi-Abhari S.A., Azizabadi-Farahani M.: The lithium ratio and the incidence of side effects. Prog. Neuropsychopharmacol. Biol. Psychiatry 22: 959-970, 1998. Go to original source... Go to PubMed...
    22. Dreno B., Chosidow O., Revuz J., Moyse D.: The study investigator group. Lithium gluconate 8% vs ketoconazole 2% in the treatment of seborrhoeic dermatitis: a multicentre, randomized study. Br. J. Dermatol. 148: 1230-1236, 2003. Go to original source... Go to PubMed...
    23. Drummond A.H.: Lithium affects G protein receptor coupling. Nature 331: 388, 1988. Go to original source... Go to PubMed...
    24. Eldar-Finkelman H.: Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol. Med. 8: 126-132, 2002. Go to original source... Go to PubMed...
    25. Frost R.E. and Messiha F.S.: Clinical uses of lithium salts. Brain Res. Bull. 11: 219-231, 1983. Go to original source... Go to PubMed...
    26. Gallicchio V.S.: Transport of the lithium ion. In: Bach R.O. and V.C. Gallicchio (eds.): Lithium and cell physiology. Springer Verlag 1990, pp. 47-57. Go to original source...
    27. Geisler A. and Mork A.: The interaction of lithium with magnesium-dependent enzymes. In: In: Bach R.O. and Gallicchio V.C. (eds.): Lithium and Cell Physiology. Springer Verlag 1990, pp.125-136. Go to original source...
    28. Gomez-Ramos A., Smith M.A., Perry G., Avila J.: Tau phosphorylation and assembly. Acta Neurobiol. Exp. (Wars). 64: 33-39, 2004. Go to PubMed...
    29. Gould T.D., Zarate C.A., Manji H.K.: Glycogen synthase kinase-3: a target for novel bipolar disorder treatments. J. Clin. Psychiatry 65: 10-21, 2004a. Go to original source...
    30. Gould T.D., Quiroz J.A., Singh J., Zarate C.A., Manji H.K.: Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers. Mol. Psychiatry 9: 734-755, 2004b. Go to original source... Go to PubMed...
    31. Grof P., Alda M., Grof E., Zvolsky P., Walsh M.: Lithium response and genetics od affective disorders. J. Affect. Disord. 32: 85-95, 1994. Go to original source... Go to PubMed...
    32. Grof P., Hux M., Grof E., Arato M.: Prediction of response to stabilizing lithium treatment. Pharmacopsychiat. 16: 195-200, 1983. Go to original source... Go to PubMed...
    33. Hallcher L.M. and Sherman W.R.: The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J. Biol. Chem. 255: 10896-10901, 1980. Go to original source...
    34. Harvey B.H., Meyer C.L., Gallichio V.S., Manji H.K.: Lithium salts in AIDS and AIDS-related dementia. Psychopharmacol. Bull. 36: 5-26, 2002.
    35. Harwood A.J.: Life, the universe and development. Current Biol. 10: R116-R119, 2000. Go to original source... Go to PubMed...
    36. Hedgepeth C., Conrad L., Zhang Z. et al.: Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Develop. Biol. 185: 82-91, 1997. Go to original source... Go to PubMed...
    37. Hong M., Chen D.C., Klein P., Lee V.M.: Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J. Biol. Chem. 272: 25326-25332, 1997. Go to original source... Go to PubMed...
    38. Johnson C.D., Puntis M., Davidson N., Todd S., Bryce R.: Randomized, dose-finding phase III study of lithium gamolenate in patients with advanced pancreatic adenocarcinoma. Br. J. Surg. 88, 662-668, 2001 Go to original source... Go to PubMed...
    39. Johnson F.N., J.F.J. Cade: The historical background to lithium research and therapy. In: Johnson F.N. (ed.): Lithium research and therapy, Academic Press Inc. (London)1975, pp. 9-22.
    40. Khachaturian Z. S.: An overview of Alzheimer's disease research. Am. J. Med. 104: 26S-31S, 1998. Go to original source... Go to PubMed...
    41. Klein P.S. and Melton D.A.: A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA 93: 8455-8459, 1996. Go to original source... Go to PubMed...
    42. Koong S.S., Reynolds J.C., Movius E.G. et al.: Lithium as a potential adjuvant to 131I therapy of metastatic, well differentiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 84: 912-916, 1999. Go to original source...
    43. Lenox R. and Wang H.L.E.: molecular basis of lithium action: Integration of lithium- responsive signaling and gene expression networks. Molec. Psychiatry 8: 135-144, 2003. Go to original source... Go to PubMed...
    44. Leroy K., Boutajangout A., Authelet M. et al.: The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. Acta Neuropathol. 103: 91-99, 2002. Go to original source...
    45. Levy-Lahad E., Wasco W., Poorkaj P. et al.: Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269: 973-977, 1995. Go to original source... Go to PubMed...
    46. Liu S.J., Zhang A.H., Li H.L. et al.: Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J. Neurochem. 87:1333-1344, 2003. Go to original source... Go to PubMed...
    47. Lovestone S., Davis D.R., Webster M.T. et al.: Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol. Psychiatry 45: 995-1003, 1999. Go to original source... Go to PubMed...
    48. Manji H.K. and Lenox R.H.: Long-term action of lithium: a role for transcriptional and posttranscriptional factors regulated by protein kinase C. Synapse 16: 11-28, 1994. Go to original source... Go to PubMed...
    49. Manji H.K., Potter W.Z., Lenox R.H.: Signal transduction pathways. Molecular targets for lithium's actions. Arch. Gen. Psychiatry 52: 531-543, 1995. Go to original source... Go to PubMed...
    50. Manji H. K., Moore G. J., Chen G.: Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness. J. Clin. Psychiatry 61, Suppl 9: 82-96, 2000.
    51. Miller J.R., Hocking A.M., Brown J.D., Moon R.T. : Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18: 7860-7872, 1999. Go to original source... Go to PubMed...
    52. Morgan T.H.: The relation between normal and abnormal development of the embryo of the frog, as determined by the effect of lithium chloride in solution. Arch. Entwickl. 16: 691-716, 1902. Go to original source...
    53. Mudher A., Shepherd D., Newman T.A. et al.: GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol. Psychiatry 9: 522-530, 2004. Go to original source... Go to PubMed...
    54. Munoz-Montano J.R., Moreno F.J., Avila J., Diaz-Nido J.: Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett. 411: 183-188, 1997. Go to original source... Go to PubMed...
    55. Murayama M., Tanaka S., Palacino J. et al.: Direct association of presenilin 1 with beta-catenin. FEBS Lett. 433: 73-77, 1998. Go to original source... Go to PubMed...
    56. Nieoullon A.: Alzheimer's disease: neurobiological advances supporting proposals for new therapeutical approaches. J. Appl. Biomed. 2: 123-130, 2004. Go to original source...
    57. Norton B. and Whaley L.J.: Mortality of lithium-treated population. Br. J. Psychiatry 145: 277-282, 1984. Go to original source... Go to PubMed...
    58. O'Brien W.T., Harper A.D., Jove F. et al.: Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J. Neurosci. 24: 6791-6798, 2004. Go to original source... Go to PubMed...
    59. Pap M. and Cooper G.M.: Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J. Biol. Chem. 273: 19929-19932, 1998. Go to original source... Go to PubMed...
    60. Passmore M.J., Garnham J., Duffy A. et al.: Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine. Bipolar Disord. 5: 110-114, 2003. Go to original source... Go to PubMed...
    61. Patočka J., Klár I., Strunecká A.: Molekulární mechanismy biologického účinku lithia. Čs. Fyziol. 51: 122-129, 2002.
    62. Pei J.J., Tanaka T., Tung Y.C. et al.: Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J. Neuropathol. Exp. Neurol. 56: 70-78, 1997. Go to original source... Go to PubMed...
    63. Perez M., Hernandez F., Lim F., Diaz-Nido J., Avila J.: Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis. 5:301-308, 2003. Go to original source... Go to PubMed...
    64. Phiel C.J., C.A. Wilson, V.M. Lee, P.S. Klein: GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423: 435-439, 2003. Go to original source... Go to PubMed...
    65. Phiel C.J. and Klein P.S.: Molecular targets of lithium therapy. Annu. Rev. Pharmacol. Toxicol. 41: 789-813, 2001. Go to original source... Go to PubMed...
    66. Pieri-Balandraud N., Hugueny P., Henry J.F., Tournebise H., Dupont C.: Hyperparathyroidism induced by lithium. A new case. Rev. Med. Interne 22: 460-464, 2001. Go to original source... Go to PubMed...
    67. Plenge P.: Lithium effects on brain energy metabolism. In: Gabay S., J. Harris, B.T. Ho (eds.): Metal Ions in Neurology and Psychiatry, Alan R. Liss, Inc. New York 1985, pp. 153-164.
    68. Price L.H. and Heninger G.R.: Lithium in the treatment of mood disorders. Drug Therapy 331: 591-598, 1994. Go to original source...
    69. Rana R.S. and Hokin L.E.: Role of phosphoinositides in transmembrane signaling. Physiol. Rev. 70: 115-164, 1990. Go to original source... Go to PubMed...
    70. Selkoe D.J.: Notch and presenilins in vertebrates and invertebrates: implications for neuronal development and degeneration. Curr. Opin. Neurobiol. 10: 50-57, 2000. Go to original source... Go to PubMed...
    71. Schou M.: Biology and pharmacology of lithium ion. Pharmacol. Rev. 9: 17-58, 1957. Go to PubMed...
    72. Schou M.: Clinical aspects of lithium in psychiatry. In: Birch N.J. (ed): Lithium and the Cell. Orlando, Fla: Academic Press Onc. 1-6, 1991. Go to original source...
    73. Schou M., Juel-Nielsen N., Stromgren E., Voldby H.: The treatment of manic psychoses by the administration of lithium salts. J. Neurol. Neurosurg. Psychiatry 17: 250-260, 1954. Go to original source... Go to PubMed...
    74. Schrauzer G.N.: Lithium: occurrence, dietary intakes, nutritional essentiality. J. Am. Coll. Nutr. 21:14-21, 2002. Go to original source... Go to PubMed...
    75. Shaldubina A., Agam G., Belmaker R.H.: The mechanism of lithium action: state of the art, ten years later. Prog. Neuropsychopharmacol. Biol. Psychiatry 25:855-866, 2001. Go to original source... Go to PubMed...
    76. Sherman W.R., Gish B.G., Honchar M.P., Munsell L.Y. : Effects of lithium on phosphoinositide metabolism in vivo. Federation Proc. 45: 2639-2646, 1986.
    77. Sjoholt G., Guldbransen A.K., Lovlie R. et al.: A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients. Mol. Psychiatry 5: 172-180, 2000. Go to original source... Go to PubMed...
    78. Soares, J.C., Mallinger A.G., Dippold C.S. et al.: Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study. Psychopharmacol. 149: 12-16, 2000. Go to original source... Go to PubMed...
    79. Sperber B.R., Leight S., Goedert M., Lee V.M.Y.: Glycogen synthase kinase 3β phosphorylates tau protein at multiple sites in intact cells. Neurosci Lett. 197: 149-153, 1995. Go to original source... Go to PubMed...
    80. Stambolic V., Ruel L., Woodgett J.: Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signaling in intact cells. Curr. Biol. 6:1664-1668, 1997. Go to original source...
    81. Strunecká A. and Patočka J.: Lithium a Alzheimerova choroba. Psychiatrie 8: 11-14, 2004.
    82. Strunecká A., Řípová D., Haąkovec L.: Incorporation of 32P-orthophosphate into phosphoinositides in platelets of depressive patients before and after 10-day lithium administration. Med. Sci. Res. 15: 197-198, 1987.
    83. Su Y., Ryder J., Li B. et al.: Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 43: 6899-6908, 2004. Go to original source... Go to PubMed...
    84. Takashima A., Murayama M., Murayama O. et al.: Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc. Natl. Acad. Sci. USA 95: 9637-9641, 1998. Go to original source... Go to PubMed...
    85. Tosteson D.S.: Lithium and mania. Sci. Amer. 244: 130-140, 1981. Go to original source... Go to PubMed...
    86. Turecki G., Grof P., Grof E. et al.: Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol. Psychiatry 6: 570-578, 2001. Go to original source... Go to PubMed...
    87. Wikramanayake A.H., Hong M., Lee P.N. et al.: An ancient role for nuclear beta-catenin in the evolution of axial polarity and germ layer segregation. Nature 426: 446-450, 2003. Go to original source... Go to PubMed...
    88. Williams R.S., Cheng L., Mudge A.W., Harwood A.J.: A common mechanism of action for three mood-stabilizing drugs. Nature 417: 292-295, 2002. Go to original source... Go to PubMed...
    89. Williams R, Ryves W.J., Dalton E.C. et al.: A molecular cell biology of lithium. Biochem. Soc. Trans. Pt 5: 799-802, 2004. Go to original source... Go to PubMed...
    90. Woodget J.R.: Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and bipolar disorder. Curr. Drug Targets Immun. Endocr. Metabol. Disord. 3: 281-290, 2003. Go to original source... Go to PubMed...
    91. Yu G., Chen F., Levesque G. et al.: The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J. Biol. Chem. 273:16470-16475, 1998. Go to original source... Go to PubMed...
    92. Yung C.Y.: A review of clinical trials of lithium in neurology. Pharmacol. Biochem. Behav. 21 Suppl 1:57-64, 1984.. Go to original source... Go to PubMed...

    Return to the content