Clinical Drug Investigation

, Volume 15, Issue 4, pp 337–351 | Cite as

Recurrence Risk in Bipolar Manic- Depressive Disorders after Discontinuing Lithium Maintenance Treatment: An Overview

  • Ross J. BaldessariniEmail author
  • Leonardo Tondo
Clinical Review


Lithium remains unequaled in its research support as a standard maintenance treatment for bipolar manic-depressive disorders. It has important beneficial effects on recurring bipolar depression as well as mania, and in both types I and II bipolar syndromes, with powerful antisuicide effects not demonstrated with alternative mood-stabilisers. Data collected from numerous studies indicate that discontinuing lithium maintenance treatment is followed by sharply increased morbidity and possibly mortality, particularly in the first 6 to 12 months. However, we found that gradual discontinuation markedly reduced, and not merely delayed, recurrences of mania or depression after discontinuing lithium, with an even stronger effect in bipolar type II than type I patients. Secondary long-term retreatment with lithium following discontinuation yielded only minor average losses of benefits. Increased early recurrence risk may also arise after stopping long-term treatment with other neuropsychotropic drugs. Such reactions probably reflect physiological adaptations of the brain to pharmacodynamic effects, and their impact may be limited by slow drug discontinuation. The phenomenon of high early post-treatment discontinuation recurrence risk has clinical and scientific implications for the design, management and interpretation of treatment protocols that involve discontinuing long-term treatments in disorders requiring maintenance pharmacotherapy with centrally neuropharmacologically active drugs.


Lithium Bipolar Disorder Adis International Limited Lithium Treatment Clin Drug Invest 
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.
    Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990: 665–724Google Scholar
  2. 2.
    Kessler RC, McGonigle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the national comorbidity study. Arch Gen Psychiatry 1994; 51: 8–19PubMedCrossRefGoogle Scholar
  3. 3.
    Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of affective illness. Biol Psychiatry 1976; 11: 31–42PubMedGoogle Scholar
  4. 4.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. DSM-IV. Washington, DC: American Psychiatric Association, 1994Google Scholar
  5. 5.
    Shulman KI. Mania in the elderly. Int Rev Psychiatry 1993; 5: 445–53CrossRefGoogle Scholar
  6. 6.
    Tohen M, Shulman KI, Satlin A. First-episode mania in late life. Am J Psychiatry 1994; 151: 130–32PubMedGoogle Scholar
  7. 7.
    Faedda GL, Baldessarini RJ, Suppes T, et al. Pediatric-onset bipolar disorder: a neglected clinical and public health problem. Harvard Rev Psychiatry 1995; 3: 171–95CrossRefGoogle Scholar
  8. 8.
    Baldessarini RJ, Tondo L, Suppes T, et al. Pharmacological treatment of bipolar disorder throughout the life-cycle. In: Shulman KI, Tohen M, Kutcher S, editors. Bipolar disorder through the life-cycle. New York: John Wiley & Sons, 1996: 299–338Google Scholar
  9. 9.
    Tondo L, Baldessarini RJ, Floris G, et al. Lithium maintenance treatment reduces risk of suicidal behavior in bipolar disorder patients. In: Gallicchio VS, Birch NJ, editors. Lithium: biochemical and clinical advances. Cheshire, CT: Weidner Publishing Group, 1996: 161–71Google Scholar
  10. 10.
    Tondo L, Jamison K, Baldessarini RJ. Antisuicide effects of lithium. Ann NY Acad Sci 1997; 863: 339–51CrossRefGoogle Scholar
  11. 11.
    Tondo L, Baldessarini RJ, Hennen J, et al. Lithium treatment reduces risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry. In pressGoogle Scholar
  12. 12.
    Wyatt RJ, Henter I. An economic evaluation of manic-depressive illness. Soc Psychiatry Psychiatr Epidemiol 1995; 30: 213–9PubMedGoogle Scholar
  13. 13.
    Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2: 349–52PubMedGoogle Scholar
  14. 14.
    Schou M. Lithium. Arch Gen Psychiatry 1997; 54: 9–13PubMedCrossRefGoogle Scholar
  15. 15.
    Baldessarini R. Drugs and the treatment of psychiatric disorders: antimanic and antidepressant agents. Chapter 19. In: Hardman JG, Limbird LE, Molinoff PB, et al. editors. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York, McGraw-Hill Press, 1996: 431–59Google Scholar
  16. 16.
    Emrich HM, Dose M, von Zerssen D. The use of sodium valproate, carbamazepine and oxcarbazepine in patients with affective disorders. J Affect Disord 1985; 8: 243–50PubMedCrossRefGoogle Scholar
  17. 17.
    Prien RF, Gelenberg AJ. Alternatives to lithium for preventive treatment of bipolar disorder. Am J Psychiatry 1989; 146: 840–8PubMedGoogle Scholar
  18. 18.
    Post RM, Leverich GS, Rosoff AS, et al. Carbamazepine prophylaxis in refractory affective disorders: a focus on long-term follow-up. J Clin Psychopharmacol 1990; 10: 318–27PubMedCrossRefGoogle Scholar
  19. 19.
    PopeJr HG, McElroy SL, Keck Jr PE, et al. Valproate in the treatment of acute mania: placebo-controlled study. Arch Gen Psychiatry 1991; 48: 62–8PubMedCrossRefGoogle Scholar
  20. 20.
    Patsalos PN, Duncan JS. New antiepileptic drugs: a review of their current status and clinical potential. CNS Drugs 1994; 2: 40–77CrossRefGoogle Scholar
  21. 21.
    Balfour JA, Bryson HM. Valproic acid: a review of its pharmacology and therapeutic potential in indications other than epilepsy. CNS Drugs 1994; 2: 144–73CrossRefGoogle Scholar
  22. 22.
    Bowden CL, Janicak PG, Orsulak P, et al. Relation of serum valproate concentration to response in mania. Am J Psychiatry 1996; 153: 765–70PubMedGoogle Scholar
  23. 23.
    Thies-Flechtner K, Müller-Oerlinghausen B, Scibert W, et al. Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Pharmacopsychiatry 1996; 29: 103–7PubMedCrossRefGoogle Scholar
  24. 24.
    Johnson RE, McFarland BH. Lithium use and discontinuation in a health maintenance organization. Am J Psychiatry 1996; 153: 993–1000PubMedGoogle Scholar
  25. 25.
    Cohen LS, Friedman JM, Jefferson JW, et al. A reevaluation of risk of in utero exposure to lithium. JAMA 1994; 271: 146–50PubMedCrossRefGoogle Scholar
  26. 26.
    Gitlin MJ, Cochran SD, Jamison KR. Maintenance lithium treatment: side effects and compliance. J Clin Psychiatry 1989; 50: 127–31PubMedGoogle Scholar
  27. 27.
    Kocsis JH, Shaw ED, Stokes PE, et al. Neuropsychologic effects of lithium discontinuation. J Clin Psychopharmacology 1993; 13: 268–76CrossRefGoogle Scholar
  28. 28.
    Coppen A, Abou-Saleh MT, Wood KM, et al. Decreasing lithium dosage reduces morbidity and side-effects during prophylaxis. J Affect Disord 1983; 5: 353–62PubMedCrossRefGoogle Scholar
  29. 29.
    Maj M, Starace F, Nolfe G, et al. Minimum plasma lithium levels required for effective prophylaxis in DSM-III bipolar disorder: a prospective study. Pharmacopsychiatry 1986; 19: 420–3PubMedCrossRefGoogle Scholar
  30. 30.
    Baldessarini RJ, Cohen, BM, Teicher MH. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 1988; 45: 79–91PubMedCrossRefGoogle Scholar
  31. 31.
    Waters B, Lapierre Y, Gagnon A, et al. Determination of the optimal concentration of lithium for the prophylaxis of manic-depressive disorder. Biol Psychiatry 1982; 17: 1323–9PubMedGoogle Scholar
  32. 32.
    Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989; 321: 1489–93PubMedCrossRefGoogle Scholar
  33. 33.
    Rosenbaum JF, Sachs GS, Lafer B, et al. High rates of relapse in bipolar patients abruptly changed from standard to low plasma lithium levels in a double-blind, controlled trial. Proceedings of the Annual Meeting of the New Clinical Drug Evaluations Unit (NCDEU). Boca Raton, FL: US National Institute of Mental Health (NIMH); 1992Google Scholar
  34. 34.
    Jensen HV, Plenge P, Mellerup ET, et al. Lithium prophylaxis of manic-depressive disorder: daily lithium dosing schedule versus every second day. Acta Psychiatr Scand 1995; 92: 69–74PubMedCrossRefGoogle Scholar
  35. 35.
    Suppes T, Baldessarini RJ, Faedda GL, et al. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991; 48: 1082–8PubMedCrossRefGoogle Scholar
  36. 36.
    Suppes T, Baldessarini RJ, Faedda GL, et al. Discontinuing maintenance treatment in bipolar manic-depression: risks and implications. Harvard Rev Psychiatry 1993; 1: 131–44CrossRefGoogle Scholar
  37. 37.
    Baldessarini RJ, Suppes T, Tondo L. Lithium withdrawal in bipolar disorder: implications for clinical practice and experimental therapeutics research. Am J Therapeutics 1996; 3: 492–6CrossRefGoogle Scholar
  38. 38.
    Baastrup PC, Poulsen JC, Schou M, et al. Prophylactic lithium: double-blind discontinuation in manic-depressive and recurrent depressive disorders. Lancet 1970; II: 326–30CrossRefGoogle Scholar
  39. 39.
    Melia PI. Prophylactic lithium: a double-blind trial in recurrent affective disorders. Br J Psychiatry 1970; 116: 621–4PubMedCrossRefGoogle Scholar
  40. 40.
    Coppen A, Noguera R, Bailey J, et al. Prophylactic lithium in affective disorders. Lancet 1971; II: 275–9CrossRefGoogle Scholar
  41. 41.
    Small JG, Small IF, Moore DF. Experimental withdrawal of lithium in recovered manic-depressive patients: a report of five cases. Am J Psychiatry 1971; 127: 1555–8PubMedGoogle Scholar
  42. 42.
    Cundall RL, Brooks PW, Murray LG. A controlled evaluation of lithium prophylaxis in affective disorders. Psychol Med 1972; 2: 308–11PubMedCrossRefGoogle Scholar
  43. 43.
    Hullin RP, McDonald D, Allsopp MNE. Prophylactic lithium in recurrent affective disorders. Lancet 1972; I: 1044–6CrossRefGoogle Scholar
  44. 44.
    Fyrö B, Petterson U. A double blind study of the prophylactic effect of lithium in manic-depressive disease. Acta Psychiatr Scand1977; 262: 17–22Google Scholar
  45. 45.
    Klein HE, Broucek B, Greil W. Lithium withdrawal triggers psychotic states. Br J Psychiatry 1981; 139: 255–64PubMedCrossRefGoogle Scholar
  46. 46.
    Margo A, McMahon P. Lithium withdrawal triggers psychosis. Br J Psychiatry 1982; 141: 407–10PubMedCrossRefGoogle Scholar
  47. 47.
    Mendlewicz J. Lithium discontinuation in bipolar illness: a double-blind prospective controlled study. In corsini GB, editor. Current trends in lithium and rubidium therapy. Cambridge, MA: MTP Press, 1984: 135–41CrossRefGoogle Scholar
  48. 48.
    Mander AJ, Loudon JB. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 1988; II: 15–7CrossRefGoogle Scholar
  49. 49.
    Kocsis JH, Shaw ED, Stokes PE, et al. Neuropsychologic effects of lithium discontinuation. J Clin Psychopharmacol 1993; 13: 268–76PubMedCrossRefGoogle Scholar
  50. 50.
    Grof P, Cakuls P, Dostal T. Lithium drop-outs, a follow-up study of patients who discontinued prophylactic lithium in recurrent affective disorders.Int Pharmacopsychiatry 1970; 5: 162–9Google Scholar
  51. 51.
    Schou M, Thomsen K, Baastrup PC. Studies on the course of recurrent endogenous affective disorders. Int Pharmacopsychiatry 1970; 5: 100–6Google Scholar
  52. 52.
    Lapierre YD, Gagnon A, Kokkinidis L. Rapid recurrence of mania following lithium withdrawal. Biol Psychiatry 1980; 15: 859–64PubMedGoogle Scholar
  53. 53.
    Christodoulou GN, Lykouras ER Abrupt lithium discontinuation in manic-depressive patients. Acta Psychiatr Scand 1982; 65: 310–4PubMedCrossRefGoogle Scholar
  54. 54.
    King JR, Hullin RP Withdrawal symptoms from lithium. Br J Psychiatry 1983; 143: 30–5PubMedCrossRefGoogle Scholar
  55. 55.
    Sashidaran SP, McGuire RJ. Recurrence of affective illness after withdrawal of long-term lithium treatment. Acta Psychiatr Scand 1983; 68: 126–33CrossRefGoogle Scholar
  56. 56.
    Goodnik PJ. Clinical and laboratory effects of discontinuation of lithium prophylaxis. Acta Psychiat Scand 1985; 71: 608–14CrossRefGoogle Scholar
  57. 57.
    Bouman TK, Niemantsverdriet-van Kampen JO, Sloof CJ. The effectiveness of lithium prophylaxis in bipolar and unipolar depressions and schizoaffective disorders. J Affect Disord 1986; 11: 275–80PubMedCrossRefGoogle Scholar
  58. 58.
    Mander AJ. Is there a lithium withdrawal syndrome? Br J Psychiatry 1986; 149: 498–501PubMedCrossRefGoogle Scholar
  59. 59.
    Molnar G, Pristach C, Feeney GM, et al. A pilot study of managed lithium discontinuation. Psychopharmacol Bull 1988; 24: 217–9PubMedGoogle Scholar
  60. 60.
    Nilsson A, Axelsson R. Lithium discontinuers. I. Clinical characteristics and outcome. Acta Psychiatr Scand 1990; 82: 433–8PubMedCrossRefGoogle Scholar
  61. 61.
    Strober M, Morrell W, Lampert C, et al. Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: a naturalistic study. Am J Psychiatry 1990; 147457–61PubMedGoogle Scholar
  62. 62.
    Tondo L, Rudas N. Discontinuation of long-term treatment with lithium salts. Minerva Psichiatr (Rome) 1991; 32: 245–9Google Scholar
  63. 63.
    Koukopoulos A, Reginaldi D, Minnai G, et al. The long-term prophylaxis of affective disorders. In: Gessa G, Fratta W, Pani L, Serra G, editors. Advances in biochemical psychopharmacology. New York: Raven Press, 1996: 127–47Google Scholar
  64. 64.
    Maj M, Pirozzi R, Magliano L. Nonresponse to reinstituted lithium prophylaxis in previously responsive bipolar patients: prevalence and predictors. Am J Psychiatry 1995; 152: 1810–1PubMedGoogle Scholar
  65. 65.
    Baldessarini RJ, Tondo L, Faedda GL, et al. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996; 57: 441–8PubMedCrossRefGoogle Scholar
  66. 66.
    Kraepelin E. Frequency of the individual forms-general course. In: Robertson GM, editor. Manic-depressive insanity and paranoia (1913). Translated by Barclay RM. Edinburgh: E&S Livingstone, 1921: 133–58Google Scholar
  67. 67.
    Dunner DL, Murphy D, Stallone F, et al. Episode frequency prior to lithium treatment in bipolar manic-depressive patients. Compr Psychiatry 1979; 20: 511–5PubMedCrossRefGoogle Scholar
  68. 68.
    Zis AP, Grof P, Webster M, et al. Prediction of relapse in recurrent affective disorder. Psychopharmacol Bull 1980; 16: 47–50PubMedGoogle Scholar
  69. 69.
    Angst J. The course of affective disorders. Psychopathology 1986; 19Suppl. 2: 47–52PubMedCrossRefGoogle Scholar
  70. 70.
    Cutler NR, Post RM. Life course of illness in untreated manicdepressive patients. Compr Psychiatry 1982; 23: 101–15PubMedCrossRefGoogle Scholar
  71. 71.
    Roy-Byrne P, Post RM, Uhde TW, et al. The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH. Acta Psychiatr Scand 1985; 71Suppl. 317: 1–34CrossRefGoogle Scholar
  72. 72.
    Faedda GL, Tondo L, Baldessarini RJ, et al. Outcome after rapid vs. gradual discontinuation of lithium treatment in bipolar mood disorders. Arch Gen Psychiatry 1993; 50: 448–55PubMedCrossRefGoogle Scholar
  73. 73.
    Baldessarini RJ, Tondo L, Floris G, et al. Reduced morbidity after gradually discontinuing lithium in bipolar I and II disorders: areplication study. Am J Psychiatry 1997; 154: 551–3PubMedGoogle Scholar
  74. 74.
    Viguera AC, Nonacs R, Baldessarini RJ, et al. Risks of discontinuing lithium maintenance in pregnant women with bipolar disorder [abstract]. Proc APA Ann Meeting, San Diego, CA, May, 1997Google Scholar
  75. 75.
    Post RM, Leverich GS, Altshuler LL, et al. Lithium discontinuation-induced refractoriness: preliminary observations. Am J Psychiatry 1992; 149: 1727–9PubMedGoogle Scholar
  76. 76.
    Tondo L, Baldessarini RJ, Floris G, et al. Effectiveness of retreating with lithium after its discontinuation in biopolar I and II disorders. Am J Psychiatry 1997; 154: 548–50PubMedGoogle Scholar
  77. 77.
    Manji HK, Potter WZ, Lenox RH. Signal transduction pathways: Molecular targets for lithium's actions. Arch Gen Psychiatry 1995; 52: 531–43PubMedCrossRefGoogle Scholar
  78. 78.
    Viguera AC, Baldessarini RJ, Friedberg J. Risks of interrupting continuation or maintenance treatment with antidepressants in major depressive disorders. Harvard Rev Psychiatry. In pressGoogle Scholar
  79. 79.
    Baldessarini RJ, Viguera AC. Neuroleptic withdrawal in schizophrenic patients. Arch Gen Psychiatry 1995; 52: 189–92PubMedCrossRefGoogle Scholar
  80. 80.
    Viguera AC, Baldessarini RJ, Hegarty JM, et al. Risk of discontinuing maintenance medication in schizophrenia. Arch Gen Psychiatry 1997; 4: 49–55CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Harvard Medical School, Laboratories for Psychiatric ResearchMcLean Division of Massachusetts General HospitalBelmontUSA
  2. 2.University of CagliariSardinia and Lucio Bini Mood Disorders CentreCagliariItaly

Personalised recommendations