Advertisement

Pediatric Drugs

, Volume 20, Issue 4, pp 303–314 | Cite as

Using Lithium in Children and Adolescents with Bipolar Disorder: Efficacy, Tolerability, and Practical Considerations

  • B. Grant
  • J. A. Salpekar
Review Article
  • 160 Downloads

Abstract

Lithium has been an intriguing treatment option in psychiatry for over a century. While seemingly just a simple elemental compound, it has powerful treatment effects for both depression and bipolar disorder. The evidence base for treatment of pediatric bipolar disorder is relatively small, but, in recent years, additional clinical trial data have enabled lithium to re-emerge as a valuable and, in many cases, preferred treatment. Pharmacologically, lithium is complex, with varied effects at both intracellular and extracellular levels. As a treatment for bipolar disorder in pediatrics, lithium is challenging, given its narrow therapeutic window and myriad of potential side effects. However, the efficacy of lithium continues to match that of newer pharmacologic agents, and its tolerability has been shown to be comparable with more commonly prescribed medications. Lithium is still one of few drugs that have been proven to reduce the risk of suicidality, and it may have utility in illnesses beyond affective disorders. Practically, as a primary agent or as an adjunct, lithium continues to claim a rightful place in the treatment armamentarium of child psychiatry. New dosing paradigms have improved tolerability and reduced potential side effects. Recent evidence affirms that lithium is effective for pediatric bipolar disorder in multiple phases of the illness.

Notes

Author Contributions

Both authors participated in the writing, editing, and approval of this manuscript and had full control of content throughout development.

Compliance with Ethical Standards

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Dr. Salpekar is a past educational  consultant for Sunovion, his institution receives research funding from Lundbeck, and he serves as a Data and Safety Monitoring Board chair for the National Institute of Mental Health. Dr. Grant has no conflicts of interest.

References

  1. 1.
    Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11(Suppl 2):4–9.  https://doi.org/10.1111/j.1399-5618.2009.00706.x.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schou M, Juel-Nielsen N, Stromgren E, Voldby H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry. 1954;17(4):250–60.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Carlson GA, Glovinsky I. The concept of bipolar disorder in children: a history of the bipolar controversy. Child Adolesc Psychiatr Clin N Am. 2009;18(2):257–71, vii.  https://doi.org/10.1016/j.chc.2008.11.003.
  4. 4.
    Post RM, Leverich GS, Kupka RW, Keck PE Jr, McElroy SL, Altshuler LL, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71(7):864–72.  https://doi.org/10.4088/JCP.08m04994yel.CrossRefPubMedGoogle Scholar
  5. 5.
    McClellan J, Kowatch R, Findling RL, Work Group on Quality I. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(1):107–25.  https://doi.org/10.1097/01.chi.0000242240.69678.c4.CrossRefPubMedGoogle Scholar
  6. 6.
    Van Meter AR, Moreira AL, Youngstrom EA. Meta-analysis of epidemiologic studies of pediatric bipolar disorder. J Clin Psychiatry. 2011;72(9):1250–6.  https://doi.org/10.4088/JCP.10m06290.CrossRefPubMedGoogle Scholar
  7. 7.
    Kessler RC, Avenevoli S, Green J, Gruber MJ, Guyer M, He Y, et al. National comorbidity survey replication adolescent supplement (NCS-A): III. Concordance of DSM-IV/CIDI diagnoses with clinical reassessments. J Am Acad Child Adolesc Psychiatry. 2009;48(4):386–99.  https://doi.org/10.1097/CHI.0b013e31819a1cbc.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry. 1995;34(4):454–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Leibenluft E, Charney DS, Towbin KE, Bhangoo RK, Pine DS. Defining clinical phenotypes of juvenile mania. Am J Psychiatry. 2003;160(3):430–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Hauser M, Galling B, Correll CU. Suicidal ideation and suicide attempts in children and adolescents with bipolar disorder: a systematic review of prevalence and incidence rates, correlates, and targeted interventions. Bipolar Disord. 2013;15(5):507–23.  https://doi.org/10.1111/bdi.12094.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Berry EA, Heaton PT, Kelton CM. National estimates of the inpatient burden of pediatric bipolar disorder in the United States. J Ment Health Policy Econ. 2011;14(3):115–23.PubMedGoogle Scholar
  12. 12.
    Sani G, Perugi G, Tondo L. Treatment of bipolar disorder in a lifetime perspective: is lithium still the best choice? Clin Drug Investig. 2017;37(8):713–27.  https://doi.org/10.1007/s40261-017-0531-2.CrossRefPubMedGoogle Scholar
  13. 13.
    Findling RL, Landersdorfer CB, Kafantaris V, Pavuluri M, McNamara NK, McClellan J, et al. First-dose pharmacokinetics of lithium carbonate in children and adolescents. J Clin Psychopharmacol. 2010;30(4):404–10.  https://doi.org/10.1097/JCP.0b013e3181e66a62.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Landersdorfer CB, Findling RL, Frazier JA, Kafantaris V, Kirkpatrick CM. Lithium in paediatric patients with bipolar disorder: implications for selection of dosage regimens via population pharmacokinetics/pharmacodynamics. Clin Pharmacokinet. 2017;56(1):77–90.  https://doi.org/10.1007/s40262-016-0430-3.CrossRefPubMedGoogle Scholar
  15. 15.
    Findling RL, Robb A, McNamara NK, Pavuluri MN, Kafantaris V, Scheffer R, et al. Lithium in the acute treatment of bipolar I disorder: a double-blind, placebo-controlled study. Pediatrics. 2015;136(5):885–94.  https://doi.org/10.1542/peds.2015-0743.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Findling RL, Kafantaris V, Pavuluri M, McNamara NK, Frazier JA, Sikich L, et al. Post-acute effectiveness of lithium in pediatric bipolar I disorder. J Child Adolesc Psychopharmacol. 2013;23(2):80–90.  https://doi.org/10.1089/cap.2012.0063.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Findling RL, Kafantaris V, Pavuluri M, McNamara NK, McClellan J, Frazier JA, et al. Dosing strategies for lithium monotherapy in children and adolescents with bipolar I disorder. J Child Adolesc Psychopharmacol. 2011;21(3):195–205.  https://doi.org/10.1089/cap.2010.0084.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Findling RL, Frazier JA, Kafantaris V, Kowatch R, McClellan J, Pavuluri M, et al. The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation. Child Adolesc Psychiatry Ment Health. 2008;2(1):21.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry. 2015;20(6):661–70.  https://doi.org/10.1038/mp.2015.4.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Diniz BS, Machado-Vieira R, Forlenza OV. Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders. Neuropsychiatr Dis Treat. 2013;9:493–500.  https://doi.org/10.2147/NDT.S33086.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mauer S, Vergne D, Ghaemi SN. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry. 2014;48(9):809–18.  https://doi.org/10.1177/0004867414536932.CrossRefPubMedGoogle Scholar
  22. 22.
    Arancibia A, Corvalan F, Mella F, Concha L. Absorption and disposition kinetics of lithium carbonate following administration of conventional and controlled release formulations. Int J Clin Pharmacol Ther Toxicol. 1986;24(5):240–5.PubMedGoogle Scholar
  23. 23.
    Ward ME, Musa MN, Bailey L. Clinical pharmacokinetics of lithium. J Clin Pharmacol. 1994;34(4):280–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217:266–80.  https://doi.org/10.1016/j.jad.2017.03.052.CrossRefPubMedGoogle Scholar
  25. 25.
    Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs. 2014;28(4):331–42.  https://doi.org/10.1007/s40263-014-0152-8.CrossRefPubMedGoogle Scholar
  26. 26.
    Selle V, Schalkwijk S, Vazquez GH, Baldessarini RJ. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry. 2014;47(2):43–52.  https://doi.org/10.1055/s-0033-1363258.CrossRefPubMedGoogle Scholar
  27. 27.
    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. Int J Bipolar Disord. 2014;2:15.  https://doi.org/10.1186/s40345-014-0015-8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nelson JC, Baumann P, Delucchi K, Joffe R, Katona C. A systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression. J Affect Disord. 2014;168:269–75.  https://doi.org/10.1016/j.jad.2014.05.053.CrossRefPubMedGoogle Scholar
  29. 29.
    Wingard L, Boden R, Brandt L, Tiihonen J, Tanskanen A, Kieler H, et al. Reducing the rehospitalization risk after a manic episode: a population based cohort study of lithium, valproate, olanzapine, quetiapine and aripiprazole in monotherapy and combinations. J Affect Disord. 2017;217:16–23.  https://doi.org/10.1016/j.jad.2017.03.054.CrossRefPubMedGoogle Scholar
  30. 30.
    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.  https://doi.org/10.1136/bmj.f3646.CrossRefPubMedGoogle Scholar
  31. 31.
    Geller B, Luby JL, Joshi P, Wagner KD, Emslie G, Walkup JT, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry. 2012;69(5):515–28.  https://doi.org/10.1001/archgenpsychiatry.2011.1508.CrossRefPubMedGoogle Scholar
  32. 32.
    Salpekar JA, Joshi PT, Axelson DA, Reinblatt SP, Yenokyan G, Sanyal A, et al. Depression and suicidality outcomes in the treatment of early age mania study. J Am Acad Child Adolesc Psychiatry. 2015;54(12):999–1007 e4.  https://doi.org/10.1016/j.jaac.2015.09.016.
  33. 33.
    Walkup JT, Wagner KD, Miller L, Yenokyan G, Luby JL, Joshi PT, et al. Treatment of early-age mania: outcomes for partial and nonresponders to initial treatment. J Am Acad Child Adolesc Psychiatry. 2015;54(12):1008–19.  https://doi.org/10.1016/j.jaac.2015.09.015.CrossRefPubMedGoogle Scholar
  34. 34.
    Kafantaris V, Coletti D, Dicker R, Padula G, Kane JM. Lithium treatment of acute mania in adolescents: a large open trial. J Am Acad Child Adolesc Psychiatry. 2003;42(9):1038–45.  https://doi.org/10.1097/01.CHI.0000070247.24125.24.CrossRefPubMedGoogle Scholar
  35. 35.
    Kafantaris V, Coletti DJ, Dicker R, Padula G, Pleak RR, Alvir JM. Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study. J Am Acad Child Adolesc Psychiatry. 2004;43(8):984–93.  https://doi.org/10.1097/01.chi.0000129223.89433.74.CrossRefPubMedGoogle Scholar
  36. 36.
    Patel NC, DelBello MP, Bryan HS, Adler CM, Kowatch RA, Stanford K, et al. Open-label lithium for the treatment of adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry. 2006;45(3):289–97.  https://doi.org/10.1097/01.chi.0000194569.70912.a7.CrossRefPubMedGoogle Scholar
  37. 37.
    Findling RL, McNamara NK, Gracious BL, Youngstrom EA, Stansbrey RJ, Reed MD, et al. Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad Child Adolesc Psychiatry. 2003;42(8):895–901.  https://doi.org/10.1097/01.CHI.0000046893.27264.53.CrossRefPubMedGoogle Scholar
  38. 38.
    Findling RL, McNamara NK, Stansbrey R, Gracious BL, Whipkey RE, Demeter CA, et al. Combination lithium and divalproex sodium in pediatric bipolar symptom re-stabilization. J Am Acad Child Adolesc Psychiatry. 2006;45(2):142–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Pavuluri MN, Henry DB, Carbray JA, Sampson GA, Naylor MW, Janicak PG. A one-year open-label trial of risperidone augmentation in lithium nonresponder youth with preschool-onset bipolar disorder. J Child Adolesc Psychopharmacol. 2006;16(3):336–50.  https://doi.org/10.1089/cap.2006.16.336.CrossRefPubMedGoogle Scholar
  40. 40.
    Calabrese JR, Shelton MD, Rapport DJ, Youngstrom EA, Jackson K, Bilali S, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry. 2005;162(11):2152–61.  https://doi.org/10.1176/appi.ajp.162.11.2152.CrossRefPubMedGoogle Scholar
  41. 41.
    Findling RL, McNamara NK, Youngstrom EA, Stansbrey R, Gracious BL, Reed MD, et al. Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(5):409–17.CrossRefPubMedGoogle Scholar
  42. 42.
    Strakowski SM, DelBello MP, Fleck DE, Arndt S. The impact of substance abuse on the course of bipolar disorder. Biol Psychiatry. 2000;48(6):477–85.CrossRefPubMedGoogle Scholar
  43. 43.
    Geller B, Cooper TB, Sun K, Zimerman B, Frazier J, Williams M, et al. Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry. 1998;37(2):171–8.  https://doi.org/10.1097/00004583-199802000-00009.CrossRefPubMedGoogle Scholar
  44. 44.
    Masi G, Milone A, Manfredi A, Pari C, Paziente A, Millepiedi S. Effectiveness of lithium in children and adolescents with conduct disorder: a retrospective naturalistic study. CNS Drugs. 2009;23(1):59–69.  https://doi.org/10.2165/0023210-200923010-00004.CrossRefPubMedGoogle Scholar
  45. 45.
    Campbell M, Adams PB, Small AM, Kafantaris V, Silva RR, Shell J, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1995;34(4):445–53.CrossRefPubMedGoogle Scholar
  46. 46.
    Campbell M, Small AM, Green WH, Jennings SJ, Perry R, Bennett WG, et al. Behavioral efficacy of haloperidol and lithium carbonate. A comparison in hospitalized aggressive children with conduct disorder. Arch Gen Psychiatry. 1984;41(7):650–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Berry-Kravis E, Sumis A, Hervey C, Nelson M, Porges SW, Weng N, et al. Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr. 2008;29(4):293–302.  https://doi.org/10.1097/DBP.0b013e31817dc447.CrossRefPubMedGoogle Scholar
  48. 48.
    Zhong J, Lee WH. Lithium: a novel treatment for Alzheimer’s disease? Expert Opin Drug Saf. 2007;6(4):375–83.  https://doi.org/10.1517/14740338.6.4.375.CrossRefPubMedGoogle Scholar
  49. 49.
    Kessing LV, Gerds TA, Knudsen NN, Jorgensen LF, Kristiansen SM, Voutchkova D, et al. Association of lithium in drinking water with the incidence of dementia. JAMA Psychiatry. 2017;74(10):1005–10.  https://doi.org/10.1001/jamapsychiatry.2017.2362.CrossRefPubMedGoogle Scholar
  50. 50.
    McGrath JJ, Berk M. Could lithium in drinking water reduce the incidence of dementia? JAMA Psychiatry. 2017;74(10):983–4.  https://doi.org/10.1001/jamapsychiatry.2017.2336.CrossRefPubMedGoogle Scholar
  51. 51.
    Singh D, Akingbola A, Ross-Ascuitto N, Ascuitto R. Electrocardiac effects associated with lithium toxicity in children: an illustrative case and review of the pathophysiology. Cardiol Young. 2016;26(2):221–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Yacobi S, Ornoy A. Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci. 2008;45(2):95–106.PubMedGoogle Scholar
  53. 53.
    Findling RL, Nyilas M, Forbes RA, McQuade RD, Jin N, Iwamoto T, et al. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(10):1441–51.  https://doi.org/10.4088/JCP.09m05164yel.CrossRefPubMedGoogle Scholar
  54. 54.
    Findling RL, Landbloom RL, Szegedi A, Koppenhaver J, Braat S, Zhu Q, et al. Asenapine for the acute treatment of pediatric manic or mixed episode of bipolar I disorder. J Am Acad Child Adolesc Psychiatry. 2015;54(12):1032–41.  https://doi.org/10.1016/j.jaac.2015.09.007.CrossRefPubMedGoogle Scholar
  55. 55.
    Tohen M, Kryzhanovskaya L, Carlson G, Delbello M, Wozniak J, Kowatch R, et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry. 2007;164(10):1547–56.  https://doi.org/10.1176/appi.ajp.2007.06111932.CrossRefPubMedGoogle Scholar
  56. 56.
    Pathak S, Findling RL, Earley WR, Acevedo LD, Stankowski J, Delbello MP. Efficacy and safety of quetiapine in children and adolescents with mania associated with bipolar I disorder: a 3-week, double-blind, placebo-controlled trial. J Clin Psychiatry. 2013;74(1):e100–9.  https://doi.org/10.4088/JCP.11m07424.CrossRefPubMedGoogle Scholar
  57. 57.
    Haas M, Delbello MP, Pandina G, Kushner S, Van Hove I, Augustyns I, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2009;11(7):687–700.  https://doi.org/10.1111/j.1399-5618.2009.00750.x.CrossRefPubMedGoogle Scholar
  58. 58.
    Detke HC, DelBello MP, Landry J, Usher RW. Olanzapine/Fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2015;54(3):217–24.  https://doi.org/10.1016/j.jaac.2014.12.012.CrossRefPubMedGoogle Scholar
  59. 59.
    Geller B, Fetner HH. Children’s 24-hour serum lithium level after a single dose predicts initial dose and steady-state plasma level. J Clin Psychopharmacol. 1989;9(2):155.CrossRefPubMedGoogle Scholar
  60. 60.
    Singh LK, Nizamie SH, Akhtar S, Praharaj SK. Improving tolerability of lithium with a once-daily dosing schedule. Am J Ther. 2011;18(4):288–91.  https://doi.org/10.1097/MJT.0b013e3181d070c3.CrossRefPubMedGoogle Scholar
  61. 61.
    Kowatch RA, DelBello MP. The use of mood stabilizers and atypical antipsychotics in children and adolescents with bipolar disorders. CNS Spectr. 2003;8(4):273–80.CrossRefPubMedGoogle Scholar
  62. 62.
    Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27.  https://doi.org/10.1186/s40345-016-0068-y.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet. 2016;387(10023):1085–93.  https://doi.org/10.1016/S0140-6736(16)00143-4.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Duffy A, Patten S, Goodday S, Weir A, Heffer N, Cipriani A. Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review. Int J Bipolar Disord. 2017;5(1):22.  https://doi.org/10.1186/s40345-017-0092-6.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Psychiatry, Kennedy Krieger InstituteJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations