, Volume 170, Issue 3, pp 225–234 | Cite as

The effects of lithium on cognition: an updated review

  • Arlin K. PachetEmail author
  • Amy M. Wisniewski



Adverse cognitive effects associated with lithium are often implicated as contributing to vocational and social impairment, as well as medication noncompliance. As impaired cognitive functioning caused by lithium has clear clinical implications, it is important to determine whether evidence for or against impaired cognitive functioning exists in the literature.


An attempt is made to synthesize findings from previous studies, which assess a variety of cognitive domains, to determine whether conclusions can be drawn regarding lithium-associated cognitive impairment. The "reversibility" of neuropsychological impairment following lithium discontinuation and whether lithium administration has negative cumulative effects on cognition were also reviewed.


Key word searches on "Medline" and "Psych Info" were completed for clinical articles that investigated the neuropsychological effects of lithium in clinical and normal populations between 1968 and 2000.


Despite methodological flaws, poor replicability and the subtle cognitive effects of lithium, five consistent findings emerged from the review; impairment on tasks of psychomotor speed, impaired functioning in the majority of studies examining verbal memory, no impairment on tasks of visuo-spatial constructional ability or attention/ concentration, and no negative cumulative effect.


Many patients administered lithium carbonate complained of mental slowness. Lithium carbonate also appeared to have definite, yet subtle, negative effects on psychomotor speed. Studies reviewed also showed a trend toward impaired verbal memory. Recommendations with respect to future research, methodological and statistical problems, and additional clinical implications are presented.


Lithium Memory Cognition Bipolar 



I wish to thank Dr. Shawn Gray and Dr. Peter Wass for their attentive reading of an earlier version of this article.


  1. Andrews DG, Schweitzer I, Marshall N (1990) The comparative cognitive side effects of lithium, carbamazepine, and combined lithium-carbamazepine in patients treated for affective disorders. Hum Psychopharmacol 5:41–45CrossRefGoogle Scholar
  2. Baastrup PC (1964) The use of lithium in manic-depressive psychosis. Compr Psychiatry 5:396CrossRefPubMedGoogle Scholar
  3. Benes F, Kwok E, Vincent S, Todtenkopf M (1998) A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44:88–97CrossRefPubMedGoogle Scholar
  4. Bone S, Roose SP, Dunner DL, Fieve RR (1980) Incidence of side effects in patients on long-term lithium therapy. Am J Psychiatry 137:103–104CrossRefPubMedGoogle Scholar
  5. Bowden C, Brugger A, Swann A, Calabrese J, Janicak P, Petty F et al. (1994) Efficacy of divalproex vs. lithium and placebo in the treatment of mania. J Am Med Assoc 271:918–924CrossRefGoogle Scholar
  6. Calil HM, Zwicker P, Klepacz S (1990) The effects of lithium carbonate on healthy volunteers: mood stabilization? Biol Psychiatry 27:711–722CrossRefPubMedGoogle Scholar
  7. Chamberlin E, Tsai GE (1998) A glutamatergic model of ECT-induced memory dysfunction. Harv Rev Psychiatry 5: 307–317CrossRefPubMedGoogle Scholar
  8. Chen R, Chuang D (1999) Long-term lithium treatment suppresses p53 and Bax expression, but increases bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 274:6039–6042CrossRefPubMedGoogle Scholar
  9. Chen G, Zeng W, Yuan P, Huang L, Jiang Y, Zhao Z, Manji H (1999) The mood-stabilizing agents lithium and valproate robustly increase the levels of neuroprotective protein bcl-2 in the CNS. J Neurochem 72:879–882CrossRefPubMedGoogle Scholar
  10. Christodoulou GN, Kokkevi A, Lykouras EP, Stefanis CN, Papadimitrious GN (1981) Effects of lithium on memory. Am J Psychiatry 138:847–848CrossRefPubMedGoogle Scholar
  11. Cohen J (1992) A power primer. Psychol Bull 112:155–159CrossRefPubMedGoogle Scholar
  12. Demers RG, Heninger GR (1971) Visual-motor performance during lithium treatment—a preliminary report. J Clin Pharmacol 11:274–279Google Scholar
  13. Drevets W, Price J, Simpson J, Todd R, Reich T, Vannier M, Raichle M (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature 38:824–827CrossRefGoogle Scholar
  14. Emilien G, Maloteaux J, Seghers A, Charles G (1996) Lithium compared to valproic acid and carbamazepine in the treatment of mania. A statistical meta-analysis. Eur Neuropsychopharmacol 6:245–252CrossRefPubMedGoogle Scholar
  15. Engelsmann F, Katz J, Ghadirian AM, Schachter D (1988) Lithium and memory: a long-term follow-up study. J Clin Psychopharmacol 8:207–212CrossRefPubMedGoogle Scholar
  16. Erdfelder E, Faul F, Buchner A (1996) GPOWER: a general power analysis program. Behav Res Methods Instrum Comput 28:1–11CrossRefGoogle Scholar
  17. Friedman MJ, Culver CM, Ferrell RB (1977) On the safety of long-term treatment with lithium. Am J Psychiatry 134:1123–1126CrossRefPubMedGoogle Scholar
  18. Gitlin MJ, Cochran SD, Jamison KR (1989) Maintenance lithium treatment: side effects and compliance. J Clin Psychiatry 50:127–131PubMedGoogle Scholar
  19. Glue PW, Nutt DJ, Cowen PJ, Broadbent D (1987) Selective effect of lithium on cognitive performance in man. Psychopharmacology 91:109–111CrossRefPubMedGoogle Scholar
  20. Goldberg J, Burdick K (2001) Cognitive side effects of anticonvulsants. J Clin Psychiatry 14:27–33Google Scholar
  21. Goldberg J, Harrow M (1999) Bipolar disorders: clinical course and outcome. American Psychiatric Press, WashingtonGoogle Scholar
  22. Hartigan GP (1963) The use of lithium salts in affective disorders. Br J Psychiatry 109:810CrossRefPubMedGoogle Scholar
  23. Honig A, Arts B, Ponds R, Riedel W (1999) Lithium-induced cognitive side-effects in bipolar disorder: a qualitative analysis and implications for daily practice. Int Clin Psychopharmacol 14:167–171PubMedGoogle Scholar
  24. Jauhar P, McClure I, Hillary C, Watson A (1993) Psychomotor performance of patients on maintenance lithium therapy. Hum Psychopharmacol 8:141–143CrossRefGoogle Scholar
  25. Joffe R, MacDonald C, Kutcher S (1988) Lack of differential cognitive effects of lithium and carbamazepine in bipolar affective disorder. J Clin Psychopharmacol 8:425–428CrossRefPubMedGoogle Scholar
  26. Judd LL (1979) Effect of lithium on mood, cognition, and personality function in normal subjects. Arch Gen Psychiatry 36:860–865CrossRefPubMedGoogle Scholar
  27. 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 34:463–467CrossRefPubMedGoogle Scholar
  28. Judd LL, Hubbard B, Janowsky DS, Huey LY, Attewell PA (1977b) The effect of lithium carbonate on affect, mood, and personality of normal subjects. Arch Gen Psychiatry 34:346–351CrossRefPubMedGoogle Scholar
  29. Judd LL, Hubbard B, Janowsky DS, Huey LY, Takahashi KI (1977c) The effect of lithium carbonate on the cognitive functions of normal subjects. Arch Gen Psychiatry 34:355–357CrossRefPubMedGoogle Scholar
  30. Karniol IG, Dalton J, Lader MH (1978) Acute and chronic effects of lithium chloride on physiological and psychological measures in normals Psychopharmacology 57:289–294PubMedGoogle Scholar
  31. Kocsis J, Shaw E, Stokes P, Wilner P, Elliot A, Sikes C et al. (1993) Neuropsychological effects of lithium discontinuation. J Clin Psychopharmacol 13:268–276CrossRefPubMedGoogle Scholar
  32. 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 26:235–239CrossRefPubMedGoogle Scholar
  33. Kropf D, Muller-Oerlinghausen B (1979) Changes in learning, memory, and mood during lithium treatment. Acta Psychiatr Scand 59:97–124CrossRefPubMedGoogle Scholar
  34. Kusumo KS, Vaughan M (1977) Effects of lithium salts on memory. Br J Psychiatry 131:453–457CrossRefPubMedGoogle Scholar
  35. Lenzer I, Eastwood D, Street P (1989) Reinterpreting memory complaints through neuropsychological assessment. Clin Gerontol 8:57–60CrossRefGoogle Scholar
  36. 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 64:423–430CrossRefPubMedGoogle Scholar
  37. Lund Y, Nissen M, Rafaelsen OJ (1982) Long-term lithium treatment and psychological functions. Acta Psychiatr Scandin 65:233–244CrossRefGoogle Scholar
  38. Lyskowski J, Nasrallah HA, Dunner FJ, Bucher K (1982) A longitudinal survey of side effects in a lithium clinic. J Clin Psychiatry 43:284–286PubMedGoogle Scholar
  39. Maarbjerg K, Vestergaard P, Schou M (1987) Changes in serum thyroxine and serum thyroid-stimulating hormone during prolong lithium treatment. Acta Psychiatr Scand 75:217–221CrossRefPubMedGoogle Scholar
  40. Manji H, Moore G, Chen G (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 46:929–940CrossRefPubMedGoogle Scholar
  41. Manji H, Moore G, Chen G (2000) 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 61:82–96PubMedGoogle Scholar
  42. Marusarz TZ, Wolpert EA, Koh SD (1981) Memory processing with lithium carbonate. J Clin Psychiatry 42:190–192PubMedGoogle Scholar
  43. McCreadie RG, McCormick M, Morrison DP (1985) The impact of lithium in southwest Scotland. III. The discontinuation study. Br J Psychiatry 146:77–80CrossRefPubMedGoogle Scholar
  44. Moore G, Bebchuk J, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds I, Faulk M, Koch S, Glitz D, Jolkovsky L, Manji H (2000) Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects? Biol Psychiatry 48:1–8CrossRefPubMedGoogle Scholar
  45. Muller-Oerlinghausen B (2000) Does effective lithium prophylaxis result in a symptom-free state of manic-depression illness? Some thoughts on the fine-tuning of mood stabilization. Compr Psychiatry 41:26–31CrossRefPubMedGoogle Scholar
  46. Nonaka S, Chuang DM (1998) Neuroprotective effects of lithium on focal cerebral ischemia in rats. Neuroreport 9:2081–2084CrossRefPubMedGoogle Scholar
  47. Rajkowska G (1999) Morphometric methods for studying the prefrontal cortex in suicide victims and psychiatric patients. Ann N Y Acad Sci 836:253–268CrossRefGoogle Scholar
  48. Rapp S, Thomas R (1979) Lithium and memory loss. Can J Psychiatry 24:784Google Scholar
  49. Reitan RM, Wolfson D (1993) The Halstead-Reitan neuropsychological test battery, 2nd edn. Neuropsychology Press, Tucson, pp 229–801Google Scholar
  50. Reus VI, Targum SD, Weingartner H, Post RM (1979) The effect of lithium carbonate in memory processes of bipolar affectively ill patients. Psychopharmacology 63:39–42CrossRefPubMedGoogle Scholar
  51. Salate R, Klein I (1987) Effects of lithium on the endocrine system: a review. J Lab Clin Med 110:130–136Google Scholar
  52. Sackeim H, Prudic J, Devanand D, Nobler M, Lisanby S, Peyser S et al. (2000) A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry 57:425–434CrossRefPubMedGoogle Scholar
  53. Schou M (1989) Lithium prophylaxis: myths and realities. Am J Psychiatry 146:573–576CrossRefPubMedGoogle Scholar
  54. Sharma I, Singh P (1988) Cognitive functions in patients of primary affective disorder on prophylactic lithium treatment. Indian J Med Res 88:246–252PubMedGoogle Scholar
  55. Shaw E, Mann J, Stokes P, Manevitz Z (1986) Effects of lithium carbonate on associative productivity and idiosyncrasy in bipolar outpatients. Am J Psychiatry 143:1166–1169CrossRefPubMedGoogle Scholar
  56. Shaw E, Stokes P, Mann J, Manevitz Z (1987) Effects of lithium carbonate on the memory and motor speed of bipolar outpatients. J Abnorm Psychol 96:64–69CrossRefPubMedGoogle Scholar
  57. Smigan L, Perris C (1983) Memory functions and prophylactic treatment with lithium. Psychol Med 13:529–536CrossRefPubMedGoogle Scholar
  58. Souza F, Goodwin G (1991) Lithium treatment and prophylaxis in unipolar depression: a meta-analysis. Br J Psychiatry 158:666–675CrossRefPubMedGoogle Scholar
  59. Squire LR, Judd LL, Janowsky DS, Huey LY (1980) Effects of lithium on memory and other cognitive functions. Am J Psychiatry 137:1042–1046CrossRefPubMedGoogle Scholar
  60. Stoll A, Locke C, Vuckovic A, Mayer P (1996) Lithium-associated cognitive and functional deficits reduced by a switch to DS: a case series. J Clin Psychiatry 57:356–359CrossRefPubMedGoogle Scholar
  61. Telford R, Worrall EP (1978) Cognitive functions in manic-depressives: effects of lithium and physostigmine. Br J Psychiatry 133:424–428CrossRefPubMedGoogle Scholar
  62. Tremont G, Stern RA (1997) Use of thyroid hormone to diminish the cognitive side effects of psychiatric treatment. Psychopharmacol Bull 33:273–280PubMedGoogle Scholar
  63. Van Gorp WG, Altshuler L, Theberge DC, Wilkins J, Dixon W (1998) Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. Arch Gen Psychiatry 55:41–46CrossRefGoogle Scholar
  64. Vermeulen J, Aldenkamp A (1995) Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research. Epilepsy Res 22:65–95CrossRefPubMedGoogle Scholar
  65. Weingartner H, Rudorfer MV, Linnoila M (1985) Cognitive effects of lithium treatment in normal volunteers. Psychopharmacology 86:472–474CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Brain Injury ProgramColumbia Health CentreCalgaryCanada
  2. 2.Pacific Graduate School of PsychologyPalo AltoUSA

Personalised recommendations