Skip to main content
SpringerLink
Log in

Lithium and cognitive enhancement: leave it or take it?

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Lithium is established as an effective treatment of acute mania, bipolar and unipolar depression and as prophylaxis against bipolar disorder. Accumulating evidence is also delineating a neuroprotective and neurotrophic role for lithium. However, its primary effects on cognitive functioning remain ambiguous.

Objectives

The aim of this paper is to review and combine the relevant translational studies, focusing on the putative cognitive enhancement properties of lithium, specifically on learning, memory, and attention.

Discussion

These properties are also discussed in reference to research demonstrating a protective action of lithium against cognitive deficits induced by various challenges to the nervous system, such as stress, trauma, neurodegenerative disorders, and psychiatric disorders.

Conclusions

It is suggested on the basis of the evidence that the cognitive effects of lithium are best expressed and should, therefore, be sought under conditions of functional or biological challenge to the nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Al Banchaabouchi M, Peña de Ortíz S, Menéndez R, Ren K, Maldonado-Vlaar CS (2004) Chronic lithium decreases Nurr1 expression in the rat brain and impairs spatial discrimination. Pharmacol Biochem Behav 79:607–621

    PubMed  CAS  Google Scholar 

  • Alexander GJ, Alexander RB (1978) Alcohol consumption in rats treated with lithium carbonate or rubidium chloride. Pharmacol Biochem Behav 8:533–536

    PubMed  CAS  Google Scholar 

  • Ananth J, Ghadirian AM, Engelsmann F (1987) Lithium and memory: a review. Can J Psychiatry 32:313–316

    Google Scholar 

  • Bauer M, Forsthoff A, Baethge C, Adli M, Berghofer A, Dopfmer S, Bschor T (2003) Lithium augmentation therapy in refractory depression—update 2002. Eur Arch Psychiatry Clin Neurosci 253:132–139

    PubMed  Google Scholar 

  • 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 (2007a) Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology 33:1229–1238

    PubMed  Google Scholar 

  • 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 (2007b) Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry 62(1):7–16

    PubMed  CAS  Google Scholar 

  • Bearden CE, Soares JC, Klunder AD, Nicoletti M, Dierschke N, Hayashi KM, Narr KL, Brambilla P, Sassi RB, Axelson D, Ryan N, Birmaher B, Thompson PM (2008a) Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 47(5):515–525

    PubMed  Google Scholar 

  • Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Glahn DC, Brambilla P, Sassi RB, Mallinger A, Frank E, Kupfer DJ, Nicoletti M, Soares JC (2008b) Reply: lithium and increased cortical gray matter—more tissue or more water? Biol Psychiatry 63(3):19

    Google Scholar 

  • Bersudsky Y, Shaldubina A, Belmaker RH (2007) Lithium’s effect in forced-swim test is blood level dependent but not dependent on weight loss. Behav Pharmacol 18:77–80

    PubMed  CAS  Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long term potentiation in the hippocampus. Nature 361:31–39

    PubMed  CAS  Google Scholar 

  • Borgwardt SJ, McGuire PK, Aston J, Berger G, Dazzan P, Gschwandtner U, Pflüger M, D’Souza M, Radue EW, Riecher-Rössler A (2007) Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis. Br J Psychiatry Suppl 51:s69–75

    PubMed  Google Scholar 

  • Buckley PF (2008) Update on the treatment and management of schizophrenia and bipolar disorder. CNS Spectr 13(2 Suppl 1):1–10

    PubMed  Google Scholar 

  • Caccamo A, Oddo S, Tran LX, LaFerla FM (2007) Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol 170(5):1669–1675

    PubMed  CAS  Google Scholar 

  • Calil HM, Zwicker AP, Klepacz S (1990) The effects of lithium carbonate on healthy volunteers: mood stabilization? Biol Psychiatry 27:711–722

    PubMed  CAS  Google Scholar 

  • Cappeliez P, Moore E (1988) Effects of lithium on latent inhibition in the rat. Prog Neuropychopharmacol Biol Psychiatry 12(4):431–443

    CAS  Google Scholar 

  • Cappeliez P, Moore E, Souliere M (1989) Effects of lithium on appetitive discrimination in the rat. Prog Neuropsychopharmacol Biol Psychiatry 13(5):725–734

    PubMed  CAS  Google Scholar 

  • Chenu F, Bourin M (2006) Potentiation of antidepressant-like activity with lithium: mechanism involved. Curr Drug Targets 7:159–63

    PubMed  CAS  Google Scholar 

  • Christodoulou GN, Kokkevi A, Lykouras EP, Stefanis CN, Papadimitriou GN (1981) Effects of lithium on memory. Am J Psychiatry 138:847–848

    PubMed  CAS  Google Scholar 

  • Chuang DM (2004) Lithium neuroprotection from glutamate excitotoxicity. Lithium and mood stabilizers: mechanism of action. Clin Neurosci Res 4:243–252

    CAS  Google Scholar 

  • Chuang DM, Manji HK (2007) In search of the Holy Grail for the treatment of neurodegenerative disorders: has a simple cation been overlooked? Biol Psychiatry 62(1):4–6

    PubMed  Google Scholar 

  • Chuang DM, Priller J (2006) Potential use of lithium in neurodegenerative disorders. In: Bauer M, Grof P, Müller-Oerlingausen B (eds) Lithium in neuropsychiatry: the comprehensive guide. Taylor & Francis Books, London, pp 381–397

    Google Scholar 

  • Chuang DM, Chen RW, Chalecka-Franaszek E, Ren M, Hashimoto R, Senatorov V, Kanai H, Hough C, Hiroi T, Leeds P (2002) Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord 4:129–136

    PubMed  CAS  Google Scholar 

  • Cimarosti H, Rodnight R, Tavares A et al (2001) An investigation of the neuroprotective effect of lithium in organotypic slice cultures of rat hippocampus exposed to oxygen and glucose deprivation. Neurosci Lett 315:33–36

    PubMed  CAS  Google Scholar 

  • Creson TK, Woodruff ML, Ferslew KE, Rasch EM, Monaco PJ (2003) Dose–response effects of chronic lithium regimens on spatial memory in the black molly fish. Pharmacol Biochem Behav 75(1):35–47

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Donaldson IM, Cuningham J (1983) Persisting neurologic sequelae of lithium carbonate therapy. Arch Neurol 40:747–751

    PubMed  CAS  Google Scholar 

  • Dunn N, Holmes C, Mullee M (2005) Does lithium therapy protect against the onset of dementia? Alzheimer Dis Assoc Disord 19:20–22

    PubMed  CAS  Google Scholar 

  • el-Mallakh RS (1983) The Na,K-ATPase hypothesis for manic-depression. II. The mechanism of action of lithium. Med Hypotheses 12:269–282

    PubMed  CAS  Google Scholar 

  • Engel T, Goñi-Oliver P, Gómez de Barreda E, Lucas JJ, Hernández F, Avila J (2008) Lithium, a potential protective drug in Alzheimer’s disease. Neurodegener Dis 5(3–4):247–249

    PubMed  CAS  Google Scholar 

  • Eroglu L, Hizal A (1987) Antidepressant action of lithium in behavioral despair test. Pol J Pharmacol Pharm 39:667–673

    PubMed  CAS  Google Scholar 

  • Frances H, Maurin Y, Lecrubier Y, Puech AJ, Simon P (1981) Effect of chronic lithium treatment on isolation-induced behavioral and biochemical effects in mice. Eur J Pharmacol 72:337–341

    PubMed  CAS  Google Scholar 

  • Frangou S, Donaldson S, Adjulis M et al (2005) The Maudsley bipolar disorder project: executive dysfunction in bipolar disorder I and its clinical correlates. Biol Psychiatry 58:859–864

    PubMed  Google Scholar 

  • Furusawa K (1991) Drug effects on cognitive function in mice determined by the non-matching to sample task using a 4-arm maze. Jpn J Pharmacol 56(4):483–493

    PubMed  CAS  Google Scholar 

  • Gallo C, Poletti G, Cazorla A (1990) Effects of chronic lithium administration on brain weights, acetylcholinesterase activity and learning ability in rats. Life Sci 47(6):507–513

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Forlenza OV, Nunes PV (2007) Authors’ reply. Br J Psychiatry 191:362

    Google Scholar 

  • Gelenberg AJ, Kane JM, Keller MB, Lavori P, Rosenbaum JF, Cole K, Lavelle J (1989) Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 321:1489–1493

    PubMed  CAS  Google Scholar 

  • Geoffroy M, Tvede K, Christensen AV, Schou JS (1991) The effect of imipramine and lithium on “learned helplessness” and acetylcholinesterase in rat brain. Pharmacol Biochem Behav 38:93–97

    PubMed  CAS  Google Scholar 

  • Gould TD, Einat H, O’Donnell KC, Picchini AM, Schloesser RJ, Manji HK (2007) [beta]-Catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology 32:2173–2183

    PubMed  CAS  Google Scholar 

  • Gould TD, O’Donnell KC, Dow ER, Du J, Chen G, Manji HK (2008) Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test. Neuropharmacology 54:577–87

    PubMed  CAS  Google Scholar 

  • Goswami U, Gulrajani C, Moore PB et al (2002) Neurocognitive decline in bipolar mood disorder: role of mood stabilizers. J Psychopharmacol 16(Suppl):A45

    Google Scholar 

  • Hascoet M, Bourin M, Khimake S (1994) Additive effect of lithium and clonidine with 5-HT1A agonists in the forced swimming test. Prog Neuropsychopharmacol Biol Psychiatry 18:381–396

    PubMed  CAS  Google Scholar 

  • Hines G (1985) Lithium effects on position learning with exploratory and aversive goal-box conditions. Pharmacol Biochem Behav 22(5):695–698

    PubMed  CAS  Google Scholar 

  • Hines G (1986a) Lithium effects on adjunctive alcohol consumption. I: comparison with adjunctive water consumption. Pharmacol Biochem Behav 25:1159–1162

    PubMed  CAS  Google Scholar 

  • Hines G (1986b) Effects of lithium and rubidium on shock-induced changes in open-field activity. Psychopharmacology 88:209–212

    PubMed  CAS  Google Scholar 

  • Hines G, Henslee DF (1986) Lithium effects on adjunctive alcohol consumption in rats. Psychopharmacology (Berl) 90:236–238

    CAS  Google Scholar 

  • Hines G, Poling TH (1984) Lithium effects on active and passive avoidance behavior in the rat. Psychopharmacology (Berl) 82:78–82

    CAS  Google Scholar 

  • Hirschfeld RMA, Clayton PJ, Cohen I, Fawcett J, Keck P, McCellan J et al (2000) Practice guideline for the treatment of patients with bipolar disorder. In: American Psychiatric Association Steering Committee (ed) The practice guidelines for the treatment of psychiatric disorders: compendium 2000. American Psychiatric Association Press, Washington, DC, pp 509–514

    Google Scholar 

  • Ho AK, Tsai CS (1976) Effects of lithium on alcohol preference and withdrawal. Ann N Y Acad Sci 273:371–377

    PubMed  CAS  Google Scholar 

  • Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET (2003) Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol 23:6027–6036

    PubMed  CAS  Google Scholar 

  • Honig A, Arts BM, Ponds RW, Riedel WJ (1999) Lithium induced cognitive side effects in bipolar disorder: a qualitative analysis and implications for daily practise. Int Clin Psychopharmacol 14:167–171

    PubMed  CAS  Google Scholar 

  • Jähkel M, Oehler J, Schumacher HE (1994) Influence of nootropic and antidepressive drugs on open field and running wheel behavior in spontaneously high and low active mice. Pharmacol Biochem Behav 49:263–269

    PubMed  Google Scholar 

  • Jasinski DR, Nutt JG, Haertzen CA, Griffith JD, Bunney WE (1977) Lithium: effects on subjective functioning and morphine-induced euphoria. Science 195:582–584

    PubMed  CAS  Google Scholar 

  • Jauhar P, McClure I, Hillary C, Watson A (1993) Psychomotor performance of patients on maintenance lithium therapy. Hum Psychopharmacol 8:141–143

    Google Scholar 

  • Joffe R, MacDonald C, Kutcher S (1988) Lack of differential cognitive effects of lithium and carbamazepine in bipolar affective disorder. J Clin Psychopharmacol 8:425–428

    PubMed  CAS  Google Scholar 

  • Johnson FN (1976) Lithium effects upon components of activity in rats. Experientia 32:212–214

    PubMed  CAS  Google Scholar 

  • Johnston IN, Westbrook RF (2004) Inhibition of morphine analgesia by lithium: role of peripheral and central opioid receptors. Behav Brain Res 151:151–158

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Judd LL (1979) Effect of lithium on mood, cognition, and personality function in normal subjects. Arch Gen Psychiatry 36:860–866

    PubMed  CAS  Google Scholar 

  • Judd LL, Hubbard RB, Huey LY, Attewell PA, Janowsky DS, Takahashi KI (1977a) Lithium carbonate and ethanol induced “highs” in normal subjects. Arch Gen Psychiatry 34:463–467

    PubMed  CAS  Google Scholar 

  • Judd LL, Hubbard B, Janowsky DS, Huey LY, Takahashi KI (1977b) The effect of lithium carbonate on the cognitive functions of normal subjects. Arch Gen Psychiatry 34:355–357

    PubMed  CAS  Google Scholar 

  • Judd LL, Hubbard B, Janowsky DS, Huey LY, Attewell PA (1977c) The effect of lithium carbonate on affect, mood, and personality of normal subjects. Arch Gen Psychiatry 34:346–351

    PubMed  CAS  Google Scholar 

  • Kandel E (2004) The molecular biology of memory storage: a dialog between genes and synapses. Biosci Rep 24:475–522

    PubMed  Google Scholar 

  • Karakucuk E, Yamanoglu T, Demirel O, Bora N, Zengil H (2006) Temporal variation in drug interaction between lithium and morphine-induced analgesia. Chronobiol Int 23:675–682

    PubMed  CAS  Google Scholar 

  • Karniol IG, Dalton J, Lader MH (1978) Acute and chronic effects of lithium chloride on physiological and psychological measures in normals. Psychopharmacology 57:289–294

    PubMed  CAS  Google Scholar 

  • Kennedy GJ, Golde TE, Tariot PN, Cummings JL (2007) Amyloid-based interventions in Alzheimer’s disease. CNS Spectr 12(12 Suppl 1):1–14

    Google Scholar 

  • Kessing IV (1998) Cognitive impairment in the euthymic phase of affective disorder. Psychol Med 28:1027–1038

    PubMed  CAS  Google Scholar 

  • Kim JS, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS et al (2004) Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo. J Neurochem 89(2):324–336

    PubMed  CAS  Google Scholar 

  • Kitaichi Y, Inoue T, Nakagawa S, Izumi T, Koyama T (2006) Effect of co-administration of subchronic lithium pretreatment and acute MAO inhibitors on extracellular monoamine levels and the expression of contextual conditioned fear in rats. Eur J Pharmacol 532:236–245

    PubMed  CAS  Google Scholar 

  • Kocsis JH, Shaw ED, Stokes PE, Wilner P, Elliot AS, Sikes C et al (1993) Neuropsychologic effects of lithium discontinuation. J Clin Psychopharmacol 13:268–75

    PubMed  CAS  Google Scholar 

  • Kofman O, Levin U, Alpert C (1995) Lithium attenuates hypokinesia induced by immobilization stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 19:1081–1090

    PubMed  CAS  Google Scholar 

  • Kolk A, Kathmann N, Greil W (1993) No short-term changes of cognitive performance and mood after single doses of two different lithium retard preparations. Pharmacopsychiatry 26:235–239

    PubMed  CAS  Google Scholar 

  • Kropf D, Müller-Oerlinghausen B (1979) Changes in learning, memory, and mood during lithium treatment. Approach to a research strategy. Acta Psychiatr Scand 59:97–124

    PubMed  CAS  Google Scholar 

  • Kusumo KS, Vaughan M (1977) Effects of lithium salts on memory. Br J Psychiatry 131:453–457

    PubMed  CAS  Google Scholar 

  • Lalonde R, Vikis-Freibergs V (1982) The effects of chlorpromazine and lithium on appetitive discrimination learning in the rat. Psychopharmacology (Berl) 76(3):218–221

    CAS  Google Scholar 

  • Lejoyeux M, Ades J (1993) Evaluation of lithium treatment in alcoholism. Alcohol Alcohol 28:273–279

    PubMed  CAS  Google Scholar 

  • Lenox RH, Fraze A (2002) Mechanism of action of antidepressants and mood stabilizers. In: Davis KL, Charney D, Coyle JT, Nemeroff CN (eds) Neuropsychopharmacology: the fifth generation of progress. Lippincott Williams & Wilkins, Philadelphia, pp 1139–1163

    Google Scholar 

  • Lenzer I, Eastwood D, Street P (1989) Reinterpreting memory complaints through neuropsychological assessment. Clin Gerontol 8:57–60

    Google Scholar 

  • Lillywhite LM, Saling MM, Briellmann RS, Weintrob DL, Pell GS, Jackson GD (2007) Differential contributions of the hippocampus and rhinal cortices to verbal memory in epilepsy. Epilepsy Behav 10(4):553–559

    PubMed  Google Scholar 

  • Loo H, Bonnel J, Etevenon P, Benyacoub J, Slowen P (1981) Intellectual efficiency in manic-depressive patients treated with lithium. A control study. Acta Psychiatr Scand 64(5):423–430

    PubMed  CAS  Google Scholar 

  • Lund Y, Nissen M, Rafaelsen OJ (1982) Long-term lithium treatment and psychological functions. Acta Psychiatr Scand 65:233–244

    PubMed  CAS  Google Scholar 

  • Manji HK, Moore GJ, Chen G (2001) Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers. Br J Psychiatr Suppl 41:s107–s119

    CAS  Google Scholar 

  • Marusarz TZ, Wolpert EA, Koh SD (1981) Memory processing with lithium carbonate. J Clin Psychiatry 42:190–192

    PubMed  CAS  Google Scholar 

  • Masaki T, Nakajima S (2006) Taste aversion in rats induced by forced swimming, voluntary running, forced running, and lithium chloride injection treatments. Physiol Behav 88:411–416

    PubMed  CAS  Google Scholar 

  • Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB et al (2000) Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 48:1–8

    PubMed  CAS  Google Scholar 

  • Mur M, Portella MJ, Martínez-Arán A, Pifarré J, Vieta E (2007) Persistent neuropsychological deficit in euthymic bipolar patients: executive function as a core deficit. J Clin Psychiatry 68(7):1078–1086

    Article  PubMed  Google Scholar 

  • Muraki I, Inoue T, Hashimoto S, Izumi T, Ito K, Ohmori T, Koyama T (1999) Effect of subchronic lithium carbonate treatment on anxiolytic-like effect of citalopram and MKC-242 in conditioned fear stress in the rat. Eur J Pharmacol 383:223–229

    PubMed  CAS  Google Scholar 

  • Nachman M, Ashe JH (1973) Learned taste aversions in rats as a function of dosage, concentration, and route of administration of LiCl. Physiol Behav 10:73–78

    PubMed  CAS  Google Scholar 

  • Nilsson FM, Kessing LV, Sorensen TM, Andersen PK, Bolwig TG (2002) Enduring increased risk of developing depression and mania in patients with dementia. J Neurol Neurosurg Psychiatry 73:40–44

    PubMed  CAS  Google Scholar 

  • Nixon MK, Hascoet M, Bourin M, Colombel MC (1994) Additive effects of lithium and antidepressants in the forced swimming test: further evidence for involvement of the serotoninergic system. Psychopharmacology (Berlin) 115:59–64

    CAS  Google Scholar 

  • Nocjar C, Hammonds MD, Shim SS (2007) Chronic lithium treatment magnifies learning in rats. Neuroscience 150:774–788

    PubMed  CAS  Google Scholar 

  • Nonaka S, Chuang DM (1998) Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. NeuroReport 9:2081–2084

    PubMed  CAS  Google Scholar 

  • Nonaka S, Hough CJ, Chuang DM (1998) 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 95:2642–2647

    PubMed  CAS  Google Scholar 

  • Nunes PV, Forlenza OV, Gattaz WF (2007) Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 190:359–360

    PubMed  Google Scholar 

  • O’Donnell KC, Gould TD (2007) The behavioral actions of lithium in rodent models: leads to develop novel therapeutics. Neurosci Biobehav Rev 31:932–962

    PubMed  Google Scholar 

  • O’Neill HC, Schmitt MP, Stevens KE (2003) Lithium alters measures of auditory gating in two strains of mice. Biol Psychiatry 54:847–853

    PubMed  Google Scholar 

  • Ong JC, Brody SA, Large CH, Geyer MA (2005) An investigation of the efficacy of mood stabilizers in rodent models of prepulse inhibition. J Pharmacol Exp Ther 315:1163–1171

    PubMed  CAS  Google Scholar 

  • Pachet AK, Wisniewski AM (2003) The effects of lithium on cognition: an updated review. Psychopharmacology 170:225–234

    PubMed  CAS  Google Scholar 

  • Pascual T, Gonzalez JL (1995) A protective effect of lithium on rat behaviour altered by ibotenic acid lesions of the basal forebrain cholinergic system. Brain Res 695:289–292

    PubMed  CAS  Google Scholar 

  • Phatak P, Shaldivin A, King LS, Shapiro P, Regenold WT (2006) Lithium and inositol: effects on brain water homeostasis in the rat. Psychopharmacology (Berl) 186:41–47

    CAS  Google Scholar 

  • Redrobe JP, Bourin M (1997) Effects of pretreatment with clonidine, lithium and quinine on the activities of antidepressant drugs in the mouse tail suspension test. Fundam Clin Pharmacol 11:381–386

    PubMed  CAS  Google Scholar 

  • Redrobe JP, Bourin M (1999) The effect of lithium administration in animal models of depression: a short review. Fundam Clin Pharmacol 13(3):293–299

    PubMed  CAS  Google Scholar 

  • Regenold WT (2008a) Lithium and increased cortical gray matter—more tissue or more water? Biol Psychiatry 63:e17

    PubMed  Google Scholar 

  • Regenold WT (2008b) Lithium and increased hippocampal volume: more tissue or more water? Letter to the editor. Neuropsychopharmacology 33:1773–1774

    PubMed  Google Scholar 

  • Reus VI, Targum SD, Weingarter H, Post RM (1979) Effect of lithium carbonate on memory processes of bipolar affectively ill patients. Psychopharmacology (Berl) 63:39–42

    CAS  Google Scholar 

  • Richter-Levin G, Markram H, Segal M (1992) Spontaneous recovery of deficits in spatial memory and cholinergic potentiation of NMDA in CA1 neurons during chronic lithium treatment. Hippocampus 2(3):279–286

    PubMed  CAS  Google Scholar 

  • Rockenstein E, Torrance M, Adame A, Mante M, Bar-on P, Rose JB, Crews L, Masliah E (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27(8):1981–1991

    PubMed  CAS  Google Scholar 

  • Roussinov KS, Yonkov D (1975) Comparative studies on the effect of lithium and haloperidol on learning and memory. Acta Physiol Pharmacol Bulg 3–4:51–57

    PubMed  Google Scholar 

  • Sassi RB, Nicoletti M, Brambilla P, Malinger AG, Frank E, Kupfer DJ et al (2002) Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett 329:243–245

    PubMed  CAS  Google Scholar 

  • Senturk V, Goker C, Bilgic A, Olmez S, Tugcu H, Oncu B, Atbasoglu C (2007) Impaired verbal memory and otherwise spared cognition in remitted bipolar patients on monotherapy with lithium or valproate. Bipolar Disord 9(Suppl 1):136–144

    PubMed  Google Scholar 

  • Shaldubina A, Johanson RA, O’Brien WT, Buccafusca R, Agam G, Belmaker RH, Klein PS, Bersudsky Y, Berry GT (2006) SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior. Mol Genet Metab 88:384–388

    PubMed  CAS  Google Scholar 

  • Sharma I, Singh P (1988) Cognitive functions in patients of primary affective disorder on prophylactic lithium treatment. Indian J Med Res 88:246–252

    PubMed  CAS  Google Scholar 

  • Shaw ED, Stokes PE, Mann JJ, Manevitz AZ (1987) Effects of lithium carbonate on the memory and motor speed of bipolar outpatients. J Abnorm Psychology 96:64–69

    CAS  Google Scholar 

  • Shim SS, Hammonds MD, Ganocy SJ, Calabrese JR (2007) Effects of subchronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices. Progr Neuropsychopharmacol Biol Psychiatry 31:343–347

    CAS  Google Scholar 

  • Silva R, Mesquita AR, Bessa J, Sousa JC, Sotiropoulos I, Leão P, Almeida OF, Sousa N (2008) Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3beta. Neuroscience 152(3):656–669

    PubMed  CAS  Google Scholar 

  • Smigan L, Perris C (1983) Memory functions and prophylactic treatment with lithium. Psychol Med 13:529–536

    PubMed  CAS  Google Scholar 

  • Smith DF, Smith HB (1973) The effect of prolonged lithium administration on activity, reactivity, and endurance in the rat. Psychopharmacologia 30:83–88

    PubMed  CAS  Google Scholar 

  • Son H, Yu IT, Hwang S-J, Kim JS, Lee S-H, Lee Y-S, Kaang B-K (2003) Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus. J Neurochem 85:872–881

    PubMed  CAS  Google Scholar 

  • Souza FG, Goodwin GM (1991) Lithium treatment and prophylaxis in unipolar depression: a meta-analysis. Br J Psychiatry 158:666–675

    Article  PubMed  CAS  Google Scholar 

  • Squire LR, Judd LL, Janowsky DS, Huey LY (1980) Effects of lithium carbonate on memory and other cognitive functions. Am J Psychiatry 137:1042–1046

    PubMed  CAS  Google Scholar 

  • Stewart KT, McEachron DL, Rosenwasser AM, Adler NT (1991) Lithium lengthens circadian period but fails to counteract behavioral helplessness in rats. Biol Psychiatry 30:515–518

    PubMed  CAS  Google Scholar 

  • Stip E, Dufresne J, Lussier I, Yatham L (2000) A double-blind, placebo-controlled study of the effects of lithium on cognition in healthy subjects: mild and selective effects on learning. J Affect Disord 60:147–157

    PubMed  CAS  Google Scholar 

  • Sun X, Sato S, Murayama O, Murayama M, Park JM, Yamaguchi H, Takashima A (2002) Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci Lett 321(1–2):61–64

    PubMed  CAS  Google Scholar 

  • Teixeira NA, Pereira DG, Hermini AH (1995) Chronic but not acute Li+ treatment prevents behavioral depression in rats. Braz J Med Biol Res 28:1003–1007

    PubMed  CAS  Google Scholar 

  • Telford R, Worrall EP (1978) Cognitive functions in manic-depressives: effects of lithium and physostigmine. Br J Psychiatry 133:424–428

    PubMed  CAS  Google Scholar 

  • Terao T, Nakano H, Inoue Y, Okamoto T, Nakamura J, Iwata N (2006) Lithium and dementia: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1125–1128

    PubMed  CAS  Google Scholar 

  • Tomasiewicz HC, Mague SD, Cohen BM, Carlezon WA (2006) Behavioral effects of short-term administration of lithium and valproic acid in rats. Brain Res 1093:83–94

    PubMed  CAS  Google Scholar 

  • Tomkiewicz M, Steinberg H (1974) Lithium treatment reduces morphine self-administration in addict rats. Nature 252:227–229

    PubMed  CAS  Google Scholar 

  • Toulopoulou T, Grech A, Morris RG, Schulze K, McDonald C, Chapple B, Rabe-Hesketh S, Murray RM (2004) The relationship between volumetric brain changes and cognitive function: a family study on schizophrenia. Biol Psychiatry 56:447–453

    PubMed  Google Scholar 

  • Tsaltas E, Kontis D, Boulougouris V, Papakosta VM, Giannou H, Poulopoulou C, Soldatos C (2007a) Enhancing effects of chronic lithium on memory in the rat. Behav Brain Res 177:51–60

    PubMed  CAS  Google Scholar 

  • Tsaltas E, Kyriazi T, Poulopoulou C, Kontis D, Maillis A (2007b) Enhancing effects of lithium on memory are not by-products of learning or attentional deficits. Behav Brain Res 180:241–245

    PubMed  CAS  Google Scholar 

  • Umeda K, Suemaru K, Todo N, Egashira N, Mishima K, Iwasaki K, Fujiwara M, Araki H (2006) Effects of mood stabilizers on the disruption of prepulse inhibition induced by apomorphine or dizocilpine in mice. Eur J Pharmacol 553:157–162

    PubMed  CAS  Google Scholar 

  • Van Gorp WG, Altshuler L, Theberge DC, Wilkins J, Dixon W (1998) Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Arch Gen Psychiatry 55:41–46

    PubMed  Google Scholar 

  • Vasconcellos AP, Tabajara AS, Ferrari C, Rocha E, Dalmaz C (2003) Effect of chronic stress on spatial memory in rats is attenuated by lithium treatment. Physiol Behav 79:143–149

    PubMed  CAS  Google Scholar 

  • Vasconcellos AP, Zugno AI, Dos Santos AH, Nietto FB, Crema LM, Gonçalves M, Franzon R, de Souza Wyse AT, da Rocha ER, Dalmaz C (2005) Na+,K(+)-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: effect of chronic lithium treatment and possible involvement in learning deficits. Neurobiol Learn Mem 84:102–110

    PubMed  Google Scholar 

  • Vasconcellos AP, Nieto FB, Fontella FU, da Rocha ER, Dalmaz C (2006a) The nociceptive response of stressed and lithium-treated rats is differently modulated by different flavors. Physiol Behav 88:382–388

    PubMed  Google Scholar 

  • Vasconcellos AP, Nieto FB, Crema LM, Diehl LA, de Almeida LM, Prediger ME, da Rocha ER, Dalmaz C (2006b) Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress. Neurochem Res 31(9):1141–1151

    PubMed  CAS  Google Scholar 

  • Von Gunten A, Ron MA (2004) Hippocampal volume and subjective memory impairment in depressed patients. Eur Psychiatry 19:438–440

    Google Scholar 

  • Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, Richman R, Mizusawa H, Orr HT, Shaw C, Zoghbi HY (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4(5):e182

    PubMed  Google Scholar 

  • Wegener G, Bandpey Z, Heiberg IL, Mørk A, Rosenberg R (2003) Increased extracellular serotonin level in rat hippocampus induced by chronic citalopram is augmented by subchronic lithium: neurochemical and behavioural studies in the rat. Psychopharmacology (Berl) 166:188–194

    CAS  Google Scholar 

  • Weingartner H, Rudorfer MV, Linnoila M (1985) Cognitive effects of lithium treatment in normal volunteers. Psychopharmacology (Berl) 86:472–474

    CAS  Google Scholar 

  • Yan XB, Wang SS, Hou HL, Ji R, Zhou JN (2007a) Lithium improves the behavioral disorder in rats subjected to transient global cerebral ischemia. Behav Brain Res 177(2):282–289

    PubMed  CAS  Google Scholar 

  • Yan XB, Hou HL, Wu LM, Liu J, Zhou JN (2007b) Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacology 53(4):487–495

    PubMed  CAS  Google Scholar 

  • Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell WO, Boone B, Shinohara ET, Hallahan DE (2006) Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res 66(23):11179–11186

    PubMed  CAS  Google Scholar 

  • Youngs RM, Chu MS, Meloni EG, Naydenov A, Carlezon Jr WA, Konradi C (2006) Lithium administration to preadolescent rats causes long-lasting increases in anxiety-like behavior and has molecular consequences. J Neurosci 26:6031–6039

    PubMed  CAS  Google Scholar 

  • Yucel K, MacQueen GM (2008) Reply: lithium and increased hippocampal volume—more tissue or more water? Neuropsychopharmacology 33:1775

    Google Scholar 

  • Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, Macqueen GM (2007) Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 195:357–367

    CAS  Google Scholar 

  • Zhong J, Lee WH (2007) Lithium: a novel treatment for Alzheimer’s disease? Expert Opin Drug Saf 6:375–383

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant 70/4/9100 from the Special Account for Research Grants, National and Kapodistrian University of Athens to Dr. E. Tsaltas.

Author information

Authors and Affiliations

  1. Experimental Psychology Laboratory, Department of Psychiatry, Eginition Hospital, Athens University Medical School, 74, Vas. Sofias Avenue, 115 28, Athens, Greece

    Eleftheria Tsaltas & Dimitris Kontis

  2. Psychiatric Hospital of Attica, Athens, Greece

    Dimitris Kontis

  3. Department of Experimental Psychology and the Behavioural and Clinical Neuroscience Institute (BCNI), University of Cambridge, Downing Site, CB2 3EB, Cambridge, UK

    Vasileios Boulougouris

  4. Department of Psychiatry, Eginition Hospital, Athens University Medical School, 74, Vas. Sofias Avenue, 115 28, Athens, Greece

    George N. Papadimitriou

Authors
  1. Eleftheria Tsaltas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitris Kontis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vasileios Boulougouris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George N. Papadimitriou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eleftheria Tsaltas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsaltas, E., Kontis, D., Boulougouris, V. et al. Lithium and cognitive enhancement: leave it or take it?. Psychopharmacology 202, 457–476 (2009). https://doi.org/10.1007/s00213-008-1311-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1311-8

Keywords

Search

Navigation