CNS Drugs

, Volume 25, Issue 6, pp 459–471 | Cite as

Suicidal Ideation during Antidepressant Treatment

Do Genetic Predictors Exist?
Leading Article


Suicidal thoughts during antidepressant treatment have recently been the focus of several candidate gene and genome-wide association studies. Although the clinical risk factors for such events are well known, unfortunately they do not help to predict who will have a suicidal event during antidepressant treatment and who will not. Pharmacogenomic studies have therefore attempted to use genetic variants to predict individual susceptibility to treatment-related suicidal ideation. In this perspective, several genetic predictors have been highlighted, the majority of which relate to common mechanisms of antidepressant action: genes involved in the neurotrophic and synaptic plasticity systems (CREB1, and BDNF and its receptor NTRK2), noradrenergic system (ADRA2A), glutamatergic system (GRIA3, GRIK2 and GDA), inflammatory and hypothalamic-pituitary-adrenal (HPA) axis systems (IL28RA and FKBP5) and in other brain functions (PAPLN, APOO, KCNIP4 and ELP3). Although some of these genes may be of interest in predicting antidepressant-induced suicidal ideation, they still need to be validated in better phenotypically designed samples. Several methodological factors are indeed responsible for the problems involved in implicating these findings in the causation of a clinically relevant phenotype. These include discrepancies between studies in defining phenotypes, with several different thresholds used to establish significant suicidal ideation; the use of scales not truly designed to measure suicidal ideation; and the paucity of true suicidal events (suicide attempts and/or completion) in pharmacogenomic studies.

In conclusion, pharmacogenomic studies are far from fulfilling their promise. There is a need for future pharmacogenetic studies targeting events that are clinically significant in order to find associated variants that will help clinicians to improve their treatment strategies. While awaiting these genetic predictors, clinicians need to bear in mind that all studies in this field support a beneficial effect of antidepressants on suicidal ideation. This should therefore encourage them to prescribe antidepressant medication even in patients with suicidal ideation.


  1. 1.
    Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry 2006; 63(3): 332–9PubMedCrossRefGoogle Scholar
  2. 2.
    US Food and Drug Administration. Clinical review: relationship between antidepressant drugs and suicidality in adults [online]. Available from URL: [Accessed 2008 Apr 28]
  3. 3.
    US Food and Drug Administration. Antidepressant use in children, adolescents and adults: medication guide for antidepressant drugs [online]. Available from URL: [Accessed 2008 Apr 28]
  4. 4.
    Medicines and Healthcare products Regulatory Agency. Safety of selective serotonin reuptake inhibitor antide-pressants, 2004 [online]. Available from URL: [Accessed 2010 Dec 13]
  5. 5.
    Friedman RA, Leon AC. Expanding the black box: depression, antidepressants, and the risk of suicide. N Engl J Med 2007; 356(23): 2343–6PubMedCrossRefGoogle Scholar
  6. 6.
    Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007; 164(9): 1356–63PubMedCrossRefGoogle Scholar
  7. 7.
    Healy D, Whitaker C. Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci 2003; 28(5): 331–7PubMedGoogle Scholar
  8. 8.
    Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosom 2003; 72(2): 71–9PubMedCrossRefGoogle Scholar
  9. 9.
    Machado-Vieira R, Salvadore G, Luckenbaugh DA, et al. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry 2008; 69(6): 946–58PubMedCrossRefGoogle Scholar
  10. 10.
    Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004; 292(3): 338–43PubMedCrossRefGoogle Scholar
  11. 11.
    Nutt DJ. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psycho-pharmacol 2003; 17(4): 355–64Google Scholar
  12. 12.
    Perlis RH, Beasley Jr CM, Wines Jr JD, et al. Treatment-associated suicidal ideation and adverse effects in an open, multicenter trial of fluoxetine for major depressive episodes. Psychother Psychosom 2007; 76(1): 40–6PubMedCrossRefGoogle Scholar
  13. 13.
    Teicher MH, Glod CA, Cole JO. Antidepressant drugs and the emergence of suicidal tendencies. Drug Saf 1993; 8(3): 186–212PubMedCrossRefGoogle Scholar
  14. 14.
    Akiskal HS, Benazzi F, Perugi G, et al. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord 2005; 85(3): 245–58PubMedCrossRefGoogle Scholar
  15. 15.
    Berk M, Dodd S. Are treatment emergent suicidality and decreased response to antidepressants in younger patients due to bipolar disorder being misdiagnosed as unipolar depression? Med Hypotheses 2005; 65(1): 39–43PubMedCrossRefGoogle Scholar
  16. 16.
    Harada T, Sakamoto K, Ishigooka J. Incidence and predictors of activation syndrome induced by antidepressants. Depress Anxiety 2008; 25(12): 1014–9PubMedCrossRefGoogle Scholar
  17. 17.
    Culpepper L, Davidson JR, Dietrich AJ, et al. Suicidality as a possible side effect of antidepressant treatment. J Clin Psychiatry 2004; 65(6): 742–9PubMedCrossRefGoogle Scholar
  18. 18.
    Lane RM. SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol 1998; 12(2): 192–214PubMedCrossRefGoogle Scholar
  19. 19.
    Benazzi F. Suicidal ideation and depressive mixed states. Psychother Psychosom 2005; 74(1): 61–2PubMedCrossRefGoogle Scholar
  20. 20.
    Baldassano CF, Truman CJ, Nierenberg A, et al. Akathisia: a review and case report following paroxetine treatment. Compr Psychiatry 1996; 37(2): 122–4PubMedCrossRefGoogle Scholar
  21. 21.
    Perroud N, Uher R, Marusic A, et al. Suicidal ideation during treatment of depression with escitalopram and nortriptyline in genome-based therapeutic drugs for depression (GENDEP): a clinical trial. BMC Med 2009; 7: 60PubMedCrossRefGoogle Scholar
  22. 22.
    Balazs J, Benazzi F, Rihmer Z, et al. The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention. J Affect Disord 2006; 91(2-3): 133–8PubMedCrossRefGoogle Scholar
  23. 23.
    Pokorny AD. Prediction of suicide in psychiatric patients: report of a prospective study. Arch Gen Psychiatry 1983; 40(3): 249–57PubMedCrossRefGoogle Scholar
  24. 24.
    Goldstein RB, Black DW, Nasrallah A, et al. The prediction of suicide: sensitivity, specificity, and predictive value of a multivariate model applied to suicide among 1906 patients with affective disorders. Arch Gen Psychiatry 1991; 48(5): 418–22PubMedCrossRefGoogle Scholar
  25. 25.
    van Egmond M, Diekstra RF. The predictability of suicidal behavior: the results of a meta-analysis of published studies. Crisis 1990; 11(2): 57–84PubMedGoogle Scholar
  26. 26.
    Anderson RN. Deaths: leading causes for 1999. Natl Vital Stat Rep 2001;49(11): 1–87Google Scholar
  27. 27.
    Brent DA, Mann JJ. Family genetic studies, suicide, and suicidal behavior. Am J Med Genet C Semin Med Genet 2005; 133C(1): 13–24PubMedCrossRefGoogle Scholar
  28. 28.
    Fu Q, Heath AC, Bucholz KK, et al. A twin study of genetic and environmental influences on suicidality in men. Psychol Med 2002; 32(1): 11–24PubMedCrossRefGoogle Scholar
  29. 29.
    Butler AW, Breen G, Tozzi F, et al. A genomewide linkage study on suicidality in major depressive disorder confirms evidence for linkage to 2p12. Am J Med Genet B Neuropsychiatr Genet 2010; 153B(8): 1465–73PubMedCrossRefGoogle Scholar
  30. 30.
    Cui H, Supriyanto I, Asano M, et al. A common polymorphism in the 3′-UTR of the NOS1 gene was associated with completed suicides in Japanese male population. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(6): 992–6PubMedCrossRefGoogle Scholar
  31. 31.
    Wang Y, Zhang J, Liu B, et al. Genetic polymorphisms in the SCN8A gene are associated with suicidal behavior in psychiatric disorders in the Chinese population. World J Biol Psychiatry 2010; 11(8): 956–63PubMedCrossRefGoogle Scholar
  32. 32.
    Nedic G, Nikolac M, Sviglin KN, et al. Association study of a functional catechol-O-methyltransferase (COMT) Val108/ 158Met polymorphism and suicide attempts in patients with alcohol dependence. Int J Neuropsychopharmacol 2011; 14(3): 377–88PubMedCrossRefGoogle Scholar
  33. 33.
    Zalsman G, Patya M, Frisch A, et al. Association of polymorphisms of the serotonergic pathways with clinical traits of impulsive-aggression and suicidality in adolescents: a multi-center study. World J Biol Psychiatry 2011; 12(1): 33–41PubMedCrossRefGoogle Scholar
  34. 34.
    Uher R, Perroud N. Probing the genome to understand suicide. Am J Psychiatry 2010; 167: 1425–7PubMedCrossRefGoogle Scholar
  35. 35.
    Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials 2004; 25(1): 119–42PubMedCrossRefGoogle Scholar
  36. 36.
    Uher R, Farmer A, Maier W, et al. Measuring depression: comparison and integration of three scales in the GENDEP study. Psychol Med 2008; 38(2): 289–300PubMedCrossRefGoogle Scholar
  37. 37.
    Hennings JM, Owashi T, Binder EB, et al. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients: findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res 2009; 43(3): 215–29PubMedCrossRefGoogle Scholar
  38. 38.
    Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA 2008; 299(8): 901–13PubMedCrossRefGoogle Scholar
  39. 39.
    Brent D, Melhem N, Turecki G. Pharmacogenomics of suicidal events. Pharmacogenomics 2010; 11(6): 793–807PubMedCrossRefGoogle Scholar
  40. 40.
    Perlis RH, Purcell S, Fava M, et al. Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study. Arch Gen Psychiatry 2007; 64(6): 689–97PubMedCrossRefGoogle Scholar
  41. 41.
    Laje G, Allen AS, Akula N, et al. Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients. Pharmacogenet Genomics 2009; 19(9): 666–74PubMedCrossRefGoogle Scholar
  42. 42.
    Laje G, Paddock S, Manji H, et al. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry 2007; 164(10): 1530–8PubMedCrossRefGoogle Scholar
  43. 43.
    Perroud N, Aitchison KJ, Uher R, et al. Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project. Neuropsychopharmacology 2009; 34(12): 2517–28PubMedCrossRefGoogle Scholar
  44. 44.
    Menke A, Lucae S, Kloiber S, et al. Genetic markers within glutamate receptors associated with antidepressant treatment-emergent suicidal ideation. Am J Psychiatry 2008; 165(7): 917–8PubMedCrossRefGoogle Scholar
  45. 45.
    Brent D, Melhem N, Ferrell R, et al. Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am J Psychiatry 2010; 167(2): 190–7PubMedCrossRefGoogle Scholar
  46. 46.
    Zisook S, Trivedi MH, Warden D, et al. Clinical correlates of the worsening or emergence of suicidal ideation during SSRI treatment of depression: an examination of citalopram in the STAR*D study. J Affect Disord 2009; 117(1–2): 63–73PubMedCrossRefGoogle Scholar
  47. 47.
    Perroud N, Uher R, Ng M, et al. Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenomics J. Epub 2010 Sep 28Google Scholar
  48. 48.
    Dwivedi Y, Rao JS, Rizavi HS, et al. Abnormal expression and functional characteristics of cyclic adenosine mono-phosphate response element binding protein in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60(3): 273–82PubMedCrossRefGoogle Scholar
  49. 49.
    Young LT, Bezchlibnyk YB, Chen B, et al. Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment. Biol Psychiatry 2004; 55(6): 570–7PubMedCrossRefGoogle Scholar
  50. 50.
    Baud P, Courtet P, Perroud N, et al. Catechol-O-methyl-transferase polymorphism (COMT) in suicide attempters: a possible gender effect on anger traits. Am J Med Genet B Neuropsychiatr Genet 2007; 144B(8): 1042–7PubMedCrossRefGoogle Scholar
  51. 51.
    Perlis RH, Purcell S, Fagerness J, et al. Clinical and genetic dissection of anger expression and CREB1 polymorphisms in major depressive disorder. Biol Psychiatry 2007; 62(5): 536–40PubMedCrossRefGoogle Scholar
  52. 52.
    Palucha A, Pilc A. The involvement of glutamate in the pathophysiology of depression. Drug News Perspect 2005; 18(4): 262–8PubMedCrossRefGoogle Scholar
  53. 53.
    Dwivedi Y, Rizavi HS, Conley RR, et al. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60(8): 804–15PubMedCrossRefGoogle Scholar
  54. 54.
    Altar CA, Whitehead RE, Chen R, et al. Effects of electro-convulsiveseizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 2003; 54(7): 703–9PubMedCrossRefGoogle Scholar
  55. 55.
    Coppell AL, Pei Q, Zetterstrom TS. Bi-phasic change in BDNF gene expression following antidepressant drug treatment. Neuropharmacology 2003; 44(7): 903–10PubMedCrossRefGoogle Scholar
  56. 56.
    Escriba PV, Ozaita A, Garcia-Sevilla JA. Increased mRNA expression of alpha2A-adrenoceptors, serotonin receptors and mu-opioid receptors in the brains of suicide victims. Neuropsychopharmacology 2004; 29(8): 1512–21PubMedCrossRefGoogle Scholar
  57. 57.
    Wakeno M, Kato M, Okugawa G, et al. The alpha 2A-adrenergic receptor gene polymorphism modifies antidepressant responses to milnacipran. J Clin Psychopharmacol 2008; 28(5): 518–24PubMedCrossRefGoogle Scholar
  58. 58.
    Oquendo MA, Mann JJ. The biology of impulsivity and suicidality. Psychiatr Clin North Am 2000; 23(1): 11–25PubMedCrossRefGoogle Scholar
  59. 59.
    Ising M, Depping AM, Siebertz A, et al. Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. Eur J Neurosci 2008; 28(2): 389–98PubMedCrossRefGoogle Scholar
  60. 60.
    Binder EB, Salyakina D, Lichtner P, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36(12): 1319–25PubMedCrossRefGoogle Scholar
  61. 61.
    Perroud N, Bondolfi G, Uher R, et al. Clinical and genetic correlates of suicidal ideation during antidepressant treatment in a depressed outpatient sample. Pharmacogenomics 2011; 12(3): 365–77PubMedCrossRefGoogle Scholar
  62. 62.
    Mann JJ, Currier D. A review of prospective studies of biologic predictors of suicidal behavior in mood disorders. Arch Suicide Res 2007; 11(1): 3–16PubMedCrossRefGoogle Scholar
  63. 63.
    Scammell JG, Denny WB, Valentine DL, et al. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. Gen Comp Endocrinol 2001; 124(2): 152–65PubMedCrossRefGoogle Scholar
  64. 64.
    Roy A, Gorodetsky E, Yuan Q, et al. Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology 2010; 35(8): 1674–83PubMedGoogle Scholar
  65. 65.
    Janssen HL, Brouwer JT, van der Mast RC, et al. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994; 21(2): 241–3PubMedCrossRefGoogle Scholar
  66. 66.
    Akum BF, Chen M, Gunderson SI, et al. Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nat Neurosci 2004; 7(2): 145–52PubMedCrossRefGoogle Scholar
  67. 67.
    Feyissa AM, Chandran A, Stockmeier CA, et al. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(1): 70–5PubMedCrossRefGoogle Scholar
  68. 68.
    Guipponi M, Deutsch S, Kohler K, et al. Genetic and epigenetic analysis of SSAT gene dysregulation in suicidal behavior. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(6): 799–807PubMedCrossRefGoogle Scholar
  69. 69.
    Brown G. A review of suicide assessment measures for intervention research with adults and older adults. Philadelphia (PA): University of Pennsylvania, 2002Google Scholar
  70. 70.
    Nock MK, Wedig MM, Janis IB, et al. Self-injurious thoughts and behaviors. In: Hunsley J, Mash EJ, editors. A guide to assessments that work. London: Oxford University Press, 2008: 158–78Google Scholar
  71. 71.
    Range LM, Knott EC. Twenty suicide assessment instruments: evaluation and recommendations. Death Stud 1997; 21(1): 25–58PubMedCrossRefGoogle Scholar
  72. 72.
    Winters NC, Myers K, Proud L. Ten-year review of rating scales: III. Scales assessing suicidality, cognitive style, and self-esteem. J Am Acad Child Adolesc Psychiatry 2002; 41(10): 1150–81Google Scholar
  73. 73.
    Newport DJ, Levey LC, Pennell PB, et al. Suicidal ideation in pregnancy: assessment and clinical implications. Arch Womens Ment Health 2007; 10(5): 181–7PubMedCrossRefGoogle Scholar
  74. 74.
    Kessler RC, Berglund P, Borges G, et al. Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990–1992 to 2001–2003. JAMA 2005; 293(20): 2487–95PubMedCrossRefGoogle Scholar
  75. 75.
    Suicidal behavior and psychotropic medication: accepted as a consensus statement by the ACNP Council, March 2, 1992. Neuropsychopharmacology 1993; 8 (2): 177-83Google Scholar
  76. 76.
    Meyer RE, Salzman C, Youngstrom EA, et al. Suicidality and risk of suicide: definition, drug safety concerns, and a necessary target for drug development. A consensus statement. J Clin Psychiatry 2010; 71(8): e1–21PubMedCrossRefGoogle Scholar
  77. 77.
    Meyer RE, Salzman C, Youngstrom EA, et al. Suicidality and risk of suicide: definition, drug safety concerns, and a necessary target for drug development. A brief report. J Clin Psychiatry 2010; 71(8): 1040–6Google Scholar
  78. 78.
    Price AL, Kryukov GV, de Bakker PI, et al. Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet 2010; 86(6): 832–8PubMedCrossRefGoogle Scholar
  79. 79.
    Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001; 69(1): 124–37PubMedCrossRefGoogle Scholar
  80. 80.
    Frazer KA, Murray SS, Schork NJ, et al. Human genetic variation and its contribution to complex traits. Nat Rev Genet 2009; 10(4): 241–51PubMedCrossRefGoogle Scholar
  81. 81.
    Iyengar SK, Elston RC. The genetic basis of complex traits: rare variants or “common gene, common disease”? Methods Mol Biol 2007; 376: 71–84PubMedCrossRefGoogle Scholar
  82. 82.
    Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 2008; 83(3): 311–21PubMedCrossRefGoogle Scholar
  83. 83.
    Smith DJ, Lusis AJ. The allelic structure of common disease. Hum Mol Genet 2002; 11(20): 2455–61PubMedCrossRefGoogle Scholar
  84. 84.
    Caspi A, Hariri AR, Holmes A, et al. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 2010; 167(5): 509–27PubMedCrossRefGoogle Scholar
  85. 85.
    Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci U S A 2003; 100(24): 14293–6PubMedCrossRefGoogle Scholar
  86. 86.
    Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 2010; 64(4): 341–57PubMedCrossRefGoogle Scholar
  87. 87.
    Karege F, Vaudan G, Schwald M, et al. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 2005; 136(1-2): 29–37PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity Hospitals of GenevaChêne-Bourg, GenevaSwitzerland

Personalised recommendations