Lithium: the complex mechanisms of action of the simplest metal

Author/s
Luchezar Hranov
Citation
Issue 3 Summer 2013
CEPiP.2013;1:64-73
Abstract

Lithium enhances neuronal resilience and hampers long-term neuronal (and by extension, mental) deterioration. Its mood stabilising properties are due to multi-level actions on the intracellular signal transduction pathways affecting the function of G proteins, of some intracellular messengers (mio-inositol, MARKS, Bcl-2, ER stress proteins, calmodulin-synapsin1-synaptotagmin complex), and of some key enzymes (adenilyl cyclase, protein kinases A, C? and C?, GSK-3, ERK, MAP-kinase). In the long run, mood-stabilising agents enhance blockade of excitotoxic/apoptotic pathways, phosphorylation and rearrangement of microtubular proteins, and regulation of the expression of genes implicated in processes involved in neuroplasticity, neuroprotection, even neurogenesis. Long-term stabilisation of mood has taught us the lesson that pharmacologic enhancement of neuroprotective/neurotrophic mechanisms carries a high promise for effective interventions not only in bipolar affective disorder and schizophrenia but in brain damage, dementias and other neurodegenerative diseases, and even in stress-induced mental disorders.

Keywords: lithium, bipolar disorder, signal transduction, neuroplasticity

Cite as: Cutting Edge Psychiatry in Practice 2013, 3(1):64-73; https://doi.org/10.65031/azct4953

References

  1. Angst J, Marneros A. Bipolarity from ancient to modern times: conception, birth and rebirth. J Affect Disord. 2001;67:3-19.                 
  2. Berk M, Conus P, Kapczinski F, Andreazza AC, Yucel M, Wood SJ, et al. From neuroprogression to neuroprotection: implications for clinical care. MJA. 2010;193:36-40.   
  3. Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989;59:411-9. https://doi.org/10.1016/0092-8674(89)90026-3
  4. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349-52.              
  5. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochemistry. 2000;75 (4):1729 – 34. https://doi.org/10.1046/j.1471-4159.2000.0751729.x
  6. Chen G, Zeng WZ, Yuan PX, Huang LD, Jiang YM, Zhao ZH, Manji HK. The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J Neurochem. 1999;72:879-82. https://doi.org/10.1046/j.1471-4159.1999.720879.x
  7. Chin PC, Majdzadeh N, D’Mello SR. Inhibition of GSK3beta is a common event in neuroprotection by different survival factors. Brain Res Mol Brain Res. 2005;137:193-201. https://doi.org/10.1016/j.molbrainres.2005.03.004
  8. Chiu CT, Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010;128 (2):281-304. https://doi.org/10.1016/j.pharmthera.2010.07.006
  9. DeLisi L. Critical overview of current approaches to genetic mechanisms in schizophrenia research. Brain Res Rev. 2000;31:187-92.     
  10. Drevets WC, Price JL, Simpson JR. Subgenual prefrontal cortex abnormalities in mood disorders [letter]. Nature. 1997;386:824-7. https://doi.org/10.1038/386824a0
  11. Einat H, Yuan P, Szabo ST, Dogra S, Manji HK. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology. 2007;55:123-31. https://doi.org/10.1159/000106054
  12. Freland L, Beaulieu JM. Inhibition of GSK3 by lithium, from single molecules to signaling networks [Art. 14]. Front Mol Neurosci. 2012;1-7. https://doi.org/10.3389/fnmol.2012.00014
  13. Goodwin FK, Baldessarini RJ, Dunner DL. The use of lithium in treating bipolar disorder. CNS Spectrums. 2002;7 (11):TM1-TM12         
  14. Gurvich N, Klein PS. Lithium and valproic acid: parallels and contrasts in diverse signaling contexts. Pharmacol Therapeutics. 2002;96:45-66. https://doi.org/10.1016/s0163-7258(02)00299-1
  15. Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, et al. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry. 2011;69:326-35. https://doi.org/10.1097/01.yic.0000405741.51457.8f
  16. Hranov LG. Do neurons have mood and how can it be stabilized? [abstract]. Psychiatria Danubina. 2009;21 Suppl 2:S158.   
  17. Hunsberger J, Austin DR, Henter JD, Chen G. The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci. 2009;11:333-48. https://doi.org/10.31887/dcns.2009.11.3/jhunsberger
  18. Jope RS. A bimodal model of the mechanism of action of lithium. Molecular Psychiatry. 1999;4: 21-5.                
  19. Jope RS. Anti-bipolar therapy: mechanism of action of lithium. Molecular Psychiatry. 1999;4:117-28.
  20. Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci. 2003;24:441-43. https://doi.org/10.1016/s0165-6147(03)00206-2
  21. Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets. 2006;7 (11):1421-34. https://doi.org/10.2174/1389450110607011421
  22. Lim KO, Rosenbloom MJ, Faustman WO, Sullivan EV. Cortical gray matter deficit in patients with bipolar disorder. Schizophr Res. 1999;40:219-27. https://doi.org/10.1016/s0920-9964(99)00063-8
  23. Machado-Vieira R, Salvadore G, DiazGranados N, Ibrahim L, Latov D, Wheeler-Castillo C, et al. New therapeutic targets for mood disorders. Scientific World Journal. 2010;10:713-26. https://doi.org/10.1100/tsw.2010.65
  24. Manji HK, Lenox RH. Signaling: cellular Insights into the pathophysiology of bipolar disorder. Biol Psychiatry. 2000;48:518-30. https://doi.org/10.1016/s0006-3223(00)00929-x
  25. Manji HK, McNamara R, Chen G, Lenox RH. Signalling pathways in the brain: cellular transduction of mood stabilisation in the treatment of manic-depressive illness. Aust N Z J Psychiatry. 1999;33 Suppl: 65-83. https://doi.org/10.1111/j.1440-1614.1999.00670.x
  26. Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: Implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry. 2000;48:740-54. https://doi.org/10.1016/s0006-3223(00)00979-3
  27. Manji HK, Moore GJ, Chen G. Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers. BJP. 2001;178:107-19. https://doi.org/10.1192/bjp.178.41.s107
  28. Manji HK, Young LT. Structural plasticity and neuronal resilience: are these targets for mood stabilizers and antidepressants in the treatment of bipolar disorder? Bipolar Disord. 2002;4 (2):77-9. https://doi.org/10.1034/j.1399-5618.2002.00001.x
  29. Manji HK, Zhou R, Chen G. Neuroplasticity and cellular resilience in bipolar disorder. Bipolar Disord. 2002:4 Suppl 1:56-7. https://doi.org/10.1034/j.1399-5618.4.s1.21.x
  30. Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK, Manji HK. Lithium-induced increase in human brain grey matter. Lancet. 2000;356:1241-2. https://doi.org/10.1016/s0140-6736(00)02793-8
  31. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA. 1998;95:13290-5. https://doi.org/10.1073/pnas.95.22.13290
  32. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: convergence of mechanisms. Neuropsychopharmacology. 2008;33:88-109. https://doi.org/10.1038/sj.npp.1301574
  33. Plenge P. Lithium effects on brain energy metabolism. In: Gabay SJ, Harris BT, editors. Metal ions in neurology and psychiatry. New York: Alan R. Liss, Inc.; 1985. p. 153-64.             
  34. Qu Z, Sun D, Young W. Lithium promotes neural precursor cell proliferation: evidence for the involvement of the non-canonical GSK-3P-NF-AT signaling. Cell Biosci. 2011;1:18. https://doi.org/10.1186/2045-3701-1-18
  35. Quiroz JA, Gray NA, Kato T, Manji HK. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 2008;33:2551-65. https://doi.org/10.1038/sj.npp.1301671
  36. Quiroz JA, Machado-Vieira R, Zarate CA Jr, Manji HK. Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology. 2010;62:50-60. https://doi.org/10.1159/000314310
  37. Savitz J, Nugent AC, Bogers W, Liu A, Sills R, Luckenbaugh DA, et al. Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication. Neuroimage. 2010;49 (4):2966-76. https://doi.org/10.1016/j.neuroimage.2009.11.025
  38. Schloesser RJ, Martinowich K, Manji HK. Mood-stabilizing drugs: mechanisms of action. Trends in Neurosciences. 2012;35 (1):36-46. https://doi.org/10.1016/j.tins.2011.11.009
  39. Schou M. Biology and pharmacology of lithium ion. Pharmacol Rev. 1957;17-58.               
  40. Schou M, Juel-Nielsen N, Stromgren E, Voldby H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry. 1954;17:250-60. https://doi.org/10.1136/jnnp.17.4.250
  41. Segal J. Lithium - an update on the mechanisms of action: pharmacology and signal transduction. S Afr Psychiatry Rev. 2004;7 (Pt 1):4-11.            
  42. Segal J. Lithium - an update on the mechanisms of action: neural effects and neuroanatomical substrate. S Afr Psychiatry Rev. 2004;7 (Pt 2):18-24. https://doi.org/10.4314/ajpsy.v7i3.30169
  43. Sherman WR, Gish BG, Honchar MP, Munsell LY. Effects of lithium on phosphoinositide metabolism in vivo. Fed Proc. 1986;45:2639-46.                
  44. Strunecka A, Patocka J, Sarek M. How does lithium mediate its therapeutic effects? J Appl Biomed. 2005;3:25-35.               
  45. Wood GE, Young LT, Reagan LP, Chen B, McEwen BS. Stress-induced structural remodeling in hippocampus: prevention by lithium treatment. Proc Natl Acad Sci USA. 2004;101:3973-8. https://doi.org/10.1073/pnas.0400208101
  46. Yan XB, Hou HL, Wu LM, Liu J, Zhou JN. Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacology. 2007;53:487-95. https://doi.org/10.1016/j.neuropharm.2007.06.020
  47. Yucel K, Taylor VH, McKinnon MC, McDonald K, Alda M, Young LT, et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment, Neuropsychopharmacology. 2008;33:361-7. https://doi.org/10.1038/sj.npp.1301405
  48. Zarate CA, Manji HK. Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs. 2009;23:569-82. https://doi.org/10.2165/00023210-200923070-00003
  49. Zarate CA Jr, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry. 2006;59:1006-20. https://doi.org/10.1016/j.biopsych.2005.10.021
  50. Zhou R, Gray NA, Yuan P, Li X, Chen J, Chen G, et al. The anti-apoptotic, glucocorticoid receptor cochaperone protein BAG-1 is a long-term target for the actions of mood stabilizers. J Neurosci. 2005;25:4493-502. https://doi.org/10.1523/jneurosci.4530-04.2005