Skip to main content

Advertisement

SpringerLink
Log in

Long-term responsiveness to lithium as a pharmacogenetic outcome variable: Treatment and etiologic implications

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

The importance of genes in the etiology of bipolar disorder has been substantiated through family, twin, and adoption studies. Bipolar disorder is treated at the prophylactic and episodic levels; lithium is one of the most common forms of prophylactic treatment. Recently, pharmacogenetics has come to play an active role in the elucidation of genetic factors that may play a role in modulating lithium response. This strategy has provided hope for advancements in understanding the genetics of lithium-responsive bipolar disorder. This review encompasses studies that have used populations of lithium responders and non-responders to carry out family, linkage, or association studies, as well as some insight into possible mechanisms by which lithium produces its prophylactic effect. Although data examining the pharmacogenetics of bipolar disorder remain scarce, this is a promising avenue of investigation to help genetically define more homogeneous populations or to search for genetic predictors of drug response.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. American Psychological Association: Diagnostic and Statistical Manual of Mental Disorders, edn 4. Washington, DC; American Psychiatric Press: 1994.

    Google Scholar 

  2. Grof P: Mood disorders: new definitions, treatment directions, and understanding. Can J Psychiatry 2002, 47:123–124.

    PubMed  Google Scholar 

  3. Akiskal HS, Bourgeois ML, Angst J, et al.: Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000, 59:S5-S30.

    Article  PubMed  Google Scholar 

  4. Craddock N, Jones I: Molecular genetics of bipolar disorder. Br.J.Psychiatry 2001, 41(suppl):S128-S133.

    Article  CAS  Google Scholar 

  5. Mansour HA, Alda M, Nimgaonkar VL: Pharmacogenetics of bipolar disorder. Curr Psychiatry Rep 2002, 4:117–123.

    Article  PubMed  Google Scholar 

  6. Serretti A, Franchini L, Gasperini M, et al.: Mode of inheritance in mood disorder families according to fluvoxamine response. Acta Psychiatr Scand 1998, 98:443–450.

    PubMed  CAS  Google Scholar 

  7. Morissette J, Villeneuve A, Bordeleau L, et al.: Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in quebec points to a locus of major effect on chromosome 12q23-q24. Am J Med Genet 1999, 88:567–587.

    Article  PubMed  CAS  Google Scholar 

  8. Schou M: Lithium Treatment of Manic-Depressive Illness: A Practical Guide, edn 2. Basel: Karger; 1983.

    Google Scholar 

  9. Lenox RH, Watson DG: Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness. Clin Chem 1994, 40:309–314.

    PubMed  CAS  Google Scholar 

  10. Schou M: Origin, Prevention and Treatment of Affective Disorders. London: Academic Press; 1979.

    Google Scholar 

  11. Baraban JM, Worley PF, Snyder SH: Second messenger systems and psychoactive drug action: focus on the phosphoinositide system and lithium. Am J Psychiatry 1989, 146:1251–1260.

    PubMed  CAS  Google Scholar 

  12. Jope RS, Williams MB: Lithium and brain signal transduction systems. Biochem Pharmacol 1994, 47:429–441.

    Article  PubMed  CAS  Google Scholar 

  13. Manji HK, Hsiao JK, Risby ED, et al.: The mechanisms of action of lithium: effects on serotoninergic and noradrenergic systems in normal subjects. Arch Gen Psychiatry 1991, 48:505–512.

    PubMed  CAS  Google Scholar 

  14. Manji HK, Lenox RH: Lithium: a molecular transducer of mood-stabilization in the treatment of bipolar disorder. Neuropsychopharmacology 1998, 19:161–166.

    Article  PubMed  CAS  Google Scholar 

  15. Risby ED, Hsiao JK, Manji HK, et al.: The mechanisms of action of lithium, II: effects on adenylate cyclase activity and beta-adrenergic receptor binding in normal subjects. Arch Gen Psychiatry 1991, 48:513–524.

    PubMed  CAS  Google Scholar 

  16. Berridge MJ, Downes CP, Hanley MR: Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989, 59:411–419.

    Article  PubMed  CAS  Google Scholar 

  17. Coyle JT, Manji HK: Getting balance: drugs for bipolar disorder share target. Nat Med 2002, 8:557–558.

    Article  PubMed  CAS  Google Scholar 

  18. Williams RS, Cheng L, Mudge AW, Harwood AJ: A common mechanism of action for three mood-stabilizing drugs. Nature 2002, 417:292–295. This article presents new data showing similarities between the mechanisms of action of three commonly used drugs. Their findings provide incentive for further investigation into the molecular biology and pharmacogenetics of the phosphoinositide system in particular the prolyl oligopeptidase gene.

    Article  PubMed  CAS  Google Scholar 

  19. Gitlin MJ, Altshuler LL: Unanswered questions, unknown future for one of our oldest medications. Arch Gen Psychiatry 1997, 54:21–23.

    PubMed  CAS  Google Scholar 

  20. Grof P, Alda M, Grof E, et al.: The challenge of predicting response to stabilizing lithium treatment: the importance of patient selection. Br J Psychiatry 1993, 21(suppl):16–19.

    Google Scholar 

  21. Mendlewicz J, Fieve RR, Stallone F, Fleiss JL: Genetic history as a predictor of lithium response in manic-depressive illness. Lancet 1972, 1:599–600. Although from 1972, this ground-breaking article was the first to provide evidence for the possible existence of a genetic difference between responders and non-responders to lithium based on the different recurrence rates for their relatives.

    Article  PubMed  CAS  Google Scholar 

  22. Smeraldi E, Petroccione A, Gasperini M, et al.: Outcomes on lithium treatment as a tool for genetic studies in affective disorders. J Affect Disord 1984, 6:139–151.

    Article  PubMed  CAS  Google Scholar 

  23. Prien RF, Caffey EM, Jr., Klett CJ: Factors associated with treatment success in lithium carbonate prophylaxis: report of the Veterans Administration and National Institute of Mental Health collaborative study group. Arch Gen Psychiatry 1974, 31:189–192.

    PubMed  CAS  Google Scholar 

  24. Zvolsky P, Vinarova E, Dostal T, Soucek K: Family history of manic-depressive and endogenous depressive patients and clinical effect of treatment with lithium. Acta Nerv Super (Praha) 1974, 16:194–195.

    CAS  Google Scholar 

  25. Mendlewicz J, Stallone F: Genetic factors and lithium response in manic-depressive illness. Mod Probl Pharmacopsychiatry 1975, 10:23–29.

    PubMed  CAS  Google Scholar 

  26. Alda M, Grof P, Grof E, et al.: Mode of inheritance in families of patients with lithium-responsive affective disorders. Acta Psychiatr Scand 1994, 90:304–310.

    PubMed  CAS  Google Scholar 

  27. Alda M, Grof E, Cavazzoni P, et al.: Autosomal recessive inheritance of affective disorders in families of responders to ithium prophylaxis? J Affect Disord 1997, 44:153–157.

    Article  PubMed  CAS  Google Scholar 

  28. Grof P, Alda M, Grof E, et al.: Lithium response and genetics of affective disorders. J Affect Disord 1994, 32:85–95. This article provides further support for the use of lithium response as a way to define a more homogeneous subgroup of patients with bipolar.

    Article  PubMed  CAS  Google Scholar 

  29. Maj M, Del Vecchio M, Starace F, et al.: Prediction of affective psychoses response to lithium prophylaxis: the role of sociodemographic, clinical, psychological and biological variables. Acta Psychiatr Scand 1984, 69:37–44.

    PubMed  CAS  Google Scholar 

  30. Mendlewicz J, Fieve RR, Stallone F: Relationship between the effectiveness of lithium therapy and family history. Am J Psychiatry 1973, 130:1011–1013.

    PubMed  CAS  Google Scholar 

  31. Grof P, Duffy A, Cavazzoni P, et al.: Is response to prophylactic lithium a familial trait? J Clin Psychiatry 2002, 63:942–947.

    PubMed  CAS  Google Scholar 

  32. Engstrom C, Astrom M, Nordqvist K, et al.: Relationship between prophylactic effect of lithium therapy and family history of affective disorders. Biol Psychiatry 1997, 42:425–433.

    Article  PubMed  CAS  Google Scholar 

  33. Nylander PO, Engstrom C, Nordqvist-Karlsson B, Astrom M: Family history of affective disorders and the significance for prophylactic effect of lithium treatment. Biol Psychiatry 1999, 45:1079–1081.

    Article  PubMed  CAS  Google Scholar 

  34. Coryell W, Akiskal H, Leon AC, et al.: Family history and symptom levels during treatment for bipolar I affective disorder. Biol Psychiatry 2000, 47:1034–1042.

    Article  PubMed  CAS  Google Scholar 

  35. Turecki G, Grof P, Grof E, et al.: Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol Psychiatry 2001, 6:570–578. This article provides results from the first large genome scan performed using pharmacogenetic strategies, namely selection according to excellent lithium response, in psychiatry.

    Article  PubMed  CAS  Google Scholar 

  36. Stober G, Saar K, Ruschendorf F, et al.: Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15. Am J Hum Genet 2000, 67:1201–1207.

    PubMed  CAS  Google Scholar 

  37. Wu YQ, Lin X, Liu CM, et al.: Identification of a human brainspecific gene, calneuron 1, a new member of the calmodulin superfamily. Mol Genet Metab 2001, 72:343–350.

    Article  PubMed  CAS  Google Scholar 

  38. Freimer NB, Reus VI, Escamilla MA, et al.: Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23. Nat Genet 1996, 12:436–441.

    Article  PubMed  CAS  Google Scholar 

  39. Ewald H, Wang AG, Vang M, et al.: A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands. Psychiatr Genet 1999, 9:23–34.

    Article  PubMed  CAS  Google Scholar 

  40. Turecki G, Grof P, Cavazzoni P, et al.: Lithium responsive bipolar disorder, unilineality, and chromosome 18: a linkage study. Am J Med Genet 1999, 88:411–415.

    Article  PubMed  CAS  Google Scholar 

  41. Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A 1996, 93:8455–8459.

    Article  PubMed  CAS  Google Scholar 

  42. Williams RS, Harwood AJ: Lithium therapy and signal transduction. Trends Pharmacol Sci 2000, 21:61–64.

    Article  PubMed  CAS  Google Scholar 

  43. Detera-Wadleigh SD: Lithium-related genetics of bipolar disorder. Ann Med 2001, 33:272–285.

    PubMed  CAS  Google Scholar 

  44. Jope RS, Bijur GN: Mood stabilizers, glycogen synthase kinase-3beta and cell survival. Mol Psychiatry 2002, 7:S35-S45.

    Article  PubMed  CAS  Google Scholar 

  45. Lenox RH, Wang L: Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol Psychiatry 2003, 8:135–144.

    Article  PubMed  CAS  Google Scholar 

  46. Del Zompo M, Ardau R, Palmas MA, et al.: Lithium response: association study with two candidate genes. Mol Psychiatry 1999, 4:S66.

    Article  Google Scholar 

  47. Ftouhi-Paquin N, Alda M, Grof P, et al.: Identification of three polymorphisms in the translated region of PLC-gamma1 and their investigation in lithium responsive bipolar disorder. Am J Med Genet 2001, 105:301–305.

    Article  PubMed  CAS  Google Scholar 

  48. Lovlie R, Berle JO, Stordal E, Steen VM: The phospholipase Cgamma1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism. Psychiatr Genet 2001, 11:41–43.

    Article  PubMed  CAS  Google Scholar 

  49. Steen VM, Gulbrandsen AK, Eiken HG, Berle JO: Lack of genetic variation in the coding region of the myo-inositol monophosphatase gene in lithium-treated patients with manic depressive illness. Pharmacogenetics 1996, 6:113–116.

    Article  PubMed  CAS  Google Scholar 

  50. Steen VM, Lovlie R, Osher Y, et al.: The polymorphic inositol polyphosphate 1-phosphatase gene as a candidate for pharmacogenetic prediction of lithium-responsive manicdepressive illness. Pharmacogenetics 1998, 8:259–268.

    PubMed  CAS  Google Scholar 

  51. Cavazzoni P, Alda M, Turecki G, et al.: Lithium-responsive affective disorders: no association with the tyrosine hydroxylase gene. Psychiatry Res 1996, 64:91–96.

    Article  PubMed  CAS  Google Scholar 

  52. Turecki G, Alda M, Grof P, et al.: No association between chromosome-18 markers and lithium-responsive affective disorders. Psychiatry Res 1996, 63:17–23.

    Article  PubMed  CAS  Google Scholar 

  53. Serretti A, Lilli R, Lorenzi C, et al.: Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders. Int J Neuropsychopharmcol 1998, 1:125–129.

    Article  PubMed  Google Scholar 

  54. Turecki G, Alda M, Grof P, et al.: Polyglutamine tracts: no evidence of a major role in bipolar disorder. Mol Psychiatry 1999, 4:220–221.

    Article  PubMed  CAS  Google Scholar 

  55. Turecki G, Grof P, Cavazzoni P, et al.: MAOA: association and linkage studies with lithium responsive bipolar disorder. Psychiatr Genet 1999, 9:13–16.

    Article  PubMed  CAS  Google Scholar 

  56. Serretti A, Lilli R, Lorenzi C, et al.: Dopamine receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Psychiatry Res 1999, 87:7–19.

    Article  PubMed  CAS  Google Scholar 

  57. Turecki G, Alda M, Grof P, et al.: Polyglutamine coding genes in bipolar disorder: lack of association with selected candidate loci. J Affect Disord 2000, 58:63–68.

    Article  PubMed  CAS  Google Scholar 

  58. Duffy A, Turecki G, Grof P, et al.: Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder. J Psychiatry Neurosci 2000, 25:353–358.

    PubMed  CAS  Google Scholar 

  59. Serretti A, Lorenzi C, Lilli R, Smeraldi E: Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders. J Psychiatr Res 2000, 34:89–98.

    Article  PubMed  CAS  Google Scholar 

  60. Alda M, Turecki G, Grof P, et al.: Association and linkage studies of CRH and PENK genes in bipolar disorder: a collaborative IGSLI study. Am J Med Genet 2000, 96:178–181.

    Article  PubMed  CAS  Google Scholar 

  61. Serretti A, Lorenzi C, Lilli R, et al.: Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 variants. Am J Med Genet 2002, 114:370–379.

    Article  PubMed  Google Scholar 

  62. Turecki G, Grof P, Cavazzoni P, et al.: Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder. Mol Psychiatry 1998, 3:534–538.

    Article  PubMed  CAS  Google Scholar 

  63. Sjoholt G, Molven A, Lovlie R, et al.: Genomic structure and chromosomal localization of a human myo-inositol monophosphatase gene (IMPA). Genomics 1997, 45:113–122.

    Article  PubMed  CAS  Google Scholar 

  64. Sjoholt G, Gulbrandsen AK, Lovlie R, et al.: A human myoinositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients. Mol Psychiatry 2000, 5:172–180.

    Article  PubMed  CAS  Google Scholar 

  65. Berrettini WH, Ferraro TN, Goldin LR, et al.: A linkage study of bipolar illness. Arch Gen Psychiatry 1997, 54:27–35.

    PubMed  CAS  Google Scholar 

  66. Serretti A, Lilli R, Mandelli L, et al.: Serotonin transporter gene associated with lithium prophylaxis in mood disorders. Pharmacogenomics J 2001, 1:71–77.

    PubMed  CAS  Google Scholar 

  67. Serretti A, Lilli R, Lorenzi C, et al.: Tryptophan hydroxylase gene and response to lithium prophylaxis in mood disorders. J Psychiatr Res 1999, 33:371–377.

    Article  PubMed  CAS  Google Scholar 

  68. Walther DJ, Peter JU, Bashammakh S, et al.: Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003, 299:76.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Douglas Hospital Research Centre, 6875 LaSalle Boulevard, H4H 1R3, Verdun, Quebec, Canada

    Gustavo Turecki MD, PhD

Authors
  1. Firoza Mamdani BSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iris Jaitovich Groisman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Alda MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gustavo Turecki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mamdani, F., Groisman, I.J., Alda, M. et al. Long-term responsiveness to lithium as a pharmacogenetic outcome variable: Treatment and etiologic implications. Curr Psychiatry Rep 5, 484–492 (2003). https://doi.org/10.1007/s11920-003-0088-z

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-003-0088-z

Keywords

Search

Navigation