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  • Review Article
  • Published:

The molecular bases of the suicidal brain

Key Points

  • Suicide takes a heavy toll on society but can often be avoided through adequate treatment. However, societal normalities and taboos often make it difficult for individuals who experience suicidal ideation or aspects of suicidal behaviour to seek help before it is too late.

  • Many factors contribute to suicidal behaviour and these can be globally classified as distal factors, which increase predisposition to suicide, and proximal factors, which precipitate a suicidal act.

  • Distal factors comprise a family history of suicide, indicating a genetic predisposition, genetic variation between individuals and experiences of early-life adversity. Early-life adversity can result in stable changes to gene expression, which results in increased lifetime susceptibility to suicidal behaviour.

  • Early-life adversity epigenetically regulates stress response systems and neuronal plasticity, which are associated with emotional and behavioural changes.

  • Behavioural and emotional traits are known mediators of suicide risk, with impulsive aggressive and anxiety traits being intimately linked to suicidal behaviour.

  • Proximal factors are associated with precipitation of the suicidal act and can be linked to changes in neurotransmitter levels, inflammation in the CNS and glial, notably astrocytic, dysfunction.

Abstract

Suicide ranks among the leading causes of death around the world and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors — such as familial and genetic predisposition, as well as early-life adversity — increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors are associated with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes that are associated with suicidality and discusses some promising avenues for future research.

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Figure 1: Overview of the contributors to suicidal behaviour.

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References

  1. Mann, J. J. et al. Suicide prevention strategies: a systematic review. JAMA 294, 2064–2074 (2005).

    CAS  PubMed  Google Scholar 

  2. Duffy, A. M., The quiet epidemic. The Ottawa Citizen, Supplement on Suicide (2003).

    Google Scholar 

  3. Silverman, M. M. The language of suicidology. Suicide Life Threat. Behav. 36, 519–532 (2006).

    PubMed  Google Scholar 

  4. Kapur, N., Cooper, J., O'Connor, R. C. & Hawton, K. Non-suicidal self-injury v. attempted suicide: new diagnosis or false dichotomy? Br. J. Psychiatry 202, 326–328 (2013).

    PubMed  Google Scholar 

  5. Brezo, J. et al. Identifying correlates of suicide attempts in suicidal ideators: a population-based study. Psychol. Med. 37, 1551–1562 (2007).

    PubMed  Google Scholar 

  6. Arsenault-Lapierre, G., Kim, C. & Turecki, G. Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC Psychiatry 4, 37 (2004).

    PubMed  PubMed Central  Google Scholar 

  7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).

  8. Dumais, A. et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am. J. Psychiatry 162, 2116–2124 (2005). This study clearly shows that when depressive psychopathology is controlled for, impulsive aggressive traits are strongly associated with suicide, particularly among young suicide completers.

    CAS  PubMed  Google Scholar 

  9. McGirr, A. et al. Impulsive-aggressive behaviours and completed suicide across the life cycle: a predisposition for younger age of suicide. Psychol. Med. 38, 407–417 (2008).

    CAS  PubMed  Google Scholar 

  10. Beautrais, A. L. Suicide and serious suicide attempts in youth: a multiple-group comparison study. Am. J. Psychiatry 160, 1093–1099 (2003).

    PubMed  Google Scholar 

  11. Dalca, I. M., McGirr, A., Renaud, J. & Turecki, G. Gender-specific suicide risk factors: a case-control study of individuals with major depressive disorder. J. Clin. Psychiatry 74, 1209–1216 (2013).

    PubMed  Google Scholar 

  12. O'Connor, R. C., Platt, S. & Gordon, J. (eds) International Handbook of Suicide Prevention: Research, Policy and Practice (John Wiley & Sons, 2011).

    Google Scholar 

  13. Moscicki, E. K. Gender differences in completed and attempted suicides. Ann. Epidemiol. 4, 152–158 (1994).

    CAS  PubMed  Google Scholar 

  14. Mann, J. J. Neurobiology of suicidal behaviour. Nature Rev. Neurosci. 4, 819–828 (2003).

    CAS  Google Scholar 

  15. Tidemalm, D. et al. Familial clustering of suicide risk: a total population study of 11.4 million individuals. Psychol. Med. 41, 2527–2534 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Baldessarini, R. J. & Hennen, J. Genetics of suicide: an overview. Harv. Rev. Psychiatry 12, 1–13 (2004).

    PubMed  Google Scholar 

  17. Turecki, G. Suicidal behavior: is there a genetic predisposition? Bipolar Disord. 3, 335–349 (2001).

    CAS  PubMed  Google Scholar 

  18. Brent, D. What family studies teach us about suicidal behavior: implications for research, treatment, and prevention. Eur. Psychiatry 25, 260–263 (2010).

    CAS  PubMed  Google Scholar 

  19. Brent, D. A., Bridge, J., Johnson, B. A. & Connolly, J. Suicidal behavior runs in families. A controlled family study of adolescent suicide victims. Arch. Gen. Psychiatry 53, 1145–1152 (1996). This is an important study that convincingly shows that familial aggregation of suicide is not exclusively explained by psychopathology.

    CAS  PubMed  Google Scholar 

  20. Lieb, R., Bronisch, T., Hofler, M., Schreier, A. & Wittchen, H. U. Maternal suicidality and risk of suicidality in offspring: findings from a community study. Am. J. Psychiatry 162, 1665–1671 (2005).

    PubMed  Google Scholar 

  21. Blum, R., Sudhinaraset, M. & Emerson, M. R. Youth at risk: suicidal thoughts and attempts in Vietnam, China, and Taiwan. J. Adolesc. Health 50, S37–S44 (2012).

    PubMed  Google Scholar 

  22. Kim, C. D. et al. Familial aggregation of suicidal behavior: a family study of male suicide completers from the general population. Am. J. Psychiatry 162, 1017–1019 (2005).

    PubMed  Google Scholar 

  23. McGirr, A. et al. Familial aggregation of suicide explained by cluster B traits: a three-group family study of suicide controlling for major depressive disorder. Am. J. Psychiatry 166, 1124–1134 (2009).

    PubMed  Google Scholar 

  24. Ernst, C., Mechawar, N. & Turecki, G. Suicide neurobiology. Prog. Neurobiol. 89, 315–333 (2009).

    CAS  PubMed  Google Scholar 

  25. von Borczyskowski, A., Lindblad, F., Vinnerljung, B., Reintjes, R. & Hjern, A. Familial factors and suicide: an adoption study in a Swedish National Cohort. Psychol. Med. 41, 749–758 (2011).

    CAS  PubMed  Google Scholar 

  26. Mann, J. J. The serotonergic system in mood disorders and suicidal behaviour. Phil. Trans. R. Soc. B 368, 20120537 (2013).

    PubMed  Google Scholar 

  27. Bach, H. & Arango, V. in The Neurobiological Basis of Suicide (ed. Dwivedi, Y.) (CRC Press, 2012).

    Google Scholar 

  28. Brezo, J., Klempan, T. & Turecki, G. The genetics of suicide: a critical review of molecular studies. Psychiatr. Clin. North Am. 31, 179–203 (2008).

    PubMed  Google Scholar 

  29. Laje, G. et al. Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients. Pharmacogenet. Genom. 19, 666–674 (2009).

    CAS  Google Scholar 

  30. Menke, A. et al. Genome-wide association study of antidepressant treatment-emergent suicidal ideation. Neuropsychopharmacology 37, 797–807 (2012).

    CAS  PubMed  Google Scholar 

  31. Perlis, R. H. et al. Genome-wide association study of suicide attempts in mood disorder patients. Am. J. Psychiatry 167, 1499–1507 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. Perroud, N. et al. Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenom. J. 12, 68–77 (2012).

    CAS  Google Scholar 

  33. Schosser, A. et al. Genomewide association scan of suicidal thoughts and behaviour in major depression. PLoS ONE 6, e20690 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Willour, V. L. et al. A genome-wide association study of attempted suicide. Mol. Psychiatry 17, 433–444 (2012).

    CAS  PubMed  Google Scholar 

  35. Galfalvy, H. et al. A pilot genome wide association and gene expression array study of suicide with and without major depression. World J. Biol. Psychiatry 14, 574–582 (2013).

    PubMed  Google Scholar 

  36. Perlis, R. H., Ruderfer, D., Hamilton, S. P. & Ernst, C. Copy number variation in subjects with major depressive disorder who attempted suicide. PLoS ONE 7, e46315 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Fergusson, D. M., Woodward, L. J. & Horwood, L. J. Risk factors and life processes associated with the onset of suicidal behaviour during adolescence and early adulthood. Psychol. Med. 30, 23–39 (2000).

    CAS  PubMed  Google Scholar 

  38. Angst, J., Degonda, M. & Ernst, C. The Zurich Study: XV. Suicide attempts in a cohort from age 20 to 30. Eur. Arch. Psychiatry Clin. Neurosci. 242, 135–141 (1992).

    CAS  PubMed  Google Scholar 

  39. Afifi, T. O. et al. Population attributable fractions of psychiatric disorders and suicide ideation and attempts associated with adverse childhood experiences. Am. J. Publ. Health 98, 946–952 (2008).

    Google Scholar 

  40. Gilbert, R. et al. Burden and consequences of child maltreatment in high-income countries. Lancet 373, 68–81 (2009).

    PubMed  Google Scholar 

  41. Collishaw, S. et al. Resilience to adult psychopathology following childhood maltreatment: Evidence from a community sample. Child Abuse Neglect 31, 211–229 (2007).

    PubMed  Google Scholar 

  42. Lansford, J. E. et al. A 12-year prospective study of the long-term effects of early child physical maltreatment on psychological, behavioral, and academic problems in adolescence. Arch. Pediatr. Adolescent Med. 156, 824–830 (2002).

    Google Scholar 

  43. Fanous, A. H., Prescott, C. A. & Kendler, K. S. The prediction of thoughts of death or self-harm in a population-based sample of female twins. Psychol. Med. 34, 301–312 (2004).

    CAS  PubMed  Google Scholar 

  44. Brezo, J. et al. Predicting suicide attempts in young adults with histories of childhood abuse. Br. J. Psychiatry 193, 134–139 (2008).

    PubMed  Google Scholar 

  45. Brezo, J. et al. Natural history of suicidal behaviors in a population-based sample of young adults. Psychol. Med. 37, 1563–1574 (2007).

    PubMed  Google Scholar 

  46. Lopez-Castroman, J. et al. Suicidal phenotypes associated with family history of suicidal behavior and early traumatic experiences. J. Affect Disord. 142, 193–199 (2012).

    CAS  PubMed  Google Scholar 

  47. Lopez-Castroman, J. et al. Early childhood sexual abuse increases suicidal intent. World Psychiatry 12, 149–154 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. Cole, P. M., Michel, M. K. & Teti, L. O. The development of emotion regulation and dysregulation: a clinical perspective. Monogr. Soc. Res. Child Dev. 59, 73–100 (1994).

    CAS  PubMed  Google Scholar 

  49. Malatesta, C. Z. The role of emotions in the development and organization of personality. Nebr. Symp. Motiv. 36, 1–56 (1988).

    CAS  PubMed  Google Scholar 

  50. Smith, P. N. et al. The relationships of attachment style and social maladjustment to death ideation in depressed women with a history of childhood sexual abuse. J. Clin. Psychol. 68, 78–87 (2012).

    PubMed  Google Scholar 

  51. Hertzman, C. Putting the concept of biological embedding in historical perspective. Proc. Natl Acad. Sci. USA 109 (Suppl. 2), 17160–17167 (2012).

    CAS  PubMed  Google Scholar 

  52. Raison, C. L. & Miller, A. H. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am. J. Psychiatry 160, 1554–1565 (2003).

    PubMed  Google Scholar 

  53. Heim, C., Shugart, M., Craighead, W. E. & Nemeroff, C. B. Neurobiological and psychiatric consequences of child abuse and neglect. Dev. Psychobiol 52, 671–690 (2010).

    PubMed  Google Scholar 

  54. McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neurosci. 12, 342–348 (2009). This study shows for the first time in humans that adversity in childhood can induce brain methylation changes in crucial genes.

    CAS  PubMed  Google Scholar 

  55. Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A. & Marsit, C. J. The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 8, 1321–1329 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Perroud, N. et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl. Psychiatry 1, e59 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Labonte, B. et al. Genome-wide epigenetic regulation by early-life trauma. Arch. Gen. Psychiatry 69, 722–731 (2012). This study is the first genome-wide study that examines the effect of early-life trauma on methylation in the brains of suicide completers.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. van der Knaap, L. J. et al. Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Transl. Psychiatry 4, e381 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Perroud, N. et al. Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder. Br. J. Psychiatry 204, 30–35 (2014).

    PubMed  Google Scholar 

  60. Melas, P. A. et al. Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. Int. J. Neuropsychopharmacol 16, 1513–1528 (2013).

    CAS  PubMed  Google Scholar 

  61. Davies, M. N. et al. Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol. 13, R43 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Binder, E. B. et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299, 1291–1305 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Mehta, D. et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch. Gen. Psychiatry 68, 901–910 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Willour, V. L. et al. Family-based association of FKBP5 in bipolar disorder. Mol. Psychiatry 14, 261–268 (2009).

    CAS  PubMed  Google Scholar 

  65. Supriyanto, I. et al. Association of FKBP5 gene haplotypes with completed suicide in the Japanese population. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 252–256 (2011).

    CAS  PubMed  Google Scholar 

  66. Leszczynska-Rodziewicz, A. et al. Possible association between haplotypes of the FKBP5 gene and suicidal bipolar disorder, but not with melancholic depression and psychotic features, in the course of bipolar disorder. Neuropsychiatr. Dis. Treat. 10, 243–248 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Brent, D. et al. Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am. J. Psychiatry 167, 190–197 (2010).

    PubMed  Google Scholar 

  68. Perroud, N. et al. Clinical and genetic correlates of suicidal ideation during antidepressant treatment in a depressed outpatient sample. Pharmacogenomics 12, 365–377 (2011).

    PubMed  Google Scholar 

  69. Roy, A., Gorodetsky, E., Yuan, Q., Goldman, D. & Enoch, M. A. Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology 35, 1674–1683 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Roy, A., Hodgkinson, C. A., Deluca, V., Goldman, D. & Enoch, M. A. Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior. J. Psychiatr. Res. 46, 72–79 (2012).

    PubMed  Google Scholar 

  71. Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neurosci. 16, 33–41 (2013).

    CAS  PubMed  Google Scholar 

  72. Labonte, B. et al. Genome-wide methylation changes in the brains of suicide completers. Am. J. Psychiatry 170, 511–520 (2013).

    PubMed  Google Scholar 

  73. Weder, N. et al. Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J. Am. Acad. Child Adolesc. Psychiatry 53, 417–424 (2014).

    PubMed  PubMed Central  Google Scholar 

  74. Roth, T. L., Lubin, F. D., Funk, A. J. & Sweatt, J. D. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol. Psychiatry 65, 760–769 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Roth, T. L., Zoladz, P. R., Sweatt, J. D. & Diamond, D. M. Epigenetic modification of hippocampal BDNF DNA in adult rats in an animal model of post-traumatic stress disorder. J. Psychiatr. Res. 45, 919–926 (2011).

    PubMed  PubMed Central  Google Scholar 

  76. Uchida, S. et al. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron 69, 359–372 (2011).

    CAS  PubMed  Google Scholar 

  77. Dwivedi, Y. et al. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch. Gen. Psychiatry 60, 804–815 (2003).

    CAS  PubMed  Google Scholar 

  78. Pandey, G. N. et al. Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. Int. J. Neuropsychopharmacol. 11, 1047–1061 (2008).

    CAS  PubMed  Google Scholar 

  79. Ernst, C. et al. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Arch. Gen. Psychiatry 66, 22–32 (2009).

    CAS  PubMed  Google Scholar 

  80. Maussion, G. et al. Functional DNA methylation in a transcript specific 3′UTR region of TRKB associates with suicide. Epigenetics 9, 1061–1070 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Keller, S. et al. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch. Gen. Psychiatry 67, 258–267 (2010).

    CAS  PubMed  Google Scholar 

  82. Banerjee, R., Ghosh, A. K., Ghosh, B., Bhattacharyya, S. & Mondal, A. C. Decreased mRNA and protein expression of BDNF, NGF, and their receptors in the hippocampus from suicide: an analysis in human postmortem brain. Clin. Med. Insights Pathol. 6, 1–11 (2013).

    PubMed  PubMed Central  Google Scholar 

  83. Zhang, X. et al. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell 126, 1189–1201 (2006).

    CAS  Google Scholar 

  84. Fuchikami, M. et al. DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. PLoS ONE 6, e23881 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kang, H. J. et al. BDNF promoter methylation and suicidal behavior in depressive patients. J. Affect. Disord. 151, 679–685 (2013).

    CAS  PubMed  Google Scholar 

  86. Kim, J. M. et al. Association of BDNF promoter methylation and genotype with suicidal ideation in elderly Koreans. Am. J. Geriatr. Psychiatry 22, 989–996 (2014).

    PubMed  Google Scholar 

  87. Michels, K. B. et al. Recommendations for the design and analysis of epigenome-wide association studies. Nature Methods 10, 949–955 (2013). This article outlines the key considerations for future genome-wide studies, focusing on epigenetic regulation; these recommendations will help to strengthen the data gathered from such large-scale studies.

    CAS  PubMed  Google Scholar 

  88. Yang, B. Z. et al. Child abuse and epigenetic mechanisms of disease risk. Am. J. Prev. Med. 44, 101–107 (2013).

    PubMed  PubMed Central  Google Scholar 

  89. Turecki, G., Ernst, C., Jollant, F., Labonte, B. & Mechawar, N. The neurodevelopmental origins of suicidal behavior. Trends Neurosci. 35, 14–23 (2012).

    CAS  PubMed  Google Scholar 

  90. Wanner, B., Vitaro, F., Tremblay, R. E. & Turecki, G. Childhood trajectories of anxiousness and disruptiveness explain the association between early-life adversity and attempted suicide. Psychol. Med. 42, 2373–2382 (2012). Through trajectory analyses, this study gathers longitudinal data to describe the behavioural phenotypes that link ELA to suicide attempts.

    CAS  PubMed  Google Scholar 

  91. Courtet, P., Gottesman, I., Jollant, F. & Gould, T. D. The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies? Transl. Psychiatry 1, e7 (2011).

    PubMed  PubMed Central  Google Scholar 

  92. Mann, J. J. et al. Candidate endophenotypes for genetic studies of suicidal behavior. Biol. Psychiatry 65, 556–563 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Brezo, J. et al. Childhood trajectories of anxiousness and disruptiveness as predictors of suicide attempts. Arch. Pediatr. Adolesc. Med. 162, 1015–1021 (2008).

    PubMed  Google Scholar 

  94. Brent, D. A. et al. Familial transmission of mood disorders: convergence and divergence with transmission of suicidal behavior. J. Am. Acad. Child Adolesc. Psychiatry 43, 1259–1266 (2004).

    PubMed  Google Scholar 

  95. Gureje, O. et al. Parental psychopathology and the risk of suicidal behavior in their offspring: results from the World Mental Health surveys. Mol. Psychiatry 16, 1221–1233 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. Brezo, J., Paris, J. & Turecki, G. Personality traits as correlates of suicidal ideation, suicide attempts, and suicide completions: a systematic review. Acta Psychiatr. Scand. 113, 180–206 (2006).

    CAS  PubMed  Google Scholar 

  97. Brezo, J. et al. Broad and narrow personality traits as markers of one-time and repeated suicide attempts: a population-based study. BMC Psychiatry 8, 15 (2008).

    PubMed  PubMed Central  Google Scholar 

  98. Fergusson, D. M., Beautrais, A. L. & Horwood, L. J. Vulnerability and resiliency to suicidal behaviours in young people. Psychol. Med. 33, 61–73 (2003).

    CAS  PubMed  Google Scholar 

  99. Herba, C. M., Ferdinand, R. F., van der Ende, J. & Verhulst, F. C. Long-term associations of childhood suicide ideation. J. Am. Acad. Child Adolesc. Psychiatry 46, 1473–1481 (2007).

    PubMed  Google Scholar 

  100. Sourander, A. et al. Childhood predictors of completed and severe suicide attempts: findings from the Finnish 1981 Birth Cohort Study. Arch. Gen. Psychiatry 66, 398–406 (2009).

    PubMed  Google Scholar 

  101. Sareen, J. et al. Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based longitudinal study of adults. Arch. Gen. Psychiatry 62, 1249–1257 (2005).

    PubMed  Google Scholar 

  102. Suomi, S. J. Early stress and adult emotional reactivity in rhesus monkeys. Ciba Found. Symposium 156, 171–183 (1991).

    CAS  Google Scholar 

  103. Caldji, C. et al. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc. Natl Acad. Sci. USA 95, 5335–5340 (1998).

    CAS  PubMed  Google Scholar 

  104. van der Vegt, E. J., van der Ende, J., Ferdinand, R. F., Verhulst, F. C. & Tiemeier, H. Early childhood adversities and trajectories of psychiatric problems in adoptees: evidence for long lasting effects. J. Abnorm Child Psychol. 37, 239–249 (2009).

    PubMed  Google Scholar 

  105. Johnson, J. G. et al. Childhood adversities, interpersonal difficulties, and risk for suicide attempts during late adolescence and early adulthood. Arch. Gen. Psychiatry 59, 741–749 (2002).

    PubMed  Google Scholar 

  106. Kim, C. et al. Patterns of co-morbidity in male suicide completers. Psychol. Med. 33, 1299–1309 (2003).

    CAS  PubMed  Google Scholar 

  107. Seguin, M. et al. Life trajectories and burden of adversity: mapping the developmental profiles of suicide mortality. Psychol. Med. 37, 1575–1383 (2007).

    PubMed  Google Scholar 

  108. Chachamovich, E., Ding, Y. & Turecki, G. Levels of aggressiveness are higher among alcohol-related suicides: results from a psychological autopsy study. Alcohol 46, 529–536 (2012).

    PubMed  Google Scholar 

  109. Coccaro, E. F. et al. Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. Arch. Gen. Psychiatry 46, 587–599 (1989).

    CAS  PubMed  Google Scholar 

  110. Freemantle, E., Chen, G. G., Cruceanu, C., Mechawar, N. & Turecki, G. Analysis of oxysterols and cholesterol in prefrontal cortex of suicides. Int. J. Neuropsychopharmacol. 16, 1241–1249 (2013).

    CAS  PubMed  Google Scholar 

  111. Lalovic, A. et al. Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers. Am. J. Psychiatry 161, 2123–2126 (2004).

    PubMed  Google Scholar 

  112. Lalovic, A. et al. Cholesterol content in brains of suicide completers. Int. J. Neuropsychopharmacol. 10, 159–166 (2007).

    CAS  PubMed  Google Scholar 

  113. Heikkinen, M., Aro, H. & Lonnqvist, J. Recent life events and their role in suicide as seen by the spouses. Acta Psychiatr. Scand. 86, 489–494 (1992).

    CAS  PubMed  Google Scholar 

  114. Qin, P., Agerbo, E. & Bo Mortensen, P. Suicide risk in relation to family history of completed suicide and psychiatric disorders: a nested case-control study based on longitudinal registers. Lancet 360, 1126–1130 (2002).

    PubMed  Google Scholar 

  115. Angst, F., Stassen, H. H., Clayton, P. J. & Angst, J. Mortality of patients with mood disorders: follow-up over 34–38 years. J. Affect. Disord. 68, 167–181 (2002).

    CAS  PubMed  Google Scholar 

  116. Asberg, M., Thoren, P., Traskman, L., Bertilsson, L. & Ringberger, V. Serotonin depression — a biochemical subgroup within the affective disorders. Science 191, 478–480 (1976). This is the first study to suggest that there is a link between alterations in the serotonergic system and suicidal behaviour.

    CAS  PubMed  Google Scholar 

  117. Stanley, M., Virgilio, J. & Gershon, S. Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science 216, 1337–1339 (1982).

    CAS  PubMed  Google Scholar 

  118. Stanley, M. & Mann, J. J. Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1, 214–216 (1983).

    CAS  PubMed  Google Scholar 

  119. Arango, V. et al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 25, 892–903 (2001).

    CAS  PubMed  Google Scholar 

  120. Miller, J. M. et al. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol. Psychiatry 74, 287–295 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Yanowitch, R. & Coccaro, E. F. The neurochemistry of human aggression. Adv. Genet. 75, 151–169 (2011).

    CAS  PubMed  Google Scholar 

  122. Brezo, J. et al. Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene–environment study. Mol. Psychiatry 15, 831–843 (2010).

    CAS  PubMed  Google Scholar 

  123. Smith, K. A., Fairburn, C. G. & Cowen, P. J. Relapse of depression after rapid depletion of tryptophan. Lancet 349, 915–919 (1997).

    CAS  PubMed  Google Scholar 

  124. Benkelfat, C., Ellenbogen, M. A., Dean, P., Palmour, R. M. & Young, S. N. Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch. Gen. Psychiatry 51, 687–697 (1994).

    CAS  PubMed  Google Scholar 

  125. Sequeira, A. et al. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Arch. Gen. Psychiatry 63, 35–48 (2006).

    CAS  PubMed  Google Scholar 

  126. Fiori, L. M. et al. Global gene expression profiling of the polyamine system in suicide completers. Int. J. Neuropsychopharmacol. 14, 595–605 (2011).

    CAS  PubMed  Google Scholar 

  127. Klempan, T. A. et al. Profiling brain expression of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene in suicide. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 934–943 (2009).

    CAS  Google Scholar 

  128. Chen, G. G. et al. Evidence of altered polyamine concentrations in cerebral cortex of suicide completers. Neuropsychopharmacology 35, 1477–1484 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Guipponi, M. et al. Genetic and epigenetic analysis of SSAT gene dysregulation in suicidal behavior. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 799–807 (2009).

    CAS  PubMed  Google Scholar 

  130. Le-Niculescu, H. et al. Discovery and validation of blood biomarkers for suicidality. Mol. Psychiatry 18, 1249–1264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Dahel, K.-d., Al-Saffar, N. & Flayeh, K. Polyamine oxidase activity in sera of depressed and schizophrenic patients after ECT treatment. Neurochem. Res. 26, 415–418 (2001).

    CAS  PubMed  Google Scholar 

  132. Karssen, A. M. et al. Stress-induced changes in primate prefrontal profiles of gene expression. Mol. Psychiatry 12, 1089–1102 (2007).

    CAS  PubMed  Google Scholar 

  133. Fiori, L. M., Gross, J. A. & Turecki, G. Effects of histone modifications on increased expression of polyamine biosynthetic genes in suicide. Int. J. Neuropsychopharmacol. 15, 1161–1166 (2012).

    CAS  PubMed  Google Scholar 

  134. Fiori, L. M. & Turecki, G. Epigenetic regulation of spermidine/spermine N1-acetyltransferase (SAT1) in suicide. J. Psychiatr. Res. 45, 1229–1235 (2011).

    PubMed  Google Scholar 

  135. Gross, J. A., Fiori, L. M., Labonte, B., Lopez, J. P. & Turecki, G. Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide. J. Psychiatr. Res. 47, 513–519 (2013).

    PubMed  Google Scholar 

  136. Lopez, J. P. et al. Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int. J. Neuropsychopharmacol. 17, 23–32 (2014).

    CAS  PubMed  Google Scholar 

  137. Sequeira, A. et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4, e6585 (2009).

    PubMed  PubMed Central  Google Scholar 

  138. Choudary, P. V. et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc. Natl Acad. Sci. USA 102, 15653–15658 (2005).

    CAS  PubMed  Google Scholar 

  139. Duman, R. S. Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections. Depress. Anxiety 31, 291–296 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int. J. Neuropsychopharmacol. 14, 1127–1131 (2011).

    CAS  PubMed  Google Scholar 

  141. Price, R. B. et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress. Anxiety 31, 335–343 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Raison, C. L., Capuron, L. & Miller, A. H. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 27, 24–31 (2006).

    CAS  PubMed  Google Scholar 

  143. Howren, M. B., Lamkin, D. M. & Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009).

    CAS  PubMed  Google Scholar 

  144. Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

    CAS  PubMed  Google Scholar 

  145. Liu, Y., Ho, R. C. & Mak, A. Interleukin (IL)-6, tumour necrosis factor-α (TNFα) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J. Affect Disord. 139, 230–239 (2012).

    CAS  PubMed  Google Scholar 

  146. Shelton, R. C. et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol. Psychiatry 16, 751–762 (2011).

    CAS  PubMed  Google Scholar 

  147. Capuron, L. & Miller, A. H. Cytokines and psychopathology: lessons from interferon-α. Biol. Psychiatry 56, 819–824 (2004).

    CAS  PubMed  Google Scholar 

  148. Musselman, D. L. et al. Paroxetine for the prevention of depression induced by high-dose interferon-α. N. Engl. J. Med. 344, 961–966 (2001).

    CAS  PubMed  Google Scholar 

  149. Raison, C. L. et al. Depression during pegylated interferon-α plus ribavirin therapy: prevalence and prediction. J. Clin. Psychiatry 66, 41–48 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Constant, A. et al. Mood alterations during interferon-α therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J. Clin. Psychiatry 66, 1050–1057 (2005).

    CAS  PubMed  Google Scholar 

  151. Serafini, G. et al. The role of inflammatory cytokines in suicidal behavior: a systematic review. Eur. Neuropsychopharmacol. 23, 1672–1686 (2013).

    CAS  PubMed  Google Scholar 

  152. Isung, J. et al. Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters. Transl. Psychiatry 2, e196 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Erhardt, S. et al. Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology 38, 743–752 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Sublette, M. E. et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav. Immun. 25, 1272–1278 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Carlborg, A., Jokinen, J., Jonsson, E. G., Erhardt, S. & Nordstrom, P. CSF kynurenic acid and suicide risk in schizophrenia spectrum psychosis. Psychiatry Res. 205, 165–167 (2013).

    CAS  PubMed  Google Scholar 

  156. Bay-Richter, C. et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav. Immun. http://dx.doi.org/10.1016/j.bbi.2014.07.012 (2014).

  157. Pandey, G. N. et al. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J. Psychiatr. Res. 46, 57–63 (2012).

    PubMed  Google Scholar 

  158. Tonelli, L. H. et al. Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatr. Scand. 117, 198–206 (2008).

    CAS  PubMed  Google Scholar 

  159. Torres-Platas, S. G., Cruceanu, C., Chen, G. G., Turecki, G. & Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. http://dx.doi.org/10.1016/j.bbi.2014.05.007 (2014).

  160. Steiner, J. et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 42, 151–157 (2008).

    PubMed  Google Scholar 

  161. Bellavance, M. A. & Rivest, S. The, H. P. A. - Immune axis and the immunomodulatory actions of glucocorticoids in the brain. Front. Immunol. 5, 136 (2014).

    PubMed  PubMed Central  Google Scholar 

  162. Ehlert, U. Enduring psychobiological effects of childhood adversity. Psychoneuroendocrinology 38, 1850–1857 (2013).

    PubMed  Google Scholar 

  163. Danese, A. et al. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch. Gen. Psychiatry 65, 409–415 (2008).

    PubMed  PubMed Central  Google Scholar 

  164. Czeh, B., Fuchs, E. & Flugge, G. Altered glial plasticity in animal models for mood disorders. Curr. Drug Targets 14, 1249–1261 (2013).

    CAS  PubMed  Google Scholar 

  165. Banasr, M. et al. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol. Psychiatry 15, 501–511 (2010).

    CAS  PubMed  Google Scholar 

  166. Rajkowska, G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777 (2000).

    CAS  PubMed  Google Scholar 

  167. Torres-Platas, S. G. et al. Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology 36, 2650–2658 (2011).

    PubMed  PubMed Central  Google Scholar 

  168. Ernst, C. et al. Dysfunction of astrocyte connexins 30 and 43 in dorsal lateral prefrontal cortex of suicide completers. Biol. Psychiatry 70, 312–319 (2011).

    CAS  PubMed  Google Scholar 

  169. Bernard, R. et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol. Psychiatry 16, 634–646 (2011).

    CAS  PubMed  Google Scholar 

  170. Dere, E. et al. Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open-field along with neurochemical changes. Eur. J. Neurosci. 18, 629–638 (2003).

    CAS  PubMed  Google Scholar 

  171. Frisch, C. et al. Mice with astrocyte-directed inactivation of connexin43 exhibit increased exploratory behaviour, impaired motor capacities, and changes in brain acetylcholine levels. Eur. J. Neurosci. 18, 2313–2318 (2003).

    PubMed  Google Scholar 

  172. Rose, C. R. et al. Truncated TRKB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426, 74–78 (2003).

    CAS  PubMed  Google Scholar 

  173. Razzoli, M. et al. A role for BDNF/TRKB signaling in behavioral and physiological consequences of social defeat stress. Genes Brain Behav. 10, 424–433 (2011).

    CAS  PubMed  Google Scholar 

  174. Roy, A. Hypothalamic–pituitary–adrenal axis function and suicidal behavior in depression. Biol. Psychiatry 32, 812–816 (1992).

    CAS  PubMed  Google Scholar 

  175. Coryell, W. & Schlesser, M. The dexamethasone suppression test and suicide prediction. Am. J. Psychiatry 158, 748–753 (2001).

    CAS  PubMed  Google Scholar 

  176. Pfeffer, C. R., Stokes, P. & Shindledecker, R. Suicidal behavior and hypothalamic–pituitary–adrenocortical axis indices in child psychiatric inpatients. Biol. Psychiatry 29, 909–917 (1991).

    CAS  PubMed  Google Scholar 

  177. Raadsheer, F. C. et al. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am. J. Psychiatry 152, 1372–1376 (1995).

    CAS  PubMed  Google Scholar 

  178. Raadsheer, F. C., Hoogendijk, W. J., Stam, F. C., Tilders, F. J. & Swaab, D. F. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60, 436–444 (1994).

    CAS  PubMed  Google Scholar 

  179. Wang, S. S., Kamphuis, W., Huitinga, I., Zhou, J. N. & Swaab, D. F. Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol. Psychiatry 13, 786–799 (2008).

    CAS  PubMed  Google Scholar 

  180. Nemeroff, C. B. et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226, 1342–1344 (1984).

    CAS  PubMed  Google Scholar 

  181. Nemeroff, C. B., Owens, M. J., Bissette, G., Andorn, A. C. & Stanley, M. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch. Gen. Psychiatry 45, 577–579 (1988).

    CAS  PubMed  Google Scholar 

  182. Lopez, J. F. et al. Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoid receptor mRNA in pituitaries of suicide victims. Neuroendocrinology 56, 491–501 (1992).

    CAS  PubMed  Google Scholar 

  183. Dumser, T., Barocka, A. & Schubert, E. Weight of adrenal glands may be increased in persons who commit suicide. Am. J. Forens. Med. Pathol. 19, 72–76 (1998).

    CAS  Google Scholar 

  184. Szigethy, E., Conwell, Y., Forbes, N. T., Cox, C. & Caine, E. D. Adrenal weight and morphology in victims of completed suicide. Biol. Psychiatry 36, 374–380 (1994).

    CAS  PubMed  Google Scholar 

  185. McGirr, A. et al. Dysregulation of the sympathetic nervous system, hypothalamic-pituitary-adrenal axis and executive function in individuals at risk for suicide. J. Psychiatry Neurosci. 35, 399–408 (2010).

    PubMed  PubMed Central  Google Scholar 

  186. Malhi, G. S., Tanious, M., Das, P., Coulston, C. M. & Berk, M. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs 27, 135–153 (2013).

    PubMed  Google Scholar 

  187. Goodwin, F. K. et al. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 290, 1467–1473 (2003).

    CAS  PubMed  Google Scholar 

  188. Cipriani, A., Hawton, K., Stockton, S. & Geddes, J. R. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 346, f3646 (2013).

    PubMed  Google Scholar 

  189. Ripke, S. et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature Genet. 45, 1150–1159 (2013).

    CAS  PubMed  Google Scholar 

  190. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Purcell, S. M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Lesch, M. & Nyhan, W. L. A. Familial disorder of uric acid metabolism and central nervous system function. Am. J. Med. 36, 561–570 (1964).

    CAS  PubMed  Google Scholar 

  193. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013). This is an important study showing that during prenatal and postnatal brain development, neurons and non-neuronal cells undergo different patterns of dynamic methylation at CpG and non-CpG sequences, as well as in 5-hydroxymethylcytosine. This work shows that there is a clear link between these methylation changes and important brain plastic changes, such as synaptogenesis.

    PubMed  PubMed Central  Google Scholar 

  196. Liang, P. et al. Genome-wide survey reveals dynamic widespread tissue-specific changes in DNA methylation during development. BMC Genomics 12, 231 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Xin, Y. et al. Genome-wide divergence of DNA methylation marks in cerebral and cerebellar cortices. PLoS ONE 5, e11357 (2010).

    PubMed  PubMed Central  Google Scholar 

  198. Xin, Y. et al. Role of CpG context and content in evolutionary signatures of brain DNA methylation. Epigenetics 6, 1308–1318 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Nakamura, N. et al. Laser capture microdissection for analysis of single cells. Methods Mol. Med. 132, 11–18 (2007).

    CAS  PubMed  Google Scholar 

  200. Jiang, Y., Matevossian, A., Huang, H. S., Straubhaar, J. & Akbarian, S. Isolation of neuronal chromatin from brain tissue. BMC Neurosci. 9, 42 (2008).

    PubMed  PubMed Central  Google Scholar 

  201. Guintivano, J., Aryee, M. J. & Kaminsky, Z. A. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics 8, 290–302 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Liu, D. et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662 (1997). This landmark study establishes a link between maternal grooming of pups and regulation of the HPA axis in offspring.

    CAS  PubMed  Google Scholar 

  203. Murgatroyd, C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neurosci. 12, 1559–1566 (2009). This important study in mice shows that ELA regulates DNA methylation of an intergenic region that regulates the activity of AVP and results in enduring hypersecretion of corticosterone and alterations in passive stress coping and memory.

    CAS  PubMed  Google Scholar 

  204. Weaver, I. C. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004). This ground-breaking study shows that maternal behaviour regulates the expression of the glucocorticoid receptor by inducing promoter methylation changes.

    CAS  PubMed  Google Scholar 

  205. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89–97 (2006).

    CAS  PubMed  Google Scholar 

  206. Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Ziller, M. J. et al. Charting a dynamic DNA methylation landscape of the human genome. Nature 500, 477–481 (2013). This study shows that only a minority of CpG nucleotides have variable levels of methylation and that they are mostly located in regulatory gene elements, such as enhancers and transcription factor-binding sites.

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Turner, J. D. & Muller, C. P. Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: identification, and tissue distribution of multiple new human exon 1. J. Mol. Endocrinol. 35, 283–292 (2005).

    CAS  PubMed  Google Scholar 

  209. McCormick, J. A. et al. 5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol. Endocrinol. 14, 506–517 (2000).

    CAS  PubMed  Google Scholar 

  210. Wu, Y., Patchev, A. V., Daniel, G., Almeida, O. F. & Spengler, D. Early-life stress reduces DNA methylation of the Pomc gene in male mice. Endocrinology 155, 1751–1762 (2014).

    PubMed  Google Scholar 

  211. Bowen, M. T. et al. Active coping towards predatory stress is associated with lower corticosterone and progesterone plasma levels and decreased methylation in the medial amygdala vasopressin system. Horm. Behav. 66, 561–566 (2014).

    CAS  PubMed  Google Scholar 

  212. Bester-Meredith, J. K., Young, L. J. & Marler, C. A. Species differences in paternal behavior and aggression in peromyscus and their associations with vasopressin immunoreactivity and receptors. Horm. Behav. 36, 25–38 (1999).

    CAS  PubMed  Google Scholar 

  213. Wersinger, S. R., Caldwell, H. K., Christiansen, M. & Young, W. S. 3rd. Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice. Genes Brain Behav. 6, 653–660 (2007).

    CAS  PubMed  Google Scholar 

  214. Wersinger, S. R., Ginns, E. I., O'Carroll, A. M., Lolait, S. J. & Young, W. S. 3rd. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry 7, 975–984 (2002).

    CAS  PubMed  Google Scholar 

  215. Barkat, T. R., Polley, D. B. & Hensch, T. K. A critical period for auditory thalamocortical connectivity. Nature Neurosci. 14, 1189–1194 (2011).

    CAS  PubMed  Google Scholar 

  216. Fisher, H. L. et al. The varying impact of type, timing and frequency of exposure to childhood adversity on its association with adult psychotic disorder. Psychol. Med. 40, 1967–1978 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Jun, H. J. et al. Child abuse and smoking among young women: the importance of severity, accumulation, and timing. J. Adolesc. Health 43, 55–63 (2008).

    PubMed  PubMed Central  Google Scholar 

  218. Blaauw, E., Arensman, E., Kraaij, V., Winkel, F. W. & Bout, R. Traumatic life events and suicide risk among jail inmates: the influence of types of events, time period and significant others. J. Trauma Stress 15, 9–16 (2002).

    CAS  PubMed  Google Scholar 

  219. Talens, R. P. et al. Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J. 24, 3135–3144 (2010).

    CAS  PubMed  Google Scholar 

  220. Ouellet-Morin, I. et al. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychol. Med. 43, 1813–1823 (2013).

    CAS  PubMed  Google Scholar 

  221. Kim, J. M. et al. A longitudinal study of SLC6A4 DNA promoter methylation and poststroke depression. J. Psychiatr. Res. 47, 1222–1227 (2013).

    PubMed  Google Scholar 

  222. Kim, J. M. et al. A longitudinal study of BDNF promoter methylation and genotype with poststroke depression. J. Affect. Disord. 149, 93–99 (2013).

    CAS  PubMed  Google Scholar 

  223. Fiori, L. M. & Turecki, G. Implication of the polyamine system in mental disorders. J. Psychiatry Neurosci. 33, 102–110 (2008).

    PubMed  PubMed Central  Google Scholar 

  224. Pegg, A. E. & Casero, R. A. Jr. Current status of the polyamine research field. Methods Mol. Biol. 720, 3–35 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Bastida, C. M. et al. Sexual dimorphism of ornithine decarboxylase in the mouse adrenal: influence of polyamine deprivation on catecholamine and corticoid levels. Am. J. Physiol. Endocrinol. Metab. 292, E1010–E1017 (2007).

    CAS  PubMed  Google Scholar 

  226. Williams, K. Modulation and block of ion channels: a new biology of polyamines. Cell. Signal. 9, 1–13 (1997).

    CAS  PubMed  Google Scholar 

  227. Brackley, P. et al. Spermine and philanthotoxin potentiate excitatory amino acid responses of Xenopus oocytes injected with rat and chick brain RNA. Neurosci. Lett. 114, 51–56 (1990).

    CAS  PubMed  Google Scholar 

  228. Galea, E., Regunathan, S., Eliopoulos, V., Feinstein, D. L. & Reis, D. J. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem. J. 316, 247–249 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Reis, D. J. & Regunathan, S. Is agmatine a novel neurotransmitter in brain? Trends Pharmacol. Sci. 21, 187–193 (2000).

    CAS  PubMed  Google Scholar 

  230. Doyle, K. M., Kirby, B. P., Murphy, D. & Shaw, G. G. Effect of L-type calcium channel antagonists on spermine-induced CNS excitation in vivo. Neurosci. Lett. 380, 247–251 (2005).

    CAS  PubMed  Google Scholar 

  231. Gilad, G. M. & Gilad, V. H. Overview of the brain polyamine-stress-response: regulation, development, and modulation by lithium and role in cell survival. Cell. Mol. Neurobiol. 23, 637–649 (2003).

    CAS  PubMed  Google Scholar 

  232. Hayashi, Y., Tanaka, J., Morizumi, Y., Kitamura, Y. & Hattori, Y. Polyamine levels in brain and plasma after acute restraint or water-immersion restraint stress in mice. Neurosci. Lett. 355, 57–60 (2004).

    CAS  PubMed  Google Scholar 

  233. Lee, M., Wynder, C., Schmidt, D., McCafferty, D. & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563–570 (2006).

    CAS  PubMed  Google Scholar 

  234. Piletz, J. E. et al. Agmatine: clinical applications after 100 years in translation. Drug Discov. Today 18, 880–893 (2013).

    CAS  PubMed  Google Scholar 

  235. Gupta, N., Zhang, H. & Liu, P. Behavioral and neurochemical effects of acute putrescine depletion by difluoromethylornithine in rats. Neuroscience 161, 691–706 (2009).

    CAS  PubMed  Google Scholar 

  236. Shopsin, B. The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta Neuropsychiatr. 25, 113–118 (2013).

    PubMed  Google Scholar 

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Acknowledgements

Preparation of this Review was supported by grants from the Canadian Institute of Health Research (CIHR), MOP119429 and MOP119430, and by the Fonds de Recherche du Québec – Santé (FRQS), through a Chercheur National salary award to the author and through support to the Réseau québécois sur le suicide, les troubles de l'humeur et les troubles associés (RQSHA). The author is indebted to S. Daniels for expert and essential help in the preparation of this Review.

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Genome-wide studies on genes contributing to suicidal behaviour (PDF 291 kb)

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Association between methylation of the GR-encoding gene, early-life adversity and suicidal behaviour (PDF 200 kb)

Glossary

Suicidality

This broad term encompasses all forms of suicidal behaviour and suicidal ideation.

Suicidal ideation

This term describes the wish to die, including thoughts of actively ending one's life.

Suicidal behaviour

This term describes behaviours that result in self-injury and is generally used to refer to suicide attempts and suicide completion.

Self-harm

This broad term includes suicidal behaviour and non-suicidal self-injurious behaviours.

Non-suicidal self-injurious behaviours

Deliberate self-injury, often in the form of superficial skin cuts that are made with the intent to decrease emotional pain rather than to die.

Suicidal behaviour disorder

This disorder has recently been proposed as a condition for further study in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and is defined by the occurrence of at least one suicide attempt with some intent to die within the last 24 months. Conditions for further study in the DSM are disorders that should be investigated and considered for its future versions.

Suicidal crisis

Period when suicidal ideation becomes acute, which is often associated with emotional instability.

Distal risk factors

Predisposing factors that occur or are expressed temporally distant from the onset of the phenotype.

Early-life adversity

(ELA). Acts by a parent or caregiver that result in physical, sexual and/or psychological abuse of a child or that lead to neglect of essential physical or psychological needs of childhood.

Treatment-emergent suicidal events

This term describes suicidal ideation or suicidal behaviour that occurs in association with treatment and is a common term used in clinical trials of antidepressants.

Childhood sexual abuse

Any completed or attempted sexual act, or exposure to sexual interactions, with or without physical contact, with a child by a caregiver.

Childhood physical abuse

The intentional use of physical force against a child that results in, or has the potential to result in, physical injury.

Parental neglect

Failure to meet a child's basic physical, emotional, medical or dental, or educational needs, or a failure to ensure a child's safety.

Attachment styles

Stereotypical interpersonal styles that are rooted in early-life interactions with caregivers.

Biological embedding

The effects of early-life experiences on the differential regulation of biological systems and development.

Mediators

Variables that can fully or partially explain the relationship between a predictor and a dependent variable.

Endophenotypes

Traits that associate with an illness in the population, are heritable, state independent, and co-segregate with the condition investigated and are present in non-affected family members of affected individuals at a higher rate than in the general population.

Impulsive aggressive behaviours

The tendency to react with animosity or overt hostility without consideration of the possible consequences when piqued or under stress.

Proximal risk factors

Precipitating factors that occur or are expressed temporally close to the onset of the phenotype.

State markers

Biological, psychological, behavioural or clinical markers associated with a given phenotype.

Trait markers

Biological, psychological, behavioural or clinical markers that indicate a predisposition to or risk of a given phenotype.

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Turecki, G. The molecular bases of the suicidal brain. Nat Rev Neurosci 15, 802–816 (2014). https://doi.org/10.1038/nrn3839

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