Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Malhi GS, Gershon S. Ion men and their mettle. Aust N Z J Psychiatry. 2009;43:1091–5.
Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry. 2009;10(2):85–116.
Baldessarini RJ, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review [see comment]. [erratum appears in Bipolar Disord 2007 May;9(3):314]. Bipolar Disord 2006 Oct;8(5 Pt 2):625–39.
Malhi GS, Adams D, Berk M. Is lithium in a class of its own? A brief profile of its clinical use. Aust N Z J Psychiatry. 2009;43:1093–104.
Goodwin FK, Fireman B, Simon GE, et al. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290(11):1467–73.
Bowden CL. Bipolar pathophysiology and development of improved treatments. Brain Res. 2008;1235:92–7.
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):S46–56.
Berk M. Neuroprogression: pathways to progressive brain changes in bipolar disorder. Int J Neuropsychopharmacol. 2009;12(4):441–5.
Quiroz JA, Machado-Vieira R, Zarate JCA, et al. Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology. 2010;62(1):50–60.
Post RM, Speer AM, Hough CJ, et al. Neurobiology of bipolar illness: implications for future study and therapeutics. Ann Clin Psychiatry. 2003;15(2):85–94.
Chen G, Rajkowska G, Du F, et al. Enhancement of hippocampal neurogenesis by lithium. J Neurochem. 2000;75(4):1729–34.
Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience Biobehav Rev. 2011;35(3):804–17.
Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch Gen Psychiatry. 2000;57(2):187–90.
Bowden CL, Mosolov S, Hranov L, et al. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int Clin Psychopharmacol. 2010;25(2):60–7.
Yildiz A, Vieta E, Leucht S, et al. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36(2):375–89.
Shafti SS. Olanzapine vs. lithium in management of acute mania. J Affect Disord. 2010;122(3):273–6.
Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol. 1998;21(3):176–80.
Gershon S, Chengappa KR, Malhi GS. Lithium specificity in bipolar illness: a classic agent for a classic disorder. Bipolar Disord. 2009;11(Suppl. 2):34–44.
Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217–22.
Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306–15.
Berk M, Malhi GS. Should antipsychotics take pole position in mania treatment? Lancet. 2011;378(9799):1279–81.
National Institute for Health and Clinical Excellence. Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care: clinical guideline 38. London: National Institute for Health and Clinical Excellence; 2006.
Yatham LN, Kennedy SH, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(Suppl.3):5–69.
Yatham LN, Kennedy SH, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord. 2006;8(6):721–39.
Malhi GS, Adams DA, Lampe L, et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand. 2009;119(Suppl. 439):27–46.
Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002;59(1):62–9.
Bhagwagar Z, Goodwin GM. The role of lithium in the treatment of bipolar depression. Clin Neurosci Res. 2002;2(3–4):222–7.
Van Lieshout RJ, MacQueen GM. Efficacy and acceptability of mood stabilisers in the treatment of acute bipolar depression: systematic review. Br J Psychiatry. 2010;196(4):266–73.
Fountoulakis KN. An update of evidence-based treatment of bipolar depression: where do we stand? Curr Opin Psychiatry. 2010;23(1):19–24.
Fountoulakis KN, Grunze H, Panagiotidis P, et al. Treatment of bipolar depression: an update. J Affect Disord. 2008;109(1–2):21–34.
Vieta E, Locklear J, Gunther O, et al. Treatment options for bipolar depression: a systematic review of randomized, controlled trials. J Clin Pyschopharmacol. 2010;30:579–90.
Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach. Part I: clinical efficacy in bipolar disorder. CNS Drugs. 2009;23(3):225–40.
Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11(3):225–55.
Young AH, Hammond JM. Lithium in mood disorders: increasing evidence base, declining use? Br J Psychiatry. 2007;191:474–6.
Coryell W. Maintenance treatment in bipolar disorder: a reassessment of lithium as the first choice. Bipolar Disord. 2009;11:77–83.
Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385–95.
Silverstone T. Is lithium still the maintenance treatment of choice for bipolar disorder? CNS Drugs. 2000;14(2):81–94.
Perlis R, Sachs G, Lafer B, et al. Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data. Am J Psychiatry. 2002;159(7):1155–9.
Cavanagh J, Smyth R, Goodwin GM. Relapse into mania or depression following lithium discontinuation: a 7-year follow-up. Acta Psychiatr Scand. 2004;109(2):91–5.
Klein E, Lavie P, Meiraz R, et al. Increased motor activity and recurrent manic episodes: predictors of rapid relapse in remitted bipolar disorder patients after lithium discontinuation. Biol Psychiatry. 1992;31(3):279–84.
Bowden C, Gögüs A, Grunze H, et al. A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. Int Clin Psychopharmacol. 2008;23(5):254–62.
Malhi GS, Adams D, Cahill CM, et al. The management of individuals with bipolar disorder: a review of the evidence and its integration into clinical practice. Drugs. 2009;69(15):2063–101.
Bowden CL. The ability of lithium and other mood stabilisers to decrease suicide risk and prevent relapse. Curr Psychiatr Rep. 2000;2:490–4.
Muller-Oerlinghausen B. Arguments for the specificity of the antisuicidal effect of lithium. Eur Arch Psychiatry Clin Neurosci. 2001;251(Suppl. 2)):II/72–5.
Cipriani A, Pretty H, Hawton K, et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials [see comment]. Am J Psychiatry. 2005;162(10):1805–19.
Wingo AP, Wingo TS, Harvey PD, et al. Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry. 2009;70(11):1588–97.
Engelsmann F, Katz J, Ghadirian AM, et al. Lithium and memory: a long term follow-up study. J Clin Psychopharmacol. 1988;8(3):207–12.
Smigan L, Perris C. Memory functions and prophylactic lithium treatment. Psychol Med. 1983;13:529–36.
Pachet AK, Wisniewski AM. The effects of lithium on cognition: an updated review. Psychopharmacology (Berl). 2003;170:225–34.
Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? Bipolar Disord. 2010;12(1):87–94.
Arts B, Jabben N, Krabbendam L, et al. A 2-year naturalistic study on cognitive functioning in bipolar disorder. Acta Psychiatr Scand. 2011;123(3):190–205.
Rybakowski JK, Permoda-Osip A, Borkowska A. Response to prophylactic lithium in bipolar disorder may be associated with a preservation of executive cognitive functions. Eur Neuropsychopharmacol. 2009;19(11):791–5.
Anand A, Shekhar A. Brain imaging studies in mood and anxiety disorders. Ann N Y Acad Sci. 2003;985(1):370–88.
Bell EC, Willson MC, Wilman AH, et al. Differential effects of chronic lithium and valproate on brain activation in healthy volunteers. Hum Psychopharmacol Clin Exp. 2005;20(6):415–24.
Bell EC, Willson MC, Wilman AH, et al. Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation. Hum Psychopharmacol. 2005;20(2):87–96.
Silverstone PH, Bell EC, Willson MC, et al. Lithium alters brain activation in bipolar disorder in a task- and state-dependent manner: an fMRI study. Ann Gen Psychiatry. 2005;4(14):1–7.
Tsaltas E, Kontis D, Boulougouris V, et al. Lithium and cognitive enhancement: leave it or take it? Psychopharmacology (Berl). 2009;202(1–3):457–76.
Emsell L, McDonald C. The structural neuroimaging of bipolar disorder. Int Rev Psychiatry. 2009;21(4):297–313.
Kempton MJ, Geddes JR, Ettinger U, et al. Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry. 2008;65(9):1017–32.
Strakowski SM, DelBello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry. 2005;10:105–16.
Hajek T, Cullis J, Novak T, et al. Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment. Bipolar Disord. 2012;14(3):261–70.
Chepenik LG, Wang F, Spencer L, et al. Structure-function associations in hippocampus in bipolar disorder. Biol Psychol. 2012;90(1):18–22.
Savitz J, Nugent AC, Bogers W, 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.
Foland-Ross LC. Brooks Iii JO, Mintz J, et al. Mood-state effects on amygdala volume in bipolar disorder. J Affect Disord. 2012;139(3):298–301.
Hajek T, Gunde E, Slaney C, et al. Striatal volumes in affected and unaffected relatives of bipolar patients: high-risk study. J Psychiatr Res. 2009;43(7):724–9.
DelBello MP, Zimmerman ME, Mills NP, et al. Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. Bipolar Disord. 2004;6(1):43–52.
Strakowski SM, DelBello MP, Zimmerman ME, et al. Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry. 2002;159:1841–7.
Drevets WC, Price JL, Simpson JR, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386(6627):824–7.
Sassi RB, Brambilla P, Hatch JP, et al. Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry. 2004;56(7):467–75.
López-Larson MP, DelBello MP, Zimmerman ME, et al. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry. 2002;52(2):93–100.
Brooks JO 3rd, Bonner JC, Rosen AC, et al. Dorsolateral and dorsomedial prefrontal gray matter density changes associated with bipolar depression. Psychiatry Res. 2009;172(3):200–4.
Rajkowska G. Cell pathology in bipolar disorder. Bipolar Disord. 2002;4(2):105–16.
Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry. 2001;49(9):741–52.
Öngür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci. 1998;95(22):13290–5.
Brambilla P, Nicoletti MA, Harenski K, et al. Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology. 2002;27(5):792–9.
Fornito A, Malhi GS, Lagopoulos J, et al. Anatomical abnormalities of the anterior cingulate and paracingulate cortex in patients with bipolar I disorder. Psychiatry Res Neuroimaging. 2008;162(2):123–32.
Brambilla P, Harenski K, Nicoletti M, et al. Differential effects of age on brain gray matter in bipolar patients and healthy individuals. Neuropsychobiology. 2001;43(4):242–7.
Bearden CE, Thompson PM, Dalwani M, et al. Greater cortical gray matter density in lithium-treated patients with bipolar disorder [see comment]. Biol Psychiatry. 2007;62(1):7–16.
Sassi RB, Nicoletti M, Brambilla P, et al. Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett. 2002;329(2):243–5.
Adler CM, Levine AD, DelBello MP, et al. Changes in gray matter volume in patients with bipolar disorder. Biol Psychiatry. 2005;58(2):151–7.
Takahashi T, Malhi GS, Wood SJ, et al. Gray matter reduction of the superior temporal gyrus in patients with established bipolar I disorder. J Affect Disord. 2010;123:276–82.
Usher J, Menzel P, Schneider-Axmann T, et al. Increased right amygdala volume in lithium-treated patients with bipolar I disorder. Acta Psychiatr Scand. 2010;121:119–24.
Foland LC, Altshuler LL, Sugar CA, et al. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport. 2008;19(2):221–4.
Hallahan B, Newell J, Soares JC, et al. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry. 2011;69(4):326–35.
van Erp TGM, Thompson PM, Kieseppä T, et al. Hippocampal morphology in lithium and non-lithium-treated bipolar I disorder patients, non-bipolar co-twins, and control twins. Hum Brain Mapp. 2012;33(3):501–10.
Yucel K, Taylor VH, McKinnon MC, et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology. 2008;33(2):361–7.
Moore GJ, Cortese BM, Glitz DA, et al. 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(5):699–705.
Schildkraut JJ. The catecholamine hypothesis of affective-disorders: a review of supporting evidence. Am J Psychiatry. 1965;122(5):509–22.
Pert A, Rosenblatt JE, Sivit C, et al. Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity. Science. 1978;201(4351):171–3.
Knapp S, Mandell AJ. Short- and long-term lithium administration: effects on the brain’s serotonergic biosynthetic systems. Science. 1973;180(4086):645–7.
Belmaker RH. Bipolar disorder. N Engl J Med. 2004;351(5):476–86.
Berk M, Dodd S, Kauer-Sant’Anna M, et al. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand. 2007;116(Suppl. 434):41–9.
Cousins DA, Butts K, Young AH. The role of dopamine in bipolar disorder. Bipolar Disord. 2010;11:787–806.
Jacobs D, Silverstone T. Dextroamphetamine-induced arousal in human subjects as a model for mania. Psychol Med. 1986;16(02):323–9.
Post RM, Jimerson DC, Bunney WE, et al. Dopamine and mania: behavioral and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmacology (Berl). 1980;67(3):297–305.
Staunton DA, Magistretti PJ, Shoemaker WJ, et al. Effects of chronic lithium treatment on dopamine receptors in the rat corpus striatum: I. Locomotor activity and behavioral supersensitivity. Brain Res. 1982;232(2):391–400.
Gambarana C, Ghiglieri O, Masi F, et al. The effects of long-term administration of rubidium or lithium on reactivity to stress and on dopamine output in the nucleus accumbens in rats. Brain Res. 1999;826(2):200–9.
Ichikawa J, Dai J, Meltzer HY. Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT1A receptor antagonism. Brain Res. 2005;1049:182–90.
Ferrie L, Young AH, McQuade R. Effect of lithium and lithium withdrawal on potassium-evoked dopamine release and tyrosine hydroxylase expression in the rat. Int J Neuropsychopharmacol. 2006;9(6):729–35.
Ferrie L, Young AH, McQuade R. Effect of chronic lithium and withdrawal from chronic lithium on presynaptic dopamine function in the rat. J Psychopharmacol (Oxf). 2005;19(3):229–34.
Malhi GS, Tanious M, Gershon S. The lithiumeter: a measured approach. Bipolar Disord. 2011;13(3):219–26.
Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry. 2000;48(6):518–30.
Michael N, Erfurth A, Ohrmann P, et al. Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex. Psychopharmacology (Berl). 2003;168(3):344–6.
Öngür D, Jensen JE, Prescot AP, et al. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry. 2008;64(8):718–26.
Berk M. Lamotrigine and the treatment of mania in bipolar disorder. Eur Neuropsychopharmacol. 1999;9(Suppl. 4):S119–23.
Tsapakis EM, Travis MJ. Glutamate and psychiatric disorders. Adv Psychiatr Treat. 2002;8:189–97.
Hokin LE, Dixon JF, Los GV. A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl d-aspartate receptor in monkey and mouse cerebral cortex slices. Adv Enzyme Regul. 1996;36:229–44.
Ghasemi M, Dehpour AR. The NMDA receptor/nitric oxide pathway: a target for the therapeutic and toxic effects of lithium. Trends Pharmacol Sci. 2011;32(7):420–34.
Dixon JF, Hokin LE. Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. Proc Natl Acad Sci USA. 1998;95(14):8363–8.
Brunello N, Tascedda F. Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders. Int J Neuropsychopharmacol. 2003;6(2):181–9.
Hashimoto R, Takei N, Shimazu K, et al. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology. 2002;43(7):1173–9.
Nonaka S, Hough CJ, Chuang D-M. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-d-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci USA. 1998;95(5):2642–7.
Bown CD, Wang JF, Young LT. Attenuation of N-methyl-d-aspartate-mediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers. Neuroscience. 2003;117(4):949–55.
Ng WXD, Lau IY, Graham S, Sim K. Neurobiological evidence for thalamic, hippocampal and related glutamatergic abnormalities in bipolar disorder: a review and synthesis. Neurosci Biobehav Rev. 2009;33(3):336–54.
Brambilla P, Perez J, Barale F, et al. GABAergic dysfunction in mood disorders. Mol Psychiatry. 2003;8(8):721–37.
Kato T. Molecular neurobiology of bipolar disorder: a disease of ‘mood-stabilizing neurons’? Trends Neurosci. 2008;31(10):495–503.
Lenox RH, McNamara RK, Papke RL, et al. Neurobiology of lithium: an update. J Clin Psychiatry. 1998;59(Suppl. 6):37–47.
Shiah I, Yatham L. GABA function in mood disorders: an update and critical review. Life Sci. 1998;63(15):1289–303.
Petty F. Plasma concentrations of gamma-aminobutyric acid (GABA) and mood disorders: a blood test for manic depressive disease? Clin Chem. 1994;40(2):296–302.
Chuang D-M, Chen R-W, Chalecka-Franaszek E, et al. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord. 2002;4(2):129–36.
Ahluwalia P, Grewaal DS, Singhal RL. Brain gabaergic and dopaminergic systems following lithium treatment and withdrawal. Prog Neuropsychopharmacol. 1981;5(5–6):527–30.
Vargas C, Tannhauser M, Barros HMT. Dissimilar effects of lithium and valproic acid on GABA and glutamine concentrations in rat cerebrospinal fluid. Gen Pharmacol Vasc Syst. 1998;30(4):601–4.
Schloesser RJ, Huang J, Klein PS, et al. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology. 2008;33:110–33.
Manji HK, Lenox RH. The nature of bipolar disorder. J Clin Psychiatry. 2000;61(Suppl. 13):42–57.
Gould TD, Chen G, Manji HK. Mood stabilizer psychopharmacology. Clin Neurosci Res. 2002;2(3–4):193–212.
Marmol F. Lithium: bipolar disorder and neurodegenerative diseases. Possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1761–71.
Jope RS. Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry. 1999;4:117–28.
Montezinho LP, Mørk A, Duarte CB, et al. Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D2-like receptors. Bipolar Disord. 2007;9(3):290–7.
Jope RS. A bimodal model of the mechanism of action of lithium. Mol Psychiatry. 1999;4(1):21–5.
Mann L, Heldman E, Bersudsky Y, et al. Inhibition of specific adenylyl cyclase isoforms by lithium and carbamazepine, but not valproate, may be related to their anti-depressant effect. Bipolar Disord. 2009;11:885–96.
Ikonomov OC, Manji HK. Molecular mechanisms underlying mood stabilization in manic-depressive illness: the phenotype challenge. Am J Psychiatry. 1999;156(10):1506–14.
Machado-Vieira R, Manji HK, Zarate CA Jr, et al. 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.
Silverstone PH, McGrath BM. Lithium and valproate and their possible effects on the myo-inositol second messenger system in healthy volunteers and bipolar patients. Int Rev Psychiatry. 2009;21(4):414–23.
Calker Dv, Belmaker RH. The high affinity inositol transport system: implications for the pathophysiology and treatment of bipolar disorder. Bipolar Disord. 2000;2(2):102–7.
Willmroth F, Drieling T, Lamla U, et al. 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(1):63–71.
Deranieh RM, Greenberg ML. Cellular consequences of inositol depletion. Biochem Soc Trans. 2009;37:1099–103.
Berridge MJ. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J. 1984;220:345–60.
Lenox RH, Wang L. Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol Psychiatry. 2003;8(2):135–44.
Silverstone PH, McGrath BM, Kim H, et al. Bipolar disorder and myo-inositol: a review of the magnetic resonance spectroscopy findings. Bipolar Disord. 2005;7(1):1–10.
Chen G, Hasanat KA, Bebchuk JM, et al. Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosom Med. 1999;61(5):599–617.
Davanzo P, Thomas MA, Yue K, et al. Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology. 2001;24(4):359–69.
Moore GJ, Bebchuk JM, Parrish JK, et al. Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. Am J Psychiatry. 1999;156(12):1902–8.
Chiu CT, Chuang DM. Neuroprotective action of lithium in disorders of the central nervous system. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2011;36(6):461–76.
Zarate CA, Manji HK. Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs. 2009;23(7):569–82.
Hahn C-G, Friedman E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord. 1999;1(2):81–6.
Szabo ST, Machado-Vieira R, Yuan P, et al. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology. 2009;56(1):47–55.
Manji HK, Etcheberrigaray R, Chen G, et al. Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the α isozyme. J Neurochem. 1993;61(6):2303–10.
Lenox RH, Watson DG, Ellis J. Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res. 1992;570:333–40.
Friedman E, Hoau Yan W, Levinson D, et al. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry. 1993;33(7):520–5.
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(3–4):201–13.
Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4(7):517–29.
Carafoli E, Santella L, Branca D, et al. Generation, control, and processing of cellular calcium signals. Crit Rev Biochem Mol Biol. 2001;36(2):107–260.
Berk M, Plein H, Ferreira D. Platelet glutamate receptor supersensitivity in major depressive disorder. Clin Neuropharmacol. 2001;24(3):129–32.
Berk M, Plein H, Belsham B. The specificity of platelet glutamate receptor supersensitivity in psychotic disorders. Life Sci. 2000;66(25):2427–32.
Plein H, Berk M. Changes in the platelet intracellular calcium response to serotonin in patients with major depression treated with electroconvulsive therapy: state or trait marker status. Int Clin Psychopharmacol. 2000;15(2):93–8.
Berk M, Kirchmann NH, Butkow N. Lithium blocks 45Ca2+ uptake into platelets in bipolar affective disorder and controls. Clin Neuropharmacol. 1996;19(1):48–51.
Sourial-Bassillious N, Rydelius PA, Aperia A, et al. Glutamate-mediated calcium signaling: a potential target for lithium action. Neuroscience. 2009;161(4):1126–34.
Perova T, Kwan M, Li PP, et al. Differential modulation of intracellular Ca2+ responses in B lymphoblasts by mood stabilizers. Int J Neuropsychopharmacol. 2010;13(06):693–702.
Crespo-Biel N, Camins A, Canudas AM, et al. Kainate-induced toxicity in the hippocampus: potential role of lithium. Bipolar Disord. 2010;12(4):425–36.
Camins A, Crespo-Biel N, Junyent F, et al. Calpains as a target for therapy of neurodegenerative diseases: putative role of lithium. Curr Drug Metab. 2009;10(5):433–47.
Chang K, Barnea-Goraly N, Karchemskiy A, et al. Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder. Biol Psychiatry. 2005;58(3):197–203.
Rajkowska G. Cell pathology in bipolar disorder. Bipolar Disord. 2002;4:105–16.
Mielke K, Herdegen T. JNK and p38 stress kinases: degenerative effectors of signal-transduction-cascades in the nervous system. Prog Neurobiol. 2000;61(1):45–60.
Chen R-W, Qin Z-H, Ren M, et al. Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection. J Neurochem. 2003;84(3):566–75.
Chiu C-T, Chuang D-M. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010;128(2):281–304.
Chen R-W, Chuang D-M. Long-term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. J Biol Chem. 1999;274(10):6039–42.
Berk M, Conus P, Kapczinski F, et al. From neuroprogression to neuroprotection: implications for clinical care. Med J Aust. 2010;193(4):S36–40.
Ng F, Berk M, Dean OM, et al. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008;11:851–76.
Machado-Vieira R, Pivovarova NB, Stanika RI, et al. The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry. 2011;69(4):344–52.
Scola G, Kim HK, Young LT, et al. A fresh look at complex I in microarray data: clues to understanding disease-specific mitochondrial alterations in bipolar disorder. Biol Psychiatry. 2013;73:e4–5.
Maurer IC, Schippel P, Volz H-P. Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord. 2009;11(5):515–22.
Eskandari M, Fard J, Hosseini M-J, et al. Glutathione mediated reductive activation and mitochondrial dysfunction play key roles in lithium induced oxidative stress and cytotoxicity in liver. Biometals. 2012;25(5):863–73.
Berk M, Ng F, Dean O, et al. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci. 2008;29(7):346–51.
Frey BN, Martins MR, Petronilho FC, et al. Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania. Bipolar Disord. 2006;8(3):275–80.
Andreazza AC, Kapczinski F, Kauer-Sant’Anna M, et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci. 2009;34(4):263–71.
Andreazza AC, Shao L, Wang J-F, et al. Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder. Arch Gen Psychiatry. 2010;67(4):360–8.
Andreazza AC, Cassini C, Rosa AR, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2007;41(6):523–9.
Cecil KM, DelBello MP, Morey R, et al. Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy. Bipolar Disord. 2002;4(6):357–65.
Frey BN, Valvassori SS, Reus GZ, et al. Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci. 2006;31(5):326–32.
Machado-Vieira R, Andreazza AC, Viale CI, et al. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett. 2007;421(1):33–6.
Cunha ABM, Frey BN, Andreazza AC, et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett. 2006;398(3):215–9.
Tramontina JF, Andreazza AC, Kauer-Sant’Anna M, et al. Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neurosci Lett. 2009;452(2):111–3.
Einat H, Manji HK, Einat H, et al. Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol Psychiatry. 2006;59(12):1160–71.
Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol. 2010;13:617–22.
Vidal F, de Araujo WM, Cruz AL, et al. Lithium reduces tumorigenic potential in response to EGF signaling in human colorectal cancer cells. Int J Oncol. 2011;38(5):1365–73.
Cameron AR, Anil S, Sutherland E, et al. Zinc-dependent effects of small molecules on the insulin-sensitive transcription factor FOXO1a and gluconeogenic genes. Metallomics. 2010;2(3):195–203.
Manji HK, Moore GJ, 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. 2000;61(Suppl. 9):82–96.
Lien R, Flaisher-Grinberg S, Cleary C, et al. Behavioral effects of Bcl-2 deficiency: implications for affective disorders. Pharmacol Rep. 2008;60(4):490–8.
Chang YC, Rapoport SI, Rao JS. Chronic administration of mood stabilizers upregulates BDNF and bcl-2 expression levels in rat frontal cortex. Neurochem Res. 2009;34(3):536–41.
Ghribi O, Herman MM, Spaulding NK, et al. 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(1):137–45.
Beaulieu J-M, Sotnikova TD, Yao W-D, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA. 2004;101(14):5099–104.
Prickaerts J, Moechars D, Cryns K, et al. Transgenic mice overexpressing glycogen synthase kinase 3β: a putative model of hyperactivity and mania. J Neurosci. 2006;26(35):9022–9.
Klein E, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci. 1996;93(16):8455–9.
Li X, Friedman AB, Zhu W, et al. Lithium regulates glycogen synthase kinase-3β in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder. Biol Psychiatry. 2007;61(2):216–22.
Tajes M, Yeste-Velasco M, Zhu X, et al. Activation of Akt by lithium: pro-survival pathways in aging. Mech Ageing Dev. 2009;130:253–61.
Freland L, Beaulieu J-M. Inhibition of GSK3 by lithium, from single molecules to signaling networks. Front Mol Neurosci. 2012;5:14.
Rowe MK, Wiest C, Chuang D-M. GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder. Neurosci Biobehav Rev. 2007;31(6):920–31.
Gould TD, Einat H, Bhat R, et al. AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol. 2004;7:387–90.
Silva R, Mesquita AR, Bessa J, et al. Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3β. Neuroscience. 2008;152(3):656–69.
Wada A. Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3β, β-catenin, and neurotrophin cascades. J Pharmacol Sci. 2009;110(1):14–28.
Maiuri MC, Zalckvar E, Kimchi A, et al. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8(9):741–52.
Meléndez A, Neufeld TP. The cell biology of autophagy in metazoans: a developing story. Development. 2008;135(14):2347–60.
Sarkar S, Krishna G, Imarisio S, et al. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet. 2008;17(2):170–8.
Sarkar S, Floto RA, Berger Z, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol. 2005;170(7):1101–11.
Heiseke A, Aguib Y, Schatzl HM. Autophagy, prion infection and their mutual interactions. Curr Issues Mol Biol. 2009;12:87–98.
Camins A, Verdaguer E, Junyent F, et al. Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium. CNS Neurosci Ther. 2009;15(4):333–44.
Dean OM, Bush AI, Berk M. Translating the rosetta stone of N-acetylcysteine. Biol Psychiatry. 2012;71(11):935–6.
Gin S. Malhi has received research support from AstraZeneca, Eli Lilly, Organon, Pfizer, Servier and Wyeth; has been a speaker for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and has been a consultant for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck and Servier. Michael Berk has received research support from the Medical Benefits Fund of Australia, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma and Servier; has been a speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck, Pfizer, Sanofi-Synthelabo, Servier, Solvay and Wyeth; and has served as a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck and Servier. Michelle Tanious, Pritha Das and Carissa M. Coulston have no conflicts of interests or funding to declare. This work was supported by a National Health and Medical Research Council program grant (510135).
About this article
Cite this article
Malhi, G.S., Tanious, M., Das, P. et al. Potential Mechanisms of Action of Lithium in Bipolar Disorder. CNS Drugs 27, 135–153 (2013). https://doi.org/10.1007/s40263-013-0039-0
- Bipolar Disorder
- NMDA Receptor
- Grey Matter Volume
- cAMP Response Element Binding