Skip to main content
Log in

Role of Lithium Augmentation in the Management of Major Depressive Disorder

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

The high rate of non-responders to initial treatment with antidepressants requires subsequent treatment strategies such as augmentation of antidepressants. Clinical guidelines recommend lithium augmentation as a first-line treatment strategy for non-responding depressed patients. The objectives of this review were to discuss the current place of lithium augmentation in the management of treatment-resistant depression and to review novel findings concerning lithium’s mechanisms of action. We conducted a comprehensive and critical review of randomized, placebo-controlled trials, controlled and naturalistic comparator studies, and continuation-phase and discontinuation studies of lithium augmentation in major depression. The outcomes of interest were efficacy, factors allowing outcome prediction and results from preclinical studies investigating molecular mechanisms of lithium action. Substantial efficacy of lithium augmentation in the acute treatment of major depression has been demonstrated in more than 30 open-label studies and 10 placebo-controlled trials. In a meta-analysis addressing the efficacy of lithium in 10 randomized, controlled trials, it had a significant positive effect versus placebo, with an odds ratio of 3.11 corresponding to a number-needed-to-treat (NNT) of 5 and a mean response rate of 41.2 % (versus 14.4 % in the placebo group). The main limitations of these studies were the relatively small numbers of study participants and the fact that most studies included augmentation of tricyclic antidepressants, which are not in widespread use anymore. Evidence from continuation-phase studies is sparse but suggests that lithium augmentation should be maintained in the lithium–antidepressant combination for at least 1 year to prevent early relapses. Concerning outcome prediction, single studies have reported associations of better outcome rates with more severe depressive symptomatology, significant weight loss, psychomotor retardation, a history of more than three major depressive episodes and a family history of major depression. Additionally, one study suggested a predictive role of the −50T/C single nucleotide polymorphism of the glycogen synthase kinase 3 beta (GSK3B) gene in the probability of response to lithium augmentation. With regard to novel mechanisms of action, GABAergic, neurotrophic and genetic effects might explain the effects of lithium augmentation. In conclusion, augmentation of antidepressants with lithium remains a first-line, evidence-based management option for patients with major depression who have not responded adequately to antidepressants. While the mechanisms of action are currently widely studied, further clinical research on the role of lithium potentiation of the current generation of antidepressants is warranted to reinforce its role as a gold-standard treatment for patients who respond inadequately to antidepressants.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Bauer M, Crossley NA, Gerber S, Bschor T. The acute antidepressive effects of lithium: from monotherapy to augmentation therapy in major depression. In: Bauer M, Grof P, Müller-Oerlinghausen B, editors. Lithium in neuropsychiatry—the comprehensive guide. Abingdon: Informa Healthcare UK Ltd.; 2006. p. 109–27.

    Chapter  Google Scholar 

  2. Davis J. Lithium maintenance of unipolar depression. In: Bauer M, Grof P, Müller-Oerlinghausen B, editors. Lithium in neuropsychiatry—the comprehensive guide. Abingdon: Informa Healthcare UK Ltd; 2006. p. 99–108.

    Chapter  Google Scholar 

  3. Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67–104.

    Article  PubMed  Google Scholar 

  4. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  PubMed  Google Scholar 

  5. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980–91.

    Article  PubMed  Google Scholar 

  6. Rush AJ, Trivedi MH. Treating depression to remission. Psychiatr Ann. 1995;25:704–9.

    Google Scholar 

  7. Haussmann R, Bauer M. Lithium, thyroid hormones and further augmentation strategies in treatment-resistant depression. In: Kasper S, Montgomery S, editors. Treatment-resistant depression. Chichester: Wiley-Blackwell; 2013. p. 129–57.

    Chapter  Google Scholar 

  8. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334–85.

    Article  PubMed  Google Scholar 

  9. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68:935–40.

    Article  PubMed  CAS  Google Scholar 

  10. Carvalho AF, Machado JR, Cavalcante JL. Augmentation strategies for treatment-resistant depression. Curr Opin Psychiatry. 2009;22:7–12.

    Article  PubMed  Google Scholar 

  11. de Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic anti-depressant drug non-responders. Br J Psychiatry. 1981;138:252–6.

    Article  PubMed  Google Scholar 

  12. Bauer M, Adli M, Bschor T, Pilhatsch M, Pfennig A, Sasse J, et al. Lithium’s emerging role in the treatment of refractory major depressive episodes: augmentation of antidepressants. Neuropsychobiology. 2010;62:36–42.

    Article  PubMed  CAS  Google Scholar 

  13. Browne M, Lapierre YD, Hrdina PD, Horn E. Lithium as an adjunct in the treatment of major depression. Int Clin Psychopharmacol. 1990;5:103–10.

    Article  PubMed  CAS  Google Scholar 

  14. Kantor D, Mcnevin S, Leichner P, Harper D, Krenn M. The benefit of lithium-carbonate adjunct in refractory depression—fact or fiction. Can J Psychiatry—Revue Canadienne de Psychiatrie. 1986;31:416–8.

    CAS  Google Scholar 

  15. Zusky PM, Biederman J, Rosenbaum JF, Manschreck TC, Gross CC, Weilberg JB, et al. Adjunct low-dose lithium-carbonate in treatment-resistant depression—a placebo-controlled study. J Clin Psychopharmacol. 1988;8:120–4.

    Article  PubMed  CAS  Google Scholar 

  16. Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression—a controlled trial using lithium in low and normal doses. Br J Psychiatry. 1993;162:634–40.

    Article  PubMed  CAS  Google Scholar 

  17. Bschor T, Bauer M. Is successful lithium augmentation limited to serotonergic antidepressants? J Clin Psychopharmacol. 2004;24:240–1.

    Article  PubMed  CAS  Google Scholar 

  18. Nierenberg AA, Papakostas GI, Petersen T, Montoya HD, Worthington JJ, Tedlow J, et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol. 2003;23:92–5.

    Article  PubMed  CAS  Google Scholar 

  19. Bauer M, Monz BU, Montejo AL, Quail D, Dantchev N, Dernyttenaere K, et al. Prescribing patterns of antidepressants in Europe: results from the Factors Influencing Depression Endpoints Research (FINDER) study. Eur Psychiatry. 2008;23:66–73.

    Article  PubMed  Google Scholar 

  20. Baumann P, Nil R, Souche A, Montaldi S, Baettig D, Lambert S, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol. 1996;16:307–14.

    Article  PubMed  CAS  Google Scholar 

  21. Katona CLE, Abousaleh MT, Harrison DA, Nairac BA, Edwards DRL, Lock T, et al. Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine. Br J Psychiatry. 1995;166:80–6.

    Article  PubMed  CAS  Google Scholar 

  22. Kaptchuk TJ. The double-blind, randomized, placebo-controlled trial: gold standard or golden calf? J Clin Epidemiol. 2001;54:541–9.

    Article  PubMed  CAS  Google Scholar 

  23. Kohler S, Unger T, Hoffmann S, Steinacher B, Fydrich T, Bschor T. Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study. Pharmacopsychiatry. 2013;46:69–76.

    PubMed  CAS  Google Scholar 

  24. Fava M, Alpert J, Nierenberg A, Lagomasino I, Sonawalla S, Tedlow J, et al. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol. 2002;22:379–87.

    Article  PubMed  CAS  Google Scholar 

  25. Joffe RT, Singer W, Levitt AJ, Macdonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry. 1993;50:387–93.

    Article  PubMed  CAS  Google Scholar 

  26. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, et al. A comparison of lithium and T-3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519–30.

    Article  PubMed  Google Scholar 

  27. Bauer M, Dell′Osso L, Kasper S, Pitchot W, Dencker Vansvik E, Köhler J et al. Extended-release quetiapine fumarate (quetiapine XR) monotherapy and quetiapine XR or lithium as add-on to antidepressants in patients with treatment-resistant major depressive disorder. J Affect Disord 2013; doi:10.1016/j.jad.2013.05.079.

  28. Hoencamp E, Haffmans PMJ, Dijken WA, Hoogduin CAL, Nolen WA, Vandyck R. Brofaromine versus lithium addition to maprotiline—a double-blind-study in maprotiline refractory depressed outpatients. J Affect Disord. 1994;30:219–27.

    Article  PubMed  CAS  Google Scholar 

  29. Kok RM, Vink D, Heeren TJ, Nolen WA. Lithium augmentation compared with phenelzine in treatment-resistant depression in the elderly: an open, randomized, controlled trial. J Clin Psychiatry. 2007;68:1177–85.

    Article  PubMed  CAS  Google Scholar 

  30. Rybakowski JK, Suwalska A, Chlopocka-Wozniak M. Potentiation of antidepressants with lithium or carbamazepine in treatment-resistant depression. Neuropsychobiology. 1999;40:134–9.

    Article  PubMed  CAS  Google Scholar 

  31. Schule C, Baghai T, Eser D, Nothdurfter C, Rupprecht R. Lithium but not carbamazepine augments antidepressant efficacy of mirtazapine in unipolar depression: an open label study. World J Biol Psychiatry. 2008;25:1–10.

    Google Scholar 

  32. Dinan TG, Barry S. A comparison of electroconvulsive-therapy with a combined lithium and tricyclic combination among depressed tricyclic nonresponders. Acta Psychiatrica Scandinavica. 1989;80:97–100.

    Article  PubMed  CAS  Google Scholar 

  33. Bauer M, Bschor T, Kunz D, Berghofer A, Strohle A, Muller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000;157:1429–35.

    Article  PubMed  CAS  Google Scholar 

  34. Bschor T, Berghofer A, Strohle A, Kunz D, Adli M, Muller-Oerlinghausen B, et al. How long should the lithium augmentation strategy be maintained? A 1-year follow-up of a placebo-controlled study in unipolar refractory major depression. J Clin Psychopharmacol. 2002;22:427–30.

    Article  PubMed  CAS  Google Scholar 

  35. Hardy BG, Shulman KI, Zucchero C. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. J Clin Psychopharmacol. 1997;17:22–6.

    Article  PubMed  CAS  Google Scholar 

  36. Fahy S, Lawlor BA. Discontinuation of lithium augmentation in an elderly cohort. Int J Geriatr Psychiatry. 2001;16:1004–9.

    Article  PubMed  CAS  Google Scholar 

  37. Ross J. Discontinuation of lithium augmentation in geriatric patients with unipolar depression: a systematic review. Can J Psychiatry-Revue Canadienne de Psychiatrie. 2008;53:117–20.

    Google Scholar 

  38. Alvarez E, PerezSola V, PerezBlanco J, Queralto JM, Torrubia R, Noguera R. Predicting outcome of lithium added to antidepressants in resistant depression. J Affect Disord. 1997;42:179–86.

    Article  PubMed  CAS  Google Scholar 

  39. Bschor T, Canata B, Muller-Oerlinghausen B, Bauer M. Predictors of response to lithium augmentation in tricyclic antidepressant-resistant depression. J Affect Disord. 2001;64:261–5.

    Article  PubMed  CAS  Google Scholar 

  40. Sugawara H, Sakamoto K, Harada T, Ishigooka J. Predictors of efficacy in lithium augmentation for treatment-resistant depression. J Affect Disord. 2010;125:165–8.

    Article  PubMed  CAS  Google Scholar 

  41. Joffe RT, Levitt AJ, Bagby RM, Macdonald C, Singer W. Predictors of response to lithium and triiodothyronine augmentation of antidepressants in tricyclic nonresponders. Br J Psychiatry. 1993;163:574–8.

    Article  PubMed  CAS  Google Scholar 

  42. Schopf J, Baumann P, Lemarchand T, Rey M. Treatment of endogenous depressions resistant to tricyclic antidepressants or related drugs by lithium addition—results of a placebo-controlled double-blind-study. Pharmacopsychiatry. 1989;22:183–7.

    Article  PubMed  CAS  Google Scholar 

  43. Bschor T, Lewitzka U, Sasse J, Adli M, Koberle U, Bauer M. Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms. Pharmacopsychiatry. 2003;36:S230–4.

    Article  PubMed  CAS  Google Scholar 

  44. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiatry. 1994;151:1–36.

    Google Scholar 

  45. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721–8.

    Article  PubMed  CAS  Google Scholar 

  46. Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach. Part II: clinical pharmacology and therapeutic monitoring. CNS Drugs. 2009;23:331–49.

    Article  PubMed  CAS  Google Scholar 

  47. Bauer M, Blumentritt H, Finke R, Schlattmann P, Adli M, Baethge C, et al. Using ultrasonography to determine thyroid size and prevalence of goiter in lithium-treated patients with affective disorders. J Affect Disord. 2007;104:45–51.

    Article  PubMed  Google Scholar 

  48. Malhi GS, Berk M. Is the safety of lithium no longer in the balance? Lancet. 2012;379:690–2.

    Article  PubMed  Google Scholar 

  49. Muller-Oerlinghausen B, Bauer M, Grof P. Commentary on a recent review of lithium toxicity: what are its implications for clinical practice? BMC Med. 2012. doi:10.1186/1741-7015-10-132.

    PubMed Central  PubMed  Google Scholar 

  50. Zobel A, Schulze-Rauschebach S, Barkow K, von Widdern O, Metten M, Pfeiffer U, et al. The HPA system in depression: indicator of vulnerability and treatment response. Eur Psychiatry. 2005;20:S115–6.

    Article  Google Scholar 

  51. Sugawara M, Hashimoto K, Hattori T, Takao T, Suemaru S, Ota Z. Effects of lithium on the hypothalamo-pituitary-adrenal axis. Endocrinol Jpn. 1988;35:655–63.

    Article  PubMed  CAS  Google Scholar 

  52. Semba J, Watanabe H, Suhara T, Akanuma N. Chronic lithium chloride injection increases glucocorticoid receptor but not mineralocorticoid receptor mRNA expression in rat brain. Neurosci Res. 2000;38:313–9.

    Article  PubMed  CAS  Google Scholar 

  53. Bschor T, Adli M, Baethge C, Eichmann U, Ising M, Uhr M, et al. Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression. Neuropsychopharmacology. 2002;27:470–8.

    Article  PubMed  CAS  Google Scholar 

  54. Bschor T, Adli M, Baethge C, Eichmann U, Ising M, Uhr M, et al. Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression. Neuropsychopharmacology. 2002;27:470–8.

    Article  PubMed  CAS  Google Scholar 

  55. Bschor T, Baethge C, Adli M, Eichmann U, Ising M, Uhr M, et al. Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder. J Psychiatr Res. 2003;37:135–43.

    Article  PubMed  Google Scholar 

  56. de Montigny C, Cournoyer G, Morissette R, Langlois R, Caille G. Lithium-carbonate addition in tricyclic anti-depressant resistant unipolar depression—correlations with the neurobiologic actions of tricyclic anti-depressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry. 1983;40:1327–34.

    Article  PubMed  Google Scholar 

  57. De Montigny C, Aghajanian GK. Tricyclic antidepressants—long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science. 1978;202:1303–6.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  59. O’Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S, et al. Glycogen synthase kinase-3 beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci. 2004;24:6791–8.

    Article  PubMed  CAS  Google Scholar 

  60. Wegener G, Bandpey Z, Heiberg IL, Mork A, Rosenberg R. Increased extracellular serotonin level in rat hippocampus induced by chronic citalopram is augmented by subchronic lithium: neurochemical and behavioural studies in the rat. Psychopharmacology. 2003;166:188–94.

    PubMed  CAS  Google Scholar 

  61. Okamoto Y, Motohashi N, Hayakawa H, Muraoka M, Yamawaki S. Addition of lithium to chronic antidepressant treatment potentiates presynaptic serotonergic function without changes in serotonergic receptors in the rat cerebral cortex. Neuropsychobiology. 1996;33:17–20.

    Article  PubMed  CAS  Google Scholar 

  62. Scheuch K, Holtje M, Budde H, Lautenschlager M, Heinz A, Ahnert-Hilger G, et al. Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons. Brain Res. 2010;1307:14–21.

    Article  PubMed  CAS  Google Scholar 

  63. Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder current understanding. CNS Drugs. 2013;27:135–53.

    Article  PubMed  Google Scholar 

  64. Horch HW, Katz LC. BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci. 2002;5:1177–84.

    Article  PubMed  CAS  Google Scholar 

  65. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64:238–58.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang DM. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology. 2002;43:1173–9.

    Article  PubMed  CAS  Google Scholar 

  67. Hammonds MD, Shim SS. Effects of 4-week treatment with lithium and olanzapine on levels of brain-derived neurotrophic factor, B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus. Basic Clin Pharmacol Toxicol. 2009;105:113–9.

    Article  PubMed  CAS  Google Scholar 

  68. Tsuji K, Yoshimura R, Nakamura J. Serum brain-derived neurotrophic factor levels are increased in psychotic depressed patients responding to lithium addition to paroxetine treatment. Int Clin Psychopharmacol. 2007;22:A23.

    Article  Google Scholar 

  69. Leyhe T, Eschweiler GW, Stransky E, Gasser T, Annas P, Basun H, et al. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. J Alzheimers Dis. 2009;16:649–56.

    PubMed  CAS  Google Scholar 

  70. Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol. 2010;13:617–22.

    Article  PubMed  CAS  Google Scholar 

  71. Stamm TJ, Adli M, Kirchheiner J, Smolka MN, Kaiser R, Tremblay PB, et al. Serotonin transporter gene and response to lithium augmentation in depression. Psychiatr Genet. 2008;18:92–7.

    Article  PubMed  Google Scholar 

  72. Tharoor H, Kotambail A, Jain S, Sharma PSVN, Satyamoorthy K. Study of the association of serotonin transporter triallelic 5-HTTLPR and STin2 VNTR polymorphisms with lithium prophylaxis response in bipolar disorder. Psychiatr Genet. 2013;23:77–81.

    Article  PubMed  CAS  Google Scholar 

  73. Freland L, Beaulieu J. Inhibition of GSK3 by lithium, from single molecules to signaling networks. Front Mol Neurosci. 2012. doi:10.3389/fnmol.2012.00014.

    PubMed Central  PubMed  Google Scholar 

  74. Ackermann TF, Kempe DS, Lang F, Lang UE. Hyperactivity and enhanced curiosity of mice expressing PKB/SGK-resistant glycogen synthase kinase-3 (GSK-3). Cell Physiol Biochem. 2010;25:775–86.

    Article  PubMed  CAS  Google Scholar 

  75. Mendes CT, Mury FB, Moreira ED, Alberto FL, Forlenza OV, Dias-Neto E, et al. Lithium reduces Gsk3b mRNA levels: implications for Alzheimer disease. Eur Arch Psychiatry Clin Neurosci. 2009;259:16–22.

    Article  PubMed  Google Scholar 

  76. Benedetti F, Serretti A, Pontiggia A, Bernasconi A, Lorenzi C, Colombo C, et al. Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta −50T/C SNP. Neurosci Lett. 2005;376:51–5.

    Article  PubMed  CAS  Google Scholar 

  77. Adli M, Hollinde DL, Stamm T, Wiethoff K, Tsahuridu M, Kirchheiner J, et al. Response to lithium augmentation in depression is associated with the glycogen synthase kinase 3-beta −50T/C single nucleotide polymorphism. Biol Psychiatry. 2007;62:1295–302.

    Article  PubMed  CAS  Google Scholar 

  78. Rybakowski JK, Dmitrzak-Weglarz M, Suwalska A, Leszczynska-Rodziewicz A, Hauser J. Dopamine D1 receptor gene polymorphism is associated with prophylactic lithium response in bipolar disorder. Pharmacopsychiatry. 2009;42:20–2.

    Article  PubMed  CAS  Google Scholar 

  79. Steen VM, Lovlie R, Osher Y, Belmaker RH, Berle JO, Gulbrandsen AK. The polymorphic inositol polyphosphate 1-phosphatase gene as a candidate for pharmacogenetic prediction of lithium-responsive manic-depressive illness. Pharmacogenetics. 1998;8:259–68.

    PubMed  CAS  Google Scholar 

  80. Dmitrzak-Weglarz M, Rybakowski JK, Suwalska A, Skibinska M, Leszczynska-Rodziewicz A, Szczepankiewicz A, et al. Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients. Pharmacogenomics. 2008;9:1595–603.

    Article  PubMed  CAS  Google Scholar 

  81. Rybakowski JK, Suwalska A, Skibinska M, Szczepankiewicz A, Leszczynska-Rodziewicz A, Permoda A, et al. Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. Pharmacopsychiatry. 2005;38:166–70.

    Article  PubMed  CAS  Google Scholar 

  82. Rybakowski JK. Genetic influences on response to mood stabilizers in bipolar disorder current status of knowledge. CNS Drugs. 2013;27:165–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Ewald H, Wang AG, Vang M, Mors O, Nyegaard M, Kruse TA. A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands (vol 9, pg 23, 1999). Psychiatr Genet. 1999;9:208.

    Article  Google Scholar 

  84. Turecki G, Grof P, Grof E, D’Souza V, Lebuis L, Marineau C, et al. Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol Psychiatry. 2001;6:570–8.

    Article  PubMed  CAS  Google Scholar 

  85. Squassina A, Manchia M, Borg J, Congiu D, Costa M, Georgitsi M, et al. Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics. 2011;12:1559–69.

    Article  PubMed  CAS  Google Scholar 

  86. Perlis RH, Smoller JW, Ferreira MAR, McQuillin A, Bass N, Lawrence J, et al. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry. 2009;166:718–25.

    Article  PubMed Central  PubMed  Google Scholar 

  87. Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Nicoletti M, et al. Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry. 2007;62:7–16.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Bearden CE, Thompson PM, Dutton RA, Frey BN, Peluso MAM, Nicoletti M, et al. Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology. 2008;33:1229–38.

    Article  PubMed  CAS  Google Scholar 

  89. Moore GJ, Cortese BM, Glitz DA, Zajac-Benitez C, Quiroz JA, Uhde TW, et al. A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry. 2009;70:699–705.

    Article  PubMed  CAS  Google Scholar 

  90. Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, et al. Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett. 2002;329:243–5.

    Article  PubMed  CAS  Google Scholar 

  91. Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, et al. Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology. 2007;195:357–67.

    Article  PubMed  CAS  Google Scholar 

  92. Yucel K, Taylor VH, McKinnon MC, Macdonald K, Alda M, Young LT, et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology. 2008;33:361–7.

    Article  PubMed  CAS  Google Scholar 

  93. Lyoo IK, Dager SR, Kim JE, Yoon SJ, Friedman SD, Dunner DL, et al. Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study. Neuropsychopharmacology. 2010;35:1743–50.

    PubMed Central  PubMed  CAS  Google Scholar 

  94. Hajek T, Bauer M, Simhandl C, Rybakowski JK, O’Donovan C, Pfennig A, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2013;31:1–11.

    Google Scholar 

  95. Hajek T, Bauer M, Pfennig A, Cullis J, Ploch J, O’Donovan C, et al. Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study. J Psychiatry Neurosci. 2012;37:185–92.

    Article  PubMed Central  PubMed  Google Scholar 

  96. Kennedy SH, Lam RW, Parikh SV, Patten SB, Ravindran AV. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults introduction. J Affect Disord. 2009;117:S1–2.

    Article  PubMed  Google Scholar 

  97. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ-Br Med J. 2013. doi:10.1136/bmj.f3646.

    Google Scholar 

  98. X GR, Charney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment: an effective prescription for treatment-refractory depression. Arch Gen Psychiatry. 1983;40:1335–42.

    Article  Google Scholar 

Download references

Acknowledgments

M.B. has received grant/research support from the Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression (NARSAD), Deutsche Forschungsgemeinschaft (DFG), European Commission (FP7), American Foundation for Suicide Prevention and Bundesministerium für Bildung und Forschung (BMBF). He is a consultant for Alkermes, AstraZeneca, Bristol-Myers Squibb, Ferrer Internacional, Janssen, Lilly, Lundbeck, Otsuka, Servier and Takeda. He has received speaker honoraria from AstraZeneca, BristolMyers Squibb, GlaxoSmithKline, Lilly, Lundbeck, Otsuka and Pfizer. E.S. has received consulting fees from BristolMyers Squibb, travel support fees from Lundbeck and payment for lectures from AstraZeneca, Lundbeck and BristolMyers Squibb. M.A., R.R. and M.P. report no potential conflicts of interests. No funding was received for writing this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Bauer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bauer, M., Adli, M., Ricken, R. et al. Role of Lithium Augmentation in the Management of Major Depressive Disorder. CNS Drugs 28, 331–342 (2014). https://doi.org/10.1007/s40263-014-0152-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-014-0152-8

Keywords

Navigation