Free Access
Neuropsychobiology 2010;62:50–60
(DOI:10.1159/000314310)

Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects

Quiroz J.A.a · Machado-Vieira R.b · Zarate, Jr. C.A.b · Manji H.K.c
aHoffman-La Roche Inc., Pharma Development and Exploratory Neuroscience, Nutley, N.J., bExperimental Therapeutics, Mood and Anxiety Disorders Research Program, NIMH-NIH, Bethesda, Md., and cJohnson & Johnson Pharmaceutical Research and Development, L.L.C., Titusville, N.J., USA
email Corresponding Author


 goto top of outline Key Words

  • Neurodegenerative disorders
  • B-cell lymphoma 2
  • Protein kinase C
  • Glycogen synthase kinase 3
  • Brain-derived neurotrophic factor
  • Arachidonic acid
  • Bipolar disorder

 goto top of outline Abstract

The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Du J, Gould TD, Manji HK: Neurotrophic signaling in mood disorders; in Finkel T, Gutkind JS (eds): Signal Transduction and Human Disease. Hoboken, Wiley, 2003, pp 411–446.
  2. Trentani A, Kuipers SD, Ter Horst GJ, Den Boer JA: Selective chronic stress-induced in vivo erk1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress-related cortical pathology? Eur J Neurosci 2002;15:1681–1691.
  3. DeVries AC, Joh HD, Bernard O, Hattori K, Hurn PD, Traystman RJ, Alkayed NJ: Social stress exacerbates stroke outcome by suppressing bcl-2 expression. Proc Natl Acad Sci USA 2001;98:11824–11828.
  4. Jope RS: A bimodal model of the mechanism of action of lithium. Mol Psychiatry 1999;4:21–25.
  5. Gould TD, Chen G, Manji HK: Mood stabilizer psychopharmacology. Clin Neurosci Res 2002;2:193–212.
  6. Kofman O, Li PP, Warsh JJ: Lithium, but not carbamazepine, potentiates hyperactivity induced by intra-accumbens cholera toxin. Pharmacol Biochem Behav 1998;59:191–200.
  7. Manji HK, Duman RS: Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 2001;35:5–49.
  8. Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003;23:7311–7316.
  9. Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S: Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001;158:100–106.
  10. Angelucci F, Aloe L, Jimenez-Vasquez P, Mathe AA: Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression. Int J Neuropsychopharmacol 2003;6:225–231.
  11. Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G: The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 2001;276:31674–31683.
  12. 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;53:487–495.
  13. 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;72:879–882.
  14. Manji HK, Chen G: Pkc, map kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers. Mol Psychiatry 2002;7(suppl 1):S46–S56.
  15. Chen G, Huang LD, Zeng WZ, Manji HK: Mood stabilizers regulate cytoprotective and mRNA-binding proteins in the brain: long-term effects on cell survival and transcript stability. Int J Neuropsychopharmacol 2001;4:47–64.
  16. Chen RW, Chuang DM: Long-term lithium treatment suppresses p53 and bax expression but increases bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 1999;274:6039–6042.
  17. Ozaki N, Chuang DM: Lithium increases transcription factor binding to AP-1 and cyclic AMP-responsive element in cultured neurons and rat brain. J Neurochem 1997;69:2336–2344.
  18. Tardito D, Tiraboschi E, Kasahara J, Racagni G, Popoli M: Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus. Int J Neuropsychopharmacol 2007;10:491–496.
  19. Frey BN, Andreazza AC, Rosa AR, Martins MR, Valvassori SS, Reus GZ, Hatch JP, Quevedo J, Kapczinski F: Lithium increases nerve growth factor levels in the rat hippocampus in an animal model of mania. Behav Pharmacol 2006;17:311–318.
  20. Jacobsen JP, Mork A: The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. Brain Res 2004;1024:183–192.
  21. Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM: The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 2009;14:51–59.
  22. McQuillin A, Rizig M, Gurling HM: A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet Genomics 2007;17:605–617.
  23. Hammonds MD, Shim SS, Feng P, Calabrese JR: Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus. Basic Clin Pharmacol Toxicol 2007;100:356–359.
  24. Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang DM: Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 2002;43:1173–1179.
  25. Rybakowski JK, Suwalska A, Skibinska M, Szczepankiewicz A, Leszczynska-Rodziewicz A, Permoda A, Czerski PM, Hauser J: Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. Pharmacopsychiatry 2005;38:166–170.
  26. Stewart RJ, Chen B, Dowlatshahi D, MacQueen GM, Young LT: Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium. Brain Res Bull 2001;55:625–629.
  27. Young LT, Bezchlibnyk YB, Chen B, Wang JF, MacQueen GM: Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment. Biol Psychiatry 2004;55:570–577.
  28. Hellweg R, Lang UE, Nagel M, Baumgartner A: Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry 2002;7:604–608.
  29. Walz JC, Frey BN, Andreazza AC, Cereser KM, Cacilhas AA, Valvassori SS, Quevedo J, Kapczinski F: Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania. J Psychiatr Res 2008;42:416–421.
  30. Warner-Schmidt JL, Duman RS: VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 2008;8:14–19.
  31. Chuang DM, Chen R, Chalecka-Franaszek E, Ren M, Hashimoto R, Senatorov V, Kanai H, Hough C, Hiroi T, Leeds P: Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord 2002;4:129–136.
  32. Manji HK, Moore GJ, Chen G: Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 1999;46:929–940.
  33. Huang X, Wu DY, Chen G, Manji H, Chen DF: Support of retinal ganglion cell survival and axon regeneration by lithium through a bcl-2-dependent mechanism. Invest Ophthalmol Vis Sci 2003;44:347–354.
  34. Gould TD, Manji HK: Signaling networks in the pathophysiology and treatment of mood disorders. J Psychosom Res 2002;53:687–697.
  35. Quiroz JA, Gray NA, Kato T, Manji HK: Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 2008;33:2551–2565.
  36. Naccarato WF, Ray RE, Wells WW: Biosynthesis of myo-inositol in rat mammary gland. Isolation and properties of the enzymes. Arch Biochem Biophys 1974;164:194–201.
  37. Hallcher LM, Sherman WR: The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 1980;255:10896–10901.
  38. Ragan CI, Watling KJ, Gee NS, Aspley S, Jackson RG, Reid GG, Baker R, Billington DC, Barnaby RJ, Leeson PD: The dephosphorylation of inositol 1,4-bisphosphate to inositol in liver and brain involves two distinct Li+-sensitive enzymes and proceeds via inositol 4-phosphate. Biochem J 1988;249:143–148.
  39. Inhorn RC, Majerus PW: Properties of inositol polyphosphate 1-phosphatase. J Biol Chem 1988;263:14559–14565.
  40. Berridge MJ, Downes CP, Hanley MR: Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989;59:411–419.
  41. Berridge MJ, Downes CP, Hanley MR: Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 1982;206:587–595.
  42. Gani D, Downes CP, Batty I, Bramham J: Lithium and myo-inositol homeostasis. Biochim Biophys Acta 1993;1177:253–269.
  43. Lubrich B, van Calker D: Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs? Neuropsychopharmacology 1999;21:519–529.
  44. Bersudsky Y, Shaldubina A, Agam G, Berry GT, Belmaker RH: Homozygote inositol transporter knockout mice show a lithium-like phenotype. Bipolar Disord 2008;10:453–459.
  45. Berry GT, Buccafusca R, Greer JJ, Eccleston E: Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain. Mol Genet Metab 2004;82:87–92.
  46. Willmroth F, Drieling T, Lamla U, Marcushen M, Wark HJ, van Calker D: Sodium-myo-inositol co-transporter (SMIT-1) mRNA is increased in neutrophils of patients with bipolar 1 disorder and down-regulated under treatment with mood stabilizers. Int J Neuropsychopharmacol 2007;10:63–71.
  47. Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992;258:607–614.
  48. Goode N, Hughes K, Woodgett JR, Parker PJ: Differential regulation of glycogen synthase kinase-3 beta by protein kinase c isotypes. J Biol Chem 1992;267:16878–16882.
  49. Manji HK, Bersudsky Y, Chen G, Belmaker RH, Potter WZ: Modulation of protein kinase C isozymes and substrates by lithium: the role of myo-inositol. Neuropsychopharmacology 1996;15:370–381.
  50. Manji HK, Etcheberrigaray R, Chen G, Olds JL: Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. J Neurochem 1993;61:2303–2310.
  51. Li X, Jope RS: Selective inhibition of the expression of signal transduction proteins by lithium in nerve growth factor-differentiated PC12 cells. J Neurochem 1995;65:2500–2508.
  52. Lenox RH, Watson DG, Patel J, Ellis J: Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 1992;570:333–340.
  53. Watson DG, Lenox RH: Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation. J Neurochem 1996;67:767–777.
  54. Bebchuk JM, Arfken CL, Dolan-Manji S, Murphy J, Hasanat K, Manji HK: A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry 2000;57:95–97.
  55. Zarate CA, Singh JB, Carlson PJ, Quiroz JA, Jolkovsky L, Luckenbaugh DA, Manji HK: Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord 2007;9:561–570.
  56. Yildiz A, Guleryuz S, Ankerst DP, Ongur D, Renshaw PF: Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry 2008;65:255–263.
  57. Axelrod J, Burch RM, Jelsema CL: Receptor-mediated activation of phospholipase A2 via GTP-binding proteins: arachidonic acid and its metabolites as second messengers. Trends Neurosci 1988;11:117–123.
  58. Rapoport SI: In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling. J Mol Neurosci 2001;16:243–261; discussion 279–284.
  59. Axelrod J: Phospholipase A2 and G proteins. Trends Neurosci 1995;18:64–65.
  60. Chang MC, Contreras MA, Rosenberger TA, Rintala JJ, Bell JM, Rapoport SI: Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers. J Neurochem 2001;77:796–803.
  61. Chang MC, Grange E, Rabin O, Bell JM, Allen DD, Rapoport SI: Lithium decreases turnover of arachidonate in several brain phospholipids. Neurosci Lett 1996;220:171–174.
  62. Rapoport SI, Bosetti F: Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatry 2002;59:592–596.
  63. Chang MC, Jones CR: Chronic lithium treatment decreases brain phospholipase A2 activity. Neurochem Res 1998;23:887–892.
  64. Rintala J, Seemann R, Chandrasekaran K, Rosenberger TA, Chang L, Contreras MA, Rapoport SI, Chang MC: 85 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brain. Neuroreport 1999;10:3887–3890.
  65. Bosetti F, Rintala J, Seemann R, Rosenberger TA, Contreras MA, Rapoport SI, Chang MC: Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain. Mol Psychiatry 2002;7:845–850.
  66. Amari L, Layden B, Rong Q, Geraldes CF, Mota de Freitas D: Comparison of fluorescence, (31)P NMR, and (7)Li NMR spectroscopic methods for investigating Li(+)/Mg(2+) competition for biomolecules. Anal Biochem 1999;272:1–7.
  67. Ryves WJ, Harwood AJ: Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 2001;280:720–725.
  68. Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000;351:95–105.
  69. York JD, Ponder JW, Majerus PW: Definition of a metal-dependent/Li(+)-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure. Proc Natl Acad Sci USA 1995;92:5149–5153.
  70. Nordenberg J, Kaplansky M, Beery E, Klein S, Beitner R: Effects of lithium on the activities of phosphofructokinase and phosphoglucomutase and on glucose-1,6-diphosphate levels in rat muscles, brain and liver. Biochem Pharmacol 1982;31:1025–1031.
  71. Rhyu GI, Ray WJ Jr, Markley JL: Enzyme-bound intermediates in the conversion of glucose 1-phosphate to glucose 6-phosphate by phosphoglucomutase. Phosphorus NMR studies. Biochemistry 1984;23:252–260.
  72. Ray WJ Jr, Szymanki ES, Ng L: The binding of lithium and of anionic metabolites to phosphoglucomutase. Biochim Biophys Acta 1978;522:434–442.
  73. Masuda CA, Xavier MA, Mattos KA, Galina A, Montero-Lomeli M: Phosphoglucomutase is an in vivo lithium target in yeast. J Biol Chem 2001;276:37794–37801.
  74. Gould TD, Einat H, Bhat R, Manji HK: AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol 2004;7:387–390.
  75. Jope RS: Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 2003;24:441–443.
  76. Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996;93:8455–8459.
  77. Gould TD, Zarate CA, Manji HK: Glycogen synthase kinase-3: a target for novel bipolar disorder treatments. J Clin Psychiatry 2004;65:10–21.
  78. Beaulieu JM, Gainetdinov RR, Caron MG: Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 2009;49:327–347.
  79. Jope RS, Roh MS: Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 2006;7:1421–1434.
  80. Li X, Bijur GN, Jope RS: Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord 2002;4:137–144.
  81. Li X, Rosborough KM, Friedman AB, Zhu W, Roth KA: Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. Int J Neuropsychopharmacol 2007;10:7–19.
  82. Munoz-Montano JR, Moreno FJ, Avila J, Diaz-Nido J: Lithium inhibits Alzheimer’s disease-like tau protein phosphorylation in neurons. FEBS Lett 1997;411:183–188.
  83. Gould TD, Chen G, Manji HK: In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3. Neuropsychopharmacology 2004;29:32–38.
  84. O’Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S, Klein PS: Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004;24:6791–6798.
  85. 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.
  86. Bijur GN, De Sarno P, Jope RS: Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem 2000;275:7583–7590.
  87. Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H: Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry 2004;55:781–784.
  88. Bersudsky Y, Shaldubina A, Kozlovsky N, Woodgett JR, Agam G, Belmaker RH: Glycogen synthase kinase-3beta heterozygote knockout mice as a model of findings in postmortem schizophrenia brain or as a model of behaviors mimicking lithium action: negative results. Behav Pharmacol 2008;19:217–224.
  89. Gould TD, Einat H, O’Donnell KC, Picchini AM, Schloesser RJ, Manji HK: Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology 2007;32:2173–2183.
  90. Ghribi O, Herman MM, Spaulding NK, Savory J: Lithium inhibits aluminum-induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2 decrease, Bax elevation and caspase-3 activation. J Neurochem 2002;82:137–145.
  91. Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM: Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 2008;28:2576–2588.
  92. Yeste M, Alvira D, Verdaguer E, Tajes M, Folch J, Rimbau V, Pallas M, Camins A: Evaluation of acute antiapoptotic effects of Li+ in neuronal cell cultures. J Neural Transm 2007;114:405–416.
  93. Warsh JJ, Andreopoulos S, Li PP: Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status. Clin Neurosci Res 2004;4:201–213.
  94. Zhou R, Gray NA, Yuan P, Li X, Chen J, Chen G, Damschroder-Williams P, Du J, Zhang L, Manji HK: The anti-apoptotic, glucocorticoid receptor cochaperone protein BAG-1 is a long-term target for the actions of mood stabilizers. J Neurosci 2005;25:4493–4502.
  95. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK: Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 2000;48:1–8.
  96. Phillips ML, Travis MJ, Fagiolini A, Kupfer D: Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry 2008;165:313–320.
  97. Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME: Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386:824–827.
  98. Bowley MP, Drevets WC, Ongur D, Price JL: Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 2002;52:404–412.
  99. Moore GJ, Cortese BM, Glitz DA, Zajac-Benitez C, Quiroz JA, Uhde TW, Drevets WC, Manji HK: A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry 2009;70:699–705.
  100. Sassi RB, Brambilla P, Hatch JP, Nicoletti MA, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry 2004;56:467–475.
  101. Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett 2002;329:243–245.
  102. Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Nicoletti M, Trakhtenbroit M, Glahn DC, Brambilla P, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Soares JC: Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry 2007;62:7–16.
  103. Bearden CE, Thompson PM, Dutton RA, Frey BN, Peluso MA, Nicoletti M, Dierschke N, Hayashi KM, Klunder AD, Glahn DC, Brambilla P, Sassi RB, Mallinger AG, Soares JC: Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology 2008;33:1229–1238.
  104. Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, MacQueen GM: Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007;195:357–367.
  105. Yucel K, Taylor VH, McKinnon MC, Macdonald K, Alda M, Young LT, MacQueen GM: Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 2008;33:361–367.
  106. Machado-Vieira R, Manji HK, Zarate CA Jr: The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis, Bipolar Disord 2009;11(suppl 2):92–109.
  107. Fornai F, Longone P, Ferrucci M, Lenzi P, Isidoro C, Ruggieri S, Paparelli A: Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 2008;4:527–530.

 goto top of outline Author Contacts

Husseini K. Manji, MD, FRCPC
Johnson & Johnson Pharmaceuticals Group
1125 Trenton-Harbourton Road, E32000
Titusville, NJ 08560 (USA)
Tel. +1 609 730 2968, Fax +1 609 730 2940, E-Mail hmanji@its.jnj.com


 goto top of outline Article Information

Published online: May 7, 2010
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 0, Number of References : 107


 goto top of outline Publication Details

Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)

Vol. 62, No. 1, Year 2010 (Cover Date: June 2010)

Journal Editor: Strik W. (Bern)
ISSN: 0302-282X (Print), eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.