Other Effects of Lithium Mediated through Metabolic Pathways

  • John H. Lazarus
  • Keith J. Collard


The phenomena of cellular immunity depend on the ionic composition of the media in which the reactions are occurring. Cyclic nucleotides also play an important role in the modulation of the immune response by providing positive and negative feedback at the molecular level. The immune system can be conveniently, if artificially, divided into cellular and humoral systems. The effect of lithium on each system will be considered in this chapter.


Cyclic Nucleotide Experimental Medicine Herpes Simplex Virus Infection Lithium Chloride Megaloblastic Anemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hart DA: Modulation of concanavalin A stimulation of hamster lymphoid cells by lithium chloride. Cell Immunol 43:113–122, 1979.PubMedCrossRefGoogle Scholar
  2. 2.
    Hart DA: Potentiation of phytohemagglutinin stimulation of lymphoid cells by lithium. Exp Cell Res 119:47–53, 1979.PubMedCrossRefGoogle Scholar
  3. 3.
    Shenkman L, Borkowsky W, Holzman RS, et al: Enhancement of lymphocyte and macrophage function in vitro by lithium chloride. Clin Immunol Immunopathol 10:187–192, 1978.PubMedCrossRefGoogle Scholar
  4. 4.
    Borkowsky W, Shenkman L, Wadler S, et al: Adjuvant-like effects of lithium on peripheral blood mononuclear cells, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 417–427.CrossRefGoogle Scholar
  5. 5.
    Gelfand EW, Cheung R, Hastings D, et al: Characterization of lithium effects on two aspects of T-cell function, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 429–446.CrossRefGoogle Scholar
  6. 6.
    Gelfand EW: Lithium: A modulator of cyclic AMP-dependent events in lymphocytes? Science 203:365–367, 1979.PubMedCrossRefGoogle Scholar
  7. 7.
    Grecco AF: Lithium attenuation of chemotherapy-induced granulocytopenia: Statistical and clinical significance?, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 275–279.CrossRefGoogle Scholar
  8. 8.
    Perez-Cruet J, Dancey JT: Thymus gland involution induced by lithium chloride. Experientia 33:646–648, 1977.PubMedCrossRefGoogle Scholar
  9. 9.
    Fernandez LA, MacSween JM: Lithium and T cell colonies. Scand J Haematol 25:382–384, 1980.PubMedCrossRefGoogle Scholar
  10. 10.
    Bray J, Turner AR, Dusel F: Lithium and the mitogenic response of human lymphocytes. Clin Immunol Immunopathol 19:284–288, 1981.PubMedCrossRefGoogle Scholar
  11. 11.
    Fernandez LA, Fox RA: Perturbation of the human immune system by lithium. Clin Exp Immunol 41:527–532, 1980.PubMedGoogle Scholar
  12. 12.
    Jankovic BD, Isakovic K, Popeskovic L: Negative immune deviation induced by lithium cation. Immunol Lett 1:203–208, 1980.CrossRefGoogle Scholar
  13. 13.
    Russell JH, Dobos CB: The role of monovalent cations in the interaction between the cytotoxic T lymphocyte and its target. Eur J Immunol 11:840–843, 1981.PubMedCrossRefGoogle Scholar
  14. 14.
    Ischizaka S, Moller G: Lithium chloride induces partial responsiveness to LPS in nonresponder B cells. Nature (London) 299:363–365, 1982.CrossRefGoogle Scholar
  15. 15.
    Hart DA: Differential potentiation of in vitro lipopolysaccharide stimulation of B-lymphoid cells by lithium and ammonium ions. Cell Immunol 71:159–168, 1982.PubMedCrossRefGoogle Scholar
  16. 16.
    Morito T, Bankhurst AD, Williams RC, Jr: Studies on the pharmacologic manipulation of suppressor cells associated with impaired immunoglobulin production. J Lab Clin Med 96:232–237, 1980.PubMedGoogle Scholar
  17. 17.
    Weetman AP, McGregor AM, Lazarus JH, et al: The enhancement of immunoglobulin synthesis by human lymphocytes with lithium. Clin Immunol Immunopathol 22:400–407, 1982.PubMedCrossRefGoogle Scholar
  18. 18.
    Gronowicz E, Continho A, Melchers F: A plaque assay for all cells secreting Ig of a given type of class. Eur J Immunol 6:588–590, 1976.PubMedCrossRefGoogle Scholar
  19. 19.
    Johnstone EC, Whaley K: Antinuclear antibodies in psychiatric illness: Their relationship to diagnosis and drug treatment. Br Med J 2:724–725, 1975.PubMedCrossRefGoogle Scholar
  20. 20.
    Presley AP, Kahn A, Williamson N: Antinuclear antibodies in patients on lithium carbonate. Br Med J 2:280–281, 1976.PubMedCrossRefGoogle Scholar
  21. 21.
    Hart DA: Evidence that lithium ions can modulate lectin stimulation of lymphoid cells by multiple mechanisms. Cell Immunol 58:372–384, 1981.PubMedCrossRefGoogle Scholar
  22. 22.
    Borkowsky W, Shenkman L, Suleski P, et al: An immunodeficient child with inflammatory bowel disease: Involvement of cyclic nucleotides and effects of lithium. Dev Pharmacol Ther 3:116–128, 1981.PubMedGoogle Scholar
  23. 23.
    Perez DH, Kaplan HB, Goldstein IM, et al: Reversal of an abnormality of polymor-phonuclear leukocyte chemotaxis with lithium. Clin Immunol Immunopathol 16:308–315, 1980.PubMedCrossRefGoogle Scholar
  24. 24.
    Hart DA: Ability of monovalent cations to replace potassium during stimulation of lymphoid cells. Cell Immunol 57:209–218, 1981.PubMedCrossRefGoogle Scholar
  25. 25.
    May field D, Brown RG: The clinical laboratory and electroencephalographic effects of lithium. J Psychiatr Res 4:207–219, 1966.CrossRefGoogle Scholar
  26. 26.
    O’Connell RA: Leukocytosis during lithium carbonate treatment. Int Pharmacopsychiatry 4:30–34, 1970.Google Scholar
  27. 27.
    Shopsin B, Friedmann R, Gershon S: Lithium and leukocytosis. Clin Pharmacol Ther 12:923–928, 1971.PubMedGoogle Scholar
  28. 28.
    Ricci P, Bandini G, Franchi P, et al: Haematological effects of lithium carbonate: A study in 56 psychiatric patients. Haematologica 66:627–633, 1981.PubMedGoogle Scholar
  29. 29.
    Bille PE, Jensen MK, Jensen JPK, et al: Studies on the haematologic and cytogenetic effect of lithium. Acta Med Scand 198:281–286, 1975.PubMedCrossRefGoogle Scholar
  30. 30.
    Wessels JMC: Haematological effects of lithium: A review. Agressologie 23(B): 105–109, 1982.PubMedGoogle Scholar
  31. 31.
    Barr RD, Galbraith PR: Lithium and hematopoiesis. Can Med Assoc J 128:123–126, 1983.PubMedGoogle Scholar
  32. 32.
    Boggs DR, Joyce RA: The hematopoietic effects of lithium. Semin Hematol 20:129–138, 1983.PubMedGoogle Scholar
  33. 33.
    Tisman G, Herbert V, Rosenblatt S: Evidence that lithium induces human granulocyte proliferation: Elevated serum vitamin B12 binding capacity in vivo and granulocyte colony proliferation in vitro. Br J Haematol 24:767–771, 1973.PubMedCrossRefGoogle Scholar
  34. 34.
    Rothstein G, Clarkson DR, Larsen W, et al: Effect of lithium on neutrophil mass and production. N Engl J Med 298:178–180, 1978.PubMedCrossRefGoogle Scholar
  35. 35.
    Rossof AH, Coltman CA, Jr: The effect of lithium carbonate on the granulocyte phagocytic index. Experientia 32:238–239, 1976.PubMedCrossRefGoogle Scholar
  36. 36.
    Morley DC, Jr, Galbraith PR: Effect of lithium on granulopoiesis in culture. Can Med Assoc J 118:288–290, 1978.PubMedGoogle Scholar
  37. 37.
    Verma DS, Johnston DA, McCredie KB: Evidence for the separate human T-lymphocyte subpopulations that collaborate with autologous monocyte/macrophages in the elaboration of colony-stimulating activity and those that suppress this collaboration. Blood 62:1088–1099, 1983.PubMedGoogle Scholar
  38. 38.
    Joyce RA, Chervenick PA: The effect of lithium on release of granulocyte colony stimulating activity in vitro, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 79–86.CrossRefGoogle Scholar
  39. 39.
    Gupta RC, Robinson WA, Kurnick JE: Felty’s syndrome. Effect of lithium on granulopoiesis. Am J Med 61:29–32, 1976.PubMedCrossRefGoogle Scholar
  40. 40.
    Harker WG, Rothstein G, Clarkson D, et al: Enhancement of colony-stimulating activity production by lithium. Blood 49:263–267, 1977.PubMedGoogle Scholar
  41. 41.
    Verma DS, Spitzer G, Zander AR, et al. Myelopoietic modulation by lithium: in vitro experiments on its mechanisms of action in man, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 111–126.CrossRefGoogle Scholar
  42. 42.
    Greenberg PL, Packard B, Steed SM: Effects of lithium chloride on human and murine marrow myeloid colony formation and colony stimulating activity, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 137–144.CrossRefGoogle Scholar
  43. 43.
    Galbraith PR: Effect of lithium on colony formation and production of colony-stimu-lating factor, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 99–109.CrossRefGoogle Scholar
  44. 44.
    Rothstein G, Oshita AK, Harker WG, et al: The effect of lithium upon granulocyte production in vitro and in vivo in the mouse, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 87–98.CrossRefGoogle Scholar
  45. 45.
    Turner AR, Allalunis MJ: Oral lithium carbonate increases colony stimulating activity production from human mononuclear cells, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 127–136.CrossRefGoogle Scholar
  46. 46.
    Dexter TM, Allen TD, Lajtha LG: Conditions controlling the proliferation of haemopoietic stem cells in vitro. J Cell Physiol 91:335–344, 1977.PubMedCrossRefGoogle Scholar
  47. 47.
    Levitt LJ, Quesenberry PJ: The effect of lithium on murine hematopoiesis in a liquid culture system. N Engl J Med 302:713–719, 1980.PubMedCrossRefGoogle Scholar
  48. 48.
    Quesenberry PJ, Coppola MA, Gualtieri RJ, et al: Lithium stimulation of murine hematopoiesis in liquid culture: An effect mediated by marrow stromal cells. Blood 63:121–127, 1984.PubMedGoogle Scholar
  49. 49.
    Gallicchio VS, Chen MG: Influence of lithium on proliferation of hematopoietic stem cells. Exp Hematol 9:804–810, 1981.PubMedGoogle Scholar
  50. 50.
    Joyce RA: Sequential effects of lithium on haematopoiesis. Br J Haematol 56:307–321, 1984.PubMedCrossRefGoogle Scholar
  51. 51.
    De Vries EGE, van Luyn MJA, Mulder NH, et al: In vitro effects of lithium on granulocyte colony formation in normal men, in hematological disorders and in small-cell carcinoma of the lung. Acta Haematol 70:97–107, 1983.PubMedCrossRefGoogle Scholar
  52. 52.
    Lund JE, Padgett GA, Ott RL: Cyclic neutropenia in grey collie dogs. Blood 29:452–461, 1967.PubMedGoogle Scholar
  53. 53.
    Hammond WP, Dale DC: Cyclic hematopoiesis: Effects of lithium on colony-forming cells and colony-stimulating activity in grey collie dogs. Blood 59:179–184, 1982.PubMedGoogle Scholar
  54. 54.
    Murphy DL, Donnelly C, Moskowitz J: Inhibition by lithium of prostaglandin E1 and norepinephrine effects on cyclic adenosine monophosphate production in human platelets. Clin Pharmacol Ther 14:810–814, 1973.PubMedGoogle Scholar
  55. 55.
    Gallicchio VS, Chen MG, Watts TD: Specificity of lithium (Li+) to enhance the production of colony stimulating factor (GM-CSF) from mitogen-stimulated lymphocytes in vitro. Cell Immunol 85:58–66, 1984.PubMedCrossRefGoogle Scholar
  56. 56.
    Verma DS, Spitzer G, Gutterman JU, et al: Human leukocyte interferon-mediated granulopoietic differentiation arrest and its abrogation by lithium carbonate. Am J Hematol 12:39–46, 1982.PubMedCrossRefGoogle Scholar
  57. 57.
    Medina JL, Fareed J, Diamond S: Lithium carbonate therapy for cluster headaches: changes in number of platelets, and serotonin and histamine levels. Arch Neurol 37:559–563, 1980.PubMedCrossRefGoogle Scholar
  58. 58.
    Joffe RT, Kellner CH, Post RM, et al: Lithium increases platelet count. N Engl J Med 311:674–675, 1984.PubMedGoogle Scholar
  59. 59.
    Stein RS, Howard CA, Brennan M, et al: Lithium carbonate and granulocyte production: dose optimization. Cancer 48:2696–2701, 1981.CrossRefGoogle Scholar
  60. 60.
    Gamba-Vitalo C, Gallicchio VS, Watts TD, et al: Lithium stimulated in vitro megakaryocytopoiesis. Exp Hematol 11:382–388, 1983.PubMedGoogle Scholar
  61. 61.
    Imandt L, Tijhuis D, Wessels H, et al: Lithium inhibits adenylate cyclase of human platelets. Thrombos Hemostas 45:142–145, 1981.Google Scholar
  62. 62.
    Burstein SA, Adamson JW, Harker LA: Megakaryocytopoiesis in culture: modulation by cholinergic mechanisms. J Cell Physiol 103:201–208, 1980.PubMedCrossRefGoogle Scholar
  63. 63.
    Geerdink P, Levy-Toledano S, Wessels H, et al: Influence of lithium on aggregation, release reaction and function of human platelets. Pathol Biol 20(Suppl): 15–27, 1972.Google Scholar
  64. 64.
    Imandt L, Genders T, Wessels H, et al: The effect of lithium on platelet aggregation and platelet release reaction. Thromb Res 11:297–308, 1977.PubMedCrossRefGoogle Scholar
  65. 65.
    Barrett AJ, Griscelli C, Buriot D, et al: Lithium therapy in congenital neutropenia. Lancet 2:1357–1358, 1977.PubMedCrossRefGoogle Scholar
  66. 66.
    Chan HSL, Freedman MH, Saunders EF: Lithium therapy of children with chronic neutropenia. Am J Med 70:1073–1077, 1981.PubMedCrossRefGoogle Scholar
  67. 67.
    Ishi E, Hara T, Miyazaki S, et al: Lithium therapy for cyclic neutropenia in children. Scand J Haematol 31:193–196, 1983.CrossRefGoogle Scholar
  68. 68.
    De Alarcon PA, Goldberg J, Nelson DA, et al: Lithium therapy in childhood neutropenia. J Pediatr 102:149–152, 1983.CrossRefGoogle Scholar
  69. 69.
    Gerner RH, Wolff SM, Fauci AS, et al: Lithium carbonate for recurrent fever and neutropenia. J Am Med Assoc 246:1584–1586, 1981.CrossRefGoogle Scholar
  70. 70.
    Friedenberg WR, Marx JJ, Jr: The effect of lithium carbonate on lymphocyte, granulocyte, and platelet function. Cancer 45:91–97, 1980.PubMedCrossRefGoogle Scholar
  71. 71.
    Williams DM, Jones JV, Jr: Lithium carbonate treatment in familial cyclic neutropenia. Am J Clin Pathol 81:120–122, 1984.PubMedGoogle Scholar
  72. 72.
    Verma DS, Spitzer G, Zander AR, et al: Cyclic neutropenia and T lymphocyte suppression of granulopoiesis: abrogation of the neutropenic cycles by lithium carbonate. Leukemia Res 6:567–576, 1982.CrossRefGoogle Scholar
  73. 73.
    Blum SF: Lithium in hairy-cell leukemia. N Engl J Med 303:464–465, 1980.PubMedGoogle Scholar
  74. 74.
    Paladine WJ, Price LM, Williams HD, et al: Hairy-cell leukemia treated with lithium. N Engl J Med 304:1237–1238, 1981.PubMedGoogle Scholar
  75. 75.
    Lyman GH, Williams CC, Preston D: The use of lithium carbonate to reduce infection and leukopenia during systemic chemotherapy. N Engl J Med 302:257–260, 1980.PubMedCrossRefGoogle Scholar
  76. 76.
    Lyman GH, Williams CC, Preston D, et al: Lithium carbonate in patients with small cell lung cancer receiving combination chemotherapy. Am J Med 70:1222–1229, 1981.PubMedCrossRefGoogle Scholar
  77. 77.
    Stein RS, Beaman C, Ali MY, et al: Lithium carbonate attenuation of chemotherapyinduced neutropenia. N Engl J Med 297:430–431, 1977.PubMedCrossRefGoogle Scholar
  78. 78.
    Richman CM, Makii MM, Weiser PA, et al: The effect of lithium carbonate on chemotherapy-induced neutropenia and thrombocytopenia. Am J Hematol 16:313–323,1984.PubMedCrossRefGoogle Scholar
  79. 79.
    Catane R, Kaufman J, Mittleman A, et al: Attenuation of myelosuppression with lithium. N Engl J Med 297:452–453, 1977.PubMedCrossRefGoogle Scholar
  80. 80.
    Charron D, Barrett AJ, Faille A, et al: Lithium in acute myeloid leukaemia. Lancet 1:1307, 1977.PubMedCrossRefGoogle Scholar
  81. 81.
    Piccinini L, Zanni G, Pisa S, et al: Trattamento con carbonato di litio della leucopenia indotta da terapia mielodepressiva in pazienti con emolinfoblastosi—Nota preventiva. Boll Soc Med Chir Modena 80:15–19, 1980.Google Scholar
  82. 82.
    Gallicchio VS, Chen MG, Watts TD, et al: Lithium stimulates the recovery of granulopoiesis following acute radiation injury. Exp Hematol 11:553–563, 1983.PubMedGoogle Scholar
  83. 83.
    Stein RS, Vogler WR, Lefante J: Failure of lithium to limit neutropenia significantly during induction therapy of acute myelogenous leukemia: A Southeastern Cancer Study Group study. Am J Clin Oncol 7:365–369, 1984.PubMedCrossRefGoogle Scholar
  84. 84.
    Guistolisi R, Di Raimondo F, Guglielmo P, et al: Lithium and acute myeloid leukemia. Haematologica 67: N. 6, December 1982.Google Scholar
  85. 85.
    Carulli G, Azzara A, Caracciolo F, et al: Lithium and acute lymphocytic leukemia. Haematologica 68: N.5, September-October 1983.Google Scholar
  86. 86.
    Prakash R, Sethi N, Agrawal SS, et al: A case report of megaloblastic anemia secondary to lithium. Am J Psychiatry 138:849, 1981.PubMedGoogle Scholar
  87. 87.
    Herbert V, Colman N: Release of vitamin binding proteins from granulocytes by lithium: vitamin B12 and folate binding proteins, in Rossof AH, Robinson WA (eds): Advances in Experimental Medicine and Biology, Vol 127, Lithium Effects on Granulopoiesis and Immune Function. New York, Plenum Press, 1980, pp 61–78.CrossRefGoogle Scholar
  88. 88.
    Lieb J: Remission of recurrent herpes infection during therapy with lithium. N Engl J Med 301:942, 1979.PubMedGoogle Scholar
  89. 89.
    Lieb J: Immunopotentiation and inhibition of herpes virus activation during therapy with lithium carbonate. Med Hypotheses 7:885–980, 1981.PubMedCrossRefGoogle Scholar
  90. 90.
    Skinner GRB, Hartley C, Buchan A, et al: The effect of lithium chloride on the replication of herpes simplex virus. Med Microbiol Immunol 168:139–148, 1980.PubMedCrossRefGoogle Scholar
  91. 91.
    Trousdale MD, Gordon YJ, Peters ACB, et al: Evaluation of lithium as an inhibitory agent of herpes simplex virus in cell cultures and during reactivation of latent infection in rabbits. Antimicrob Agents Chemother 25:522–523, 1984.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1986

Authors and Affiliations

  • John H. Lazarus
    • 1
  • Keith J. Collard
    • 2
  1. 1.University of Wales College of MedicineCardiffWales, UK
  2. 2.University College CardiffCardiffWales, UK

Personalised recommendations