After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by the absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na(+)-K(+) ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment.

] Department of Psychiatry Dalhousie University Halifax NS Canada [2] Department of Psychiatry and Medical Psychology 3rd Faculty of Medicine Charles University Prague Czech Republic

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Schioldann J. History of the Introduction of Lithium into Medicine and Psychiatry. Adelaide Academic Press; Adelaide, Australia: 2009.

Cade JFJ. Lithium salts in the treatment of psychotic excitement. The Medical Journal of Australia. 1949;2:349–351. PubMed

Blanco C, Laje G, Olfson M, Marcus SC, Pincus HA. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry. 2002;159:1005–1010. PubMed

Bramness JG, Weitoft GR, Hallas J. Use of lithium in the adult populations of Denmark, Norway and Sweden. J Affect Disord. 2009;118:224–228. PubMed

Wyatt RJ, Henter ID, Jamison JC. Lithium revisited: savings brought about by the use of lithium, 1970–1991. Psychiatric Q. 2001;72:149–166. PubMed PMC

Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161:217–222. PubMed

Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. International Journal of Bipolar Disorders. in press. PubMed PMC

Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. PubMed

Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68:935–940. PubMed

Sheard MH, Marini JL, Bridges CI, Wagner E. The effect of lithium on impulsive aggressive behavior in man. Am J Psychiatry. 1976;133:1409–1413. PubMed

Muller-Oerlinghausen B, Lewitzka U. Lithium reduces pathological aggression and suicidality: a mini-review. Neuropsychobiology. 2010;62:43–49. PubMed

Ahrens B, Muller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiat. 2001;34:132–136. PubMed

Grof P, Grof E. Varieties of lithium benefit. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:689–696. PubMed

Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, 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 2013. Bipolar Disord. 2013;15:1–44. PubMed

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530–537. PubMed

Bauer M, Ritter P, Grunze H, Pfennig A. Treatment options for acute depression in bipolar disorder. Bipolar Disord. 2012;14(Suppl 2):37–50. PubMed

Taylor DM, Cornelius V, Smith L, Young AH. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand. 2014;130:452–469. PubMed

McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721–728. PubMed

Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs. 2013;27:135–153. PubMed

Chiu CT, Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther. 2010;128:281–304. PubMed PMC

Gray JD, McEwen BS. Lithium’s role in neural plasticity and its implications for mood disorders. Acta Psychiatr Scand. 2013;128:347–361. PubMed PMC

Lenox RH, Wang L. Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol Psychiatry. 2003;8:135–144. PubMed

Shorter E. The 25th anniversary of the launch of Prozac gives pause for thought: where did we go wrong? Br J Psychiatry. 2014;204:331–332. PubMed

Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch Gen Psychiatry. 2000;57:187–190. PubMed

Grof P, Alda M. Discrepancies in the efficacy of lithium. Arch Gen Psychiatry. 2000;57:191. PubMed

Kleindienst N, Greil W. Lithium in the long-term treatment of bipolar disorders. Eur Arch Psychiatr Clin Neurosci. 2003;253:120–125. PubMed

Rybakowski JK, Chlopocka-Wozniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord. 2001;3:63–70. PubMed

Manchia M, Adli M, Akula N, Ardau R, Aubry JM, Backlund L, et al. Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics (ConLiGen) report. PLoS ONE. 2013;8:e65636. PubMed PMC

Kessing LV, Hansen HV, Hvenegaard A, Christensen EM, Dam H, Gluud C, et al. Treatment in a specialised out-patient mood disorder clinic v standard out-patient treatment in the early course of bipolar disorder: randomised clinical trial. Br J Psychiatry. 2013;202:212–219. PubMed

Kallner G, Lindelius R, Petterson U, Stockman O, Tham A. Mortality in 497 patients with affective disorders attending a lithium clinic or after having left it. Pharmacopsychiat. 2000;33:8–13. PubMed

Ahrens B, Muller-Oerlinghausen B, Grof P. Length of lithium treatment needed to eliminate the high mortality of affective disorders. Br J Psychiatry. 1993;163(suppl 21):27–29. PubMed

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;95:8363–8368. PubMed PMC

Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry. 2000;48:518–530. PubMed

Scott J, Leboyer M, Hickie I, Berk M, Kapczinski F, Frank E, et al. Clinical staging in psychiatry: a cross-cutting model of diagnosis with heuristic and practical value. Br J Psychiatry. 2013;202:243–245. PubMed

Hajek T, Cullis J, Novak T, Kopecek M, Blagdon R, Propper L, et al. Brain structural signature of familial predisposition for bipolar disorder: replicable evidence for involvement of the right inferior frontal gyrus. Biol Psychiatry. 2013;73:144–152. PubMed PMC

Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113:1237–1264. PubMed

El-Mallakh RS. Ion homeostasis and the mechanism of action of lithium. Clin Neurosci Res. 2004;4:227–231.

Schou M. Biology and pharmacology of the lithium ion. Pharmacol Rev. 1957;9:17–58. PubMed

Mendels J, Frazer A. Intracellular lithium concentration and clinical response: towards a membrane theory of depression. J Psychiatr Res. 1973;10:9–18. PubMed

Dorus E, Pandey GN, Frazer A, Mendels J. Genetic determinant of lithium ion distribution. I. An in vitro monozygotic-dizygotic twin study. Arch Gen Psychiatry. 1974;31:463–465. PubMed

Rihmer Z, Arato M, Szentistvanyi I, Banki CM. The red blood cell/plasma lithium ratio: marker of biological heterogeneity within bipolar affective illness? Psychiatr Res. 1982;6:197–201. PubMed

Spirtes MA. Lithium levels in monkey and human brain after chronic, therapeutic, oral dosage. Pharmacol Biochem Behav. 1976;5:143–147. PubMed

Ehrlich BE, Diamond JM. Lithium, membranes, and manic-depressive illness. J Membr Biol. 1980;52:187–200. PubMed

Ehrlich BE, Diamond JM. Lithium fluxes in human erythrocytes. Am J Physiol. 1979;237:C102–C110. PubMed

Fernandez-Moncada I, Barros LF. Non-preferential fuelling of the Na+/K+-ATPase pump. Biochem J. 2014;460:353–361. PubMed

Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61:300–308. PubMed

Naydenov AV, MacDonald ML, Ongur D, Konradi C. Differences in lymphocyte electron transport gene expression levels between subjects with bipolar disorder and normal controls in response to glucose deprivation stress. Arch Gen Psychiatry. 2007;64(5):555–564. PubMed

Andreazza AC, Shao L, Wang JF, Young LT. Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder. Arch Gen Psychiatry. 2010;67:360–368. PubMed

Aperia A. New roles for an old enzyme: Na,K-ATPase emerges as an interesting drug target. J Intern Med. 2007;261:44–52. PubMed

Zhang L, Zhang Z, Guo H, Wang Y. Na+/K+-ATPase-mediated signal transduction and Na+/K+-ATPase regulation. Fundam Clin Pharmacol. 2008;22:615–621. PubMed

Kirshenbaum GS, Clapcote SJ, Duffy S, Burgess CR, Petersen J, Jarowek KJ, et al. Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase alpha3 sodium pump. Proc Natl Acad Sci U S A. 2011;108:18144–18149. PubMed PMC

Antia IJ, Smith CE, Wood AJ, Aronson JK. The upregulation of Na+,K+-ATPase pump numbers in lymphocytes from the first-degree unaffected relatives of patients with manic depressive psychosis in response to in vitro lithium and sodium ethacrynate. J Affect Disord. 1995;34:33–39. PubMed

Looney SW, El-Mallakh RS. Meta-analysis of erythrocyte Na,K-ATPase activity in bipolar illness. Depress Anxiety. 1997;5:53–65. PubMed

Reddy PL, Khanna S, Subhash MN, Channabasavanna SM, Rao BS. Erythrocyte membrane sodium-potassium adenosine triphosphatase activity in affective disorders. J Neural Transm Gen Sect. 1992;89:209–218. PubMed

Linnoila M, MacDonald E, Reinila M, Leroy A, Rubinow DR, Goodwin FK. RBC membrane adenosine triphosphatase activities in patients with major affective disorders. Arch Gen Psychiatry. 1983;40:1021–1026. PubMed

Huang X, Lei Z, El-Mallakh RS. Lithium normalizes elevated intracellular sodium. Bipolar Disord. 2007;9:298–300. PubMed

Banerjee U, Dasgupta A, Rout JK, Singh OP. Effects of lithium therapy on Na+-K+-ATPase activity and lipid peroxidation in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:56–61. PubMed

Jope RS, Jenden DJ, Ehrlich BE, Diamond JM. Choline accumulates in erythrocytes during lithium therapy. N Engl J Med. 1978;299:833–834. PubMed

Jope R. Effects of lithium treatment in vitro and in vivo on acetylcholine metabolism in rat brain. J Neurochem. 1979;33:487–495. PubMed

Price LH, Heninger GR. Lithium in the treatment of mood disorders. N Engl J Med. 1994;331:591–598. PubMed

Manji HK, Hsiao JK, Risby ED, Oliver J, Rudorfer MV, Potter WJ. The mechanisms of action of lithium: I: effects on serotoninergic and noradrenergic systems in normal subjects. Arch Gen Psychiatry. 1991;48:505–512. PubMed

Akiskal HS, Downs J, Jordan P, Watson S, Daugherty D, Pruitt DB. Affective disorders in referred children and younger siblings of manic-depressives. Arch Gen Psychiatry. 1985;42:996–1003. PubMed

Nonaka S, Hough CJ, Chuang DM. 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;95:2642–2647. PubMed PMC

Young LT, Li PP, Kish SJ, Siu LP, Kamble A, Hornykiewcz O, et al. Cerebral cortex Gsa protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem. 1993;61:890–898. PubMed

Jope RS. Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry. 1999;4:117–128. PubMed

Mork A, Geisler A. Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase activity in rat brain. Eur J Pharmacol. 1989;168:347–354. PubMed

Mork A, Geisler A. Effects of GTP on Hormone-Stimulated Adenylate Cyclase Activity in Cerebral Cortex, Striatum, and Hippocampus from Rats Treated Chronically with Lithium. Biol Psychiatry. 1989;26:279–288. PubMed

Mork A, Geisler A. Mode of action of lithium on the catalytic unit of adenylate cyclase from rat brain. Pharmacol Toxicol. 1987;60:241–248. PubMed

Berridge MJ. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J. 1984;220:345–360. PubMed PMC

Berridge MJ. The biology and medicine of calcium signalling. Mol Cell Endocrinol. 1994;98:119–124. PubMed

Jope RS, Song L, Li PP, Young LT, Kish SJ, Pacheco MA, et al. The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain. J Neurochem. 1996;66:2402–2409. PubMed

van Calker D, Belmaker RH. The high affinity inositol transport system--implications for the pathophysiology and treatment of bipolar disorder. Bipolar Disord. 2000;2:102–107. PubMed

Belmaker RH, Agam G, van CD, Richards MH, Kofman O. Behavioral reversal of lithium effects by four inositol isomers correlates perfectly with biochemical effects on the PI cycle: depletion by chronic lithium of brain inositol is specific to hypothalamus, and inositol levels may be abnormal in postmortem brain from bipolar patients. Neuropsychopharmacology. 1998;19:220–232. PubMed

Lubrich B, van-Calker D. Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs? Neuropsychopharmacol. 1999;21:519–529. PubMed

Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl BJ, et al. Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. Am J Psychiatry. 1999;156:1902–1908. PubMed

O’Brien WT, Klein PS. Validating GSK3 as an in vivo target of lithium action. Biochem Soc Trans. 2009;37:1133–1138. PubMed PMC

Schubert T, Stoll L, Muller WE. Therapeutic concentrations of lithium and carbamazepine inhibit cGMP accumulation in human lymphocytes. A clinical model for a possible common mechanism of action? Psychopharmacology (Berl) 1991;104:45–50. PubMed

Schubert T, Muller WE. Lithium but not cholinergic ligands influence guanylate cyclase activity in intact human lymphocytes. Biochem Pharmacol. 1990;39:439–444. PubMed

Ghasemi M, Dehpour AR. The NMDA receptor/nitric oxide pathway: a target for the therapeutic and toxic effects of lithium. Trends Pharmacol Sci. 2011;32:420–434. PubMed

Prast H, Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2001;64:51–68. PubMed

Harvey BH, Carstens ME, Taljaard JJ. Evidence that lithium induces a glutamatergic: nitric oxide-mediated response in rat brain. Neurochem Res. 1994;19:469–474. PubMed

Boer U, Cierny I, Krause D, Heinrich A, Lin H, Mayr G, et al. Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice. Neuropsychopharmacol. 2008;33:2407–2415. PubMed

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.

Emamghoreishi M, Schlichter L, Li PP, Parikh S, Sen J, Kamble A, et al. High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder. Am J Psychiatry. 1997;154(7):976–982. PubMed

Perova T, Kwan M, Li PP, Warsh JJ. Differential modulation of intracellular Ca2+ responses in B lymphoblasts by mood stabilizers. Int J Neuropsychopharmacol. 2010;13:693–702. PubMed

Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci. 2003;24:441–443. PubMed

Meffre D, Grenier J, Bernard S, Courtin F, Dudev T, Shackleford G, et al. Wnt and lithium: a common destiny in the therapy of nervous system pathologies? Cell Mol Life Sci. 2014;71:1123–1148. PubMed PMC

Lang F, Strutz-Seebohm N, Seebohm G, Lang UE. Significance of SGK1 in the regulation of neuronal function. J Physiol. 2010;588:3349–3354. PubMed PMC

Anacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni R, et al. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2013;110:8708–8713. PubMed PMC

Beaulieu JM, Caron MG. Looking at lithium: molecular moods and complex behaviour. Mol Interv. 2008;8:230–241. PubMed

Grimes CA, Jope RS. CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. J Neurochem. 2001;78:1219–1232. PubMed PMC

Beaulieu JM. A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health. J Psychiatry Neurosci. 2012;37:7–16. PubMed PMC

Mota de Freitas D, Castro MM, Geraldes CF. Is competition between Li and Mg2 the underlying theme in the proposed mechanisms for the pharmacological action of lithium salts in bipolar disorder? Acc Chem Res. 2006;39:283–291. PubMed

Layden B, Diven C, Minadeo N, Bryant FB, Mota-de-Freitas D. Li+/Mg2+ competition at therapeutic intracellular Li+ levels in human neuroblastoma SH-SY5Y cells. Bipolar Disord. 2000;2:200–204. PubMed

Dermitzakis ET. Cellular genomics for complex traits. Nat Rev Genet. 2012;13:215–220. PubMed

Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithium-induced increase in human brain grey matter. Lancet. 2000;356:1241–1242. PubMed

Hajek T, Cullis J, Novak T, Kopecek M, Hoschl C, Blagdon R, et al. Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment. Bipolar Disord. 2012;14:261–270. PubMed PMC

Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, et al. 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. PubMed

Hajek T, Bauer M, Pfennig A, Cullis J, Ploch J, O’Donovan C, et al. Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study. J Psychiatr Neurosci. 2012;37:185–192. PubMed PMC

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. PubMed

Martinsson L, Wei Y, Xu D, Melas PA, Mathe AA, Schalling M, et al. Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres. Transl Psychiatry. 2013;3:e261. PubMed PMC

Maurer IC, Schippel P, Volz HP. Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord. 2009;11:515–522. PubMed

Wood GE, Young LT, Reagan LP, Chen B, McEwen BS. Stress-induced structural remodeling in hippocampus: prevention by lithium treatment. Proc Natl Acad Sci U S A. 2004;101:3973–3978. PubMed PMC

Deshauer D, Grof E, Alda M, Grof P. Patterns of DST positivity in remitted affective disorders. Biol Psychiatry. 1999;45:1023–1029. PubMed

Bauer M, Alda M, Priller J, Young LT. Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. Pharmacopsychiat. 2003;36(Suppl 3):S250–S254. PubMed

Hajek T, Bauer M, Simhandl C, Rybakowski J, O’Donovan C, Pfennig A, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014;44:507–517. PubMed

Frank E, Swartz HA, Kupfer DJ. Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry. 2000;48:593–604. PubMed

McCarthy MJ, Welsh DK. Cellular circadian clocks in mood disorders. J Biol Rhythms. 2012;27:339–352. PubMed

Seggie J, Werstiuk E, Grota L, Brown GM. Chronic lithium treatment and twenty-four hour rhythm of serum prolactin, growth hormone and melatonin in rats. Prog Neuropsychopharmacol Biol Psychiatry. 1983;7:827–830. PubMed

Kasahara T, Kubota M, Miyauchi T, Noda Y, Mouri A, Nabeshima T, et al. Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry. 2006;11:577–593. PubMed

Jope RS. A bimodal model of the mechanism of action of lithium. Mol Psychiatry. 1999;4:21–25. PubMed

Muller-Oerlinghausen B, Berghofer A, Bauer M. Bipolar disorder. Lancet. 2002;359:241–247. PubMed

Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63:942–947. PubMed

Garnham J, Munro A, Slaney C, MacDougall M, Passmore M, Duffy A, et al. Prophylactic treatment response in bipolar disorder: Results of a naturalistic observation study. J Affect Disord. 2007;104:185–190. PubMed

Tondo L, Baldessarini RJ, Floris G. Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. Br J Psychiatry Suppl. 2001;41:s184–s190. PubMed

Licht RW, Vestergaard P, Brodersen A. Long-term outcome of patients with bipolar disorder commenced on lithium prophylaxis during hospitalization: a complete 15-year register-based follow-up. Bipolar Disord. 2008;10:79–86. PubMed

Kulhara P, Basu D, Mattoo SK, Sharan P, Chopra R. Lithium prophylaxis of recurrent bipolar affective disorder: long-term outcome and its psychosocial correlates. J Affect Disord. 1999;54:87–96. PubMed

Maj M, Pirozzi R, Magliano L, Bartoli L. Long-term outcome of lithium prophylaxis in bipolar disorder: A 5 year prospective study of 402 patients at a lithium clinic. Am J Psychiatry. 1998;155:30–35. PubMed

Grof P, Alda M, Grof E, Fox D, Cameron P. The challenge of predicting response to stabilising lithium treatment. The importance of patient selection. Br J Psychiatry. 1993;163(Suppl 21):16–19. PubMed

Calabrese JR, Fatemi SH, Kujawa M, Woyshville MJ. Predictors of response to mood stabilizers. J Clin Psychopharmacol. 1996;16:24S–31S. PubMed

Maj M. Clinical prediction of response to lithium prophylaxis in bipolar patients: a critical update. Lithium. 1992;3:15–21.

McCarthy MJ, Leckband SG, Kelsoe JR. Pharmacogenetics of lithium response in bipolar disorder. Pharmacogenomics. 2010;11:1439–1465. PubMed

Kleindienst N, Engel R, Greil W. Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders. Bipolar Disord. 2005;7:404–417. PubMed

Passmore M, Garnham J, Duffy A, MacDougall M, Munro A, Slaney C, et al. Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine. Bipolar Disord. 2003;5:110–114. PubMed

Alda M, Grof P, Grof E. MN blood groups and bipolar disorder: evidence of genotypic association and Hardy-Weinberg disequilibrium. Biol Psychiatry. 1998;44:361–363. PubMed

Rohayem J, Bayle JF, Richa S. Predictors of prophylactic response to lithium. Encephale. 2008;34:394–399. PubMed

Kleindienst N, Engel RR, Greil W. Psychosocial and demographic factors associated with response to prophylactic lithium: a systematic review for bipolar disorders. Psychol Med. 2005;35:1685–1694. PubMed

Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry. 1970;126:983–987. PubMed

Berghofer A, Alda M, Adli M, Baethge C, Bauer M, Bschor T, et al. Long-term effectiveness of lithium in bipolar disorder: a multicenter investigation of patients with typical and atypical features. J Clin Psychiatry. 2008;69:1860–1868. PubMed

Grof P, Alda M, Grof E, Zvolsky P, Walsh M. Lithium response and genetics of affective disorders. J Affect Disord. 1994;32:85–95. PubMed

Alda M, Grof P, Rouleau GA, Turecki G, Young LT. Investigating responders to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1038–1045. PubMed

McKnew DH, Cytryn L, Buchsbaum MS, Hamovit J, Lamour M, Rapoport JL, et al. Lithium in children of lithium-reponding parents. Psychiatr Res. 1981;4:171–180. PubMed

Duffy A, Alda M, Milin R, Grof P. A consecutive series of treated affected offspring of parents with bipolar disorder: is response associated with the clinical profile? Can J Psychiatry. 2007;52:369–376. PubMed

Kruger S, Alda M, Young LT, Goldapple K, Parikh S, Mayberg HS. Risk and resilience markers in bipolar disorder: brain responses to emotional challenge in bipolar patients and their healthy siblings. Am J Psychiatry. 2006;163:257–264. PubMed

Severino G, Squassina A, Costa M, Pisanu C, Calza S, Alda M, et al. Pharmacogenomics of bipolar disorder. Pharmacogenomics. 2013;14:655–674. PubMed

Geoffroy PA, Bellivier F, Leboyer M, Etain B. Can the response to mood stabilizers be predicted in bipolar disorder? Front Biosci (Elite Ed) 2014;6:120–138. PubMed

Manchia M, Squassina A, Congiu D, Chillotti C, Ardau R, Severino G, et al. Interacting genes in lithium prophylaxis: preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients. Neurosci Lett. 2009;467:67–71. PubMed

Campos-de-Sousa S, Guindalini C, Tondo L, Munro J, Osborne S, Floris G, et al. Nuclear receptor rev-erb-{alpha} circadian gene variants and lithium carbonate prophylaxis in bipolar affective disorder. J Biol Rhythms. 2010;25:132–137. PubMed

McCarthy MJ, Nievergelt CM, Shekhtman T, Kripke DF, Welsh DK, Kelsoe JR. Functional genetic variation in the Rev-Erbalpha pathway and lithium response in the treatment of bipolar disorder. Genes Brain Behav. 2011;10:852–861. PubMed PMC

Benedetti F, Serretti A, Pontiggia A, Bernasconi A, Lorenzi C, Colombo C, et al. Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta -50 T/C SNP. Neurosci Lett. 2005;376:51–55. PubMed

Serretti A, Lilli R, Mandelli L, Lorenzi C, Smeraldi E. Serotonin transporter gene associated with lithium prophylaxis in mood disorders. The Pharmacogenomics Journal. 2001;1:71–77. PubMed

Rybakowski JK, Suwalska A, Czerski PM, Dmitrzak-Weglarz M, Leszczynska-Rodziewicz A, Hauser J. Prophylactic effect of lithium in bipolar affective illness may be related to serotonin transporter genotype. Pharmacol Rep. 2005;57:124–127. PubMed

Michelon L, Meira-Lima I, Cordeiro Q, Miguita K, Breen G, Collier D, et al. Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder. Neurosci Lett. 2006;403:288–293. PubMed

Rybakowski JK, Suwalska A, Skibinska M, Szczepankiewicz A, Leszczynska-Rodziewicz A, Permoda A, et al. Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. Pharmacopsychiat. 2005;38:166–170. PubMed

Mamdani F, Alda M, Grof P, Young LT, Rouleau G, Turecki G. Lithium response and genetic variation in the CREB family of genes. Am J Med Genet B (Neuropsychiatr Genet) 2008;147B:500–504. PubMed PMC

Li M, Luo XJ, Rietschel M, Lewis CM, Mattheisen M, Muller-Myhsok B, et al. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility. Mol Psychiatry. 2014;19:452–461. PubMed PMC

Kakiuchi C, Kato T. Lithium response and -116C/G polymorphism of XBP1 in Japanese patients with bipolar disorder. Int J Neuropsychopharmacol. 2005;8:631–632. PubMed

Masui T, Hashimoto R, Kusumi I, Suzuki K, Tanaka T, Nakagawa S, et al. A possible association between the -116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder. Int J Neuropsychopharmacol. 2006;9:83–88. PubMed

Ewald H, Wang AG, Vang M, Mors O, Nyegaard M, Kruse TA. A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands. Psychiatr Genet. 1999;9:23–34. PubMed

Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B, et al. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23-q24. Am J Med Genet B (Neuropsychiatr Genet) 1999;88:567–587. PubMed

Lopez de Lara C, Jaitovich-Groisman I, Cruceanu C, Mamdani F, Lebel V, Yerko V, et al. Implication of synapse-related genes in bipolar disorder by linkage and gene expression analyses. Int J Neuropsychopharmacol. 2010;13:1397–1410. PubMed PMC

Chen CH, Lee CS, Lee MT, Ouyang WC, Chen CC, Chong MY, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med. 2014;370:119–128. PubMed

Ikeda M, Kondo K, Iwata N. Variant GADL1 and response to lithium in bipolar I disorder. N Engl J Med. 2014;370:1856–1857. PubMed

Consortium on Lithium Genetics. Hou L, Heilbronner U, Rietschel M, Kato T, Kuo PH, et al. Variant GADL1 and response to lithium in bipolar I disorder. N Engl J Med. 2014;370:1857–1859. PubMed PMC

Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40(9):1056–1058. PubMed PMC

Muhleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J, et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun. 2014;5:3339. PubMed

Nanavati D, Austin DR, Catapano LA, Luckenbaugh DA, Dosemeci A, Manji HK, et al. The effects of chronic treatment with mood stabilizers on the rat hippocampal post-synaptic density proteome. J Neurochem. 2011;119:617–629. PubMed PMC

McQuillin A, Rizig M, Gurling HMD. 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. PubMed

Leussis MP, Berry-Scott EM, Saito M, Jhuang H, de HG, Alkan O, et al. The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress. Biol Psychiatry. 2013;73:683–690. PubMed

Toker L, Belmaker RH, Agam G. Gene-expression studies in understanding the mechanism of action of lithium. Expert Rev Neurother. 2012;12:93–97. PubMed

Farah R, Khamisy-Farah R, Amit T, Youdim MB, Arraf Z. Lithium’s gene expression profile, relevance to neuroprotection A cDNA microarray study. Cell Mol Neurobiol. 2013;33:411–420. PubMed

Li PP. Transcriptional mechanisms of lithium action: therapeutic implications. Clin Neurosci Res. 2004;4:271–280.

Einat H. New ways of modeling bipolar disorder. Harv Rev Psychiatry. 2014;22:348–352. PubMed

Perlis RH, Smoller JW, Ferreira MA, McQuillin A, Bass N, Lawrence J, et al. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry. 2009;166:718–725. PubMed PMC

Squassina A, Manchia M, Borg J, Congiu D, Costa M, Georgitsi M, et al. Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics. 2011;12:1559–1569. PubMed

Schulze T. Genomic and phenomic correlates of lithium response in bipolar disorder: a consortium on lithium genetics (ConLiGen) report. Bipolar Disord. 2014;16(S1):26. (abstract)

Bergen S, Song J, Lichtenstein P, Landen M. Genome-wide association study of lithium response in a Swedish population. Bipolar Disord. 2014;16(S1):64. (abstract)

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Tissue-specific protective properties of lithium: comparison of rat kidney, erythrocytes and brain

Na+/K+-ATPase level and products of lipid peroxidation in live cells treated with therapeutic lithium for different periods in time (1, 7, and 28 days); studies of Jurkat and HEK293 cells

Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study