Abstract
Suicide is a major public health concern and a leading cause of death in most societies. Suicidal behaviour is complex and heterogeneous, likely resulting from several causes. It associates with multiple factors, including psychopathology, personality traits, early-life adversity and stressful life events, among others. Over the past decades, studies in fields ranging from neuroanatomy, genetics and molecular psychiatry have led to a model whereby behavioural dysregulation, including suicidal behaviour (SB), develops as a function of biological adaptations in key brain systems. More recently, the unravelling of the unique epigenetic processes that occur in the brain has opened promising avenues in suicide research. The present review explores the various facets of the current knowledge on suicidality and discusses how the rapidly evolving field of neurobehavioural epigenetics may fuel our ability to understand, and potentially prevent, SB.
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References
Mental health: suicide prevention. Available at http://www.who.int/mental_health/suicide-prevention/en/ (accessed date 2014).
Borges G, Nock MK, Haro Abad JM, Hwang I, Sampson NA, Alonso J et al. Twelve-month prevalence of and risk factors for suicide attempts in the World Health Organization World Mental Health Surveys. J Clin Psychiatry 2010; 71: 1617–1628.
Nock MK, Green JG, Hwang I, McLaughlin KA, Sampson NA, Zaslavsky AM et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry 2013; 70: 300–310.
Nock MK, Hwang I, Sampson N, Kessler RC, Angermeyer M, Beautrais A et al. Cross-national analysis of the associations among mental disorders and suicidal behavior: findings from the WHO World Mental Health Surveys. PLoS Med 2009; 6: e1000123.
Turecki G, Brent DA . Suicide and suicidal behaviour. Lancet 2016; 387: 1227–1239.
Arsenault-Lapierre G, Kim C, Turecki G . Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC Psychiatry 2004; 4: 37.
Hoertel N, Franco S, Wall MM, Oquendo MA, Kerridge BT, Limosin F et al. Mental disorders and risk of suicide attempt: a national prospective study. Mol Psychiatry 2015; 20: 718–726.
Hor K, Taylor M . Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 2010; 24 (4 Suppl): 81–90.
Holma KM, Haukka J, Suominen K, Valtonen HM, Mantere O, Melartin TK et al. Differences in incidence of suicide attempts between bipolar I and II disorders and major depressive disorder. Bipolar Disord 2014; 16: 652–661.
McGirr A, Renaud J, Seguin M, Alda M, Turecki G . Course of major depressive disorder and suicide outcome: a psychological autopsy study. J Clin Psychiatry 2008; 69: 966–970.
Holma KM, Melartin TK, Haukka J, Holma IA, Sokero TP, Isometsa ET . Incidence and predictors of suicide attempts in DSM-IV major depressive disorder: a five-year prospective study. Am J Psychiatry 2010; 167: 801–808.
Sokero TP, Melartin TK, Rytsala HJ, Leskela US, Lestela-Mielonen PS, Isometsa ET . Prospective study of risk factors for attempted suicide among patients with DSM-IV major depressive disorder. Br J Psychiatry 2005; 186: 314–318.
Brezo J, Bureau A, Merette C, Jomphe V, Barker ED, Vitaro F et al. Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study. Mol Psychiatry 2010; 15: 831–843.
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–389.
Brent DA, Bridge J, Johnson BA, Connolly J . Suicidal behavior runs in families. A controlled family study of adolescent suicide victims. Arch Gen Psychiatry 1996; 53: 1145–1152.
McGirr A, Alda M, Seguin M, Cabot S, Lesage A, Turecki G . Familial aggregation of suicide explained by cluster B traits: a three-group family study of suicide controlling for major depressive disorder. Am J Psychiatry 2009; 166: 1124–1134.
O'Connor RC, Nock MK . The psychology of suicidal behaviour. Lancet Psychiatry 2014; 1: 73–85.
Van Orden KA, Witte TK, Cukrowicz KC, Braithwaite SR, Selby EA, Joiner TE Jr . The interpersonal theory of suicide. Psychol Rev 2010; 117: 575–600.
Mann JJ . Neurobiology of suicidal behaviour. Nat Rev Neurosci 2003; 4: 819–828.
Moscicki EK . Gender differences in completed and attempted suicides. Ann Epidemiol 1994; 4: 152–158.
Turecki G . The molecular bases of the suicidal brain. Nat Rev Neurosci 2014; 15: 802–816.
van Heeringen K, Mann JJ . The neurobiology of suicide. Lancet Psychiatry 2014; 1: 63–72.
Oquendo MA, Sullivan GM, Sudol K, Baca-Garcia E, Stanley BH, Sublette ME et al. Toward a biosignature for suicide. Am J Psychiatry 2014; 171: 1259–1277.
Egeland JA, Sussex JN . Suicide and family loading for affective disorders. JAMA 1985; 254: 915–918.
Tidemalm D, Runeson B, Waern M, Frisell T, Carlstrom E, Lichtenstein P et al. Familial clustering of suicide risk: a total population study of 11.4 million individuals. Psychol Med 2011; 41: 2527–2534.
Fu Q, Heath AC, Bucholz KK, Nelson EC, Glowinski AL, Goldberg J et al. A twin study of genetic and environmental influences on suicidality in men. Psychol Med 2002; 32: 11–24.
Statham DJ, Heath AC, Madden PA, Bucholz KK, Bierut L, Dinwiddie SH et al. Suicidal behaviour: an epidemiological and genetic study. Psychol Med 1998; 28: 839–855.
Pedersen NL, Fiske A . Genetic influences on suicide and nonfatal suicidal behavior: twin study findings. Eur Psychiatry 2010; 25: 264–267.
Brent DA, Melhem NM, Oquendo M, Burke A, Birmaher B, Stanley B et al. Familial pathways to early-onset suicide attempt: a 5.6-year prospective study. JAMA Psychiatry 2015; 72: 160–168.
Brent DA, Oquendo M, Birmaher B, Greenhill L, Kolko D, Stanley B et al. Familial transmission of mood disorders: convergence and divergence with transmission of suicidal behavior. J Am Acad Child Adolesc Psychiatry 2004; 43: 1259–1266.
Kim CD, Seguin M, Therrien N, Riopel G, Chawky N, Lesage AD et al. Familial aggregation of suicidal behavior: a family study of male suicide completers from the general population. Am J Psychiatry 2005; 162: 1017–1019.
Sokolowski M, Wasserman J, Wasserman D . An overview of the neurobiology of suicidal behaviors as one meta-system. Mol Psychiatry 2015; 20: 56–71.
Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry 2003; 8: 646–653.
Brezo J, Klempan T, Turecki G . The genetics of suicide: a critical review of molecular studies. Psychiatr Clin North Am 2008; 31: 179–203.
Mann JJ . The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci 2013; 368: 20120537.
Dwivedi Y . Brain-derived neurotrophic factor and suicide pathogenesis. Ann Med 2010; 42: 87–96.
Mirkovic B, Laurent C, Podlipski MA, Frebourg T, Cohen D, Gerardin P . Genetic association studies of suicidal behavior: a review of the past 10 years, progress, limitations, and future directions. Front Psychiatry 2016; 7: 158.
Galfalvy H, Zalsman G, Huang YY, Murphy L, Rosoklija G, Dwork AJ et al. A pilot genome wide association and gene expression array study of suicide with and without major depression. World J Biol Psychiatry 2013; 14: 574–582.
Galfalvy H, Haghighi F, Hodgkinson C, Goldman D, Oquendo MA, Burke A et al. A genome-wide association study of suicidal behavior. Am J Med Genet B Neuropsychiatr Genet 2015; 168: 557–563.
Laje G, Allen AS, Akula N, Manji H, John Rush A, McMahon FJ . Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients. Pharmacogenet Genomics 2009; 19: 666–674.
Perlis RH, Huang J, Purcell S, Fava M, Rush AJ, Sullivan PF et al. Genome-wide association study of suicide attempts in mood disorder patients. Am J Psychiatry 2010; 167: 1499–1507.
Schosser A, Butler AW, Ising M, Perroud N, Uher R, Ng MY et al. Genomewide association scan of suicidal thoughts and behaviour in major depression. PLoS ONE 2011; 6: e20690.
Menke A, Domschke K, Czamara D, Klengel T, Hennings J, Lucae S et al. Genome-wide association study of antidepressant treatment-emergent suicidal ideation. Neuropsychopharmacology 2012; 37: 797–807.
Perroud N, Uher R, Ng MY, Guipponi M, Hauser J, Henigsberg N et al. Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenomics J 2012; 12: 68–77.
Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M, Steele J et al. A genome-wide association study of attempted suicide. Mol Psychiatry 2012; 17: 433–444.
Mullins N, Perroud N, Uher R, Butler AW, Cohen-Woods S, Rivera M et al. Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: a genome-wide association and polygenic scoring study. Am J Med Genet B Neuropsychiatr Genet 2014; 165b: 428–437.
Zai CC, Goncalves VF, Tiwari AK, Gagliano SA, Hosang G, de Luca V et al. A genome-wide association study of suicide severity scores in bipolar disorder. J Psychiatr Res 2015; 65: 23–29.
Sokolowski M, Wasserman J, Wasserman D . Polygenic associations of neurodevelopmental genes in suicide attempt. Mol Psychiatry 2016; 21: 1381–1390.
Bani-Fatemi A, Graff A, Zai C, Strauss J, De Luca V . GWAS analysis of suicide attempt in schizophrenia: main genetic effect and interaction with early life trauma. Neurosci Lett 2016; 622: 102–106.
Pocock R, Mione M, Hussain S, Maxwell S, Pontecorvi M, Aslam S et al. Neuronal function of Tbx20 conserved from nematodes to vertebrates. Dev Biol 2008; 317: 671–685.
Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.
Fergusson DM, Woodward LJ, Horwood LJ . Risk factors and life processes associated with the onset of suicidal behaviour during adolescence and early adulthood. Psychol Med 2000; 30: 23–39.
Smith PN, Gamble SA, Cort NA, Ward EA, Conwell Y, Talbot NL . The relationships of attachment style and social maladjustment to death ideation in depressed women with a history of childhood sexual abuse. J Clin Psychol 2012; 68: 78–87.
Brezo J, Paris J, Vitaro F, Hebert M, Tremblay RE, Turecki G . Predicting suicide attempts in young adults with histories of childhood abuse. Br J Psychiatry 2008; 193: 134–139.
Wanner B, Vitaro F, Tremblay RE, Turecki G . Childhood trajectories of anxiousness and disruptiveness explain the association between early-life adversity and attempted suicide. Psychol Med 2012; 42: 2373–2382.
Brezo J, Paris J, Barker ED, Tremblay R, Vitaro F, Zoccolillo M et al. Natural history of suicidal behaviors in a population-based sample of young adults. Psychol Med 2007; 37: 1563–1574.
Lopez-Castroman J, Jaussent I, Beziat S, Genty C, Olie E, de Leon-Martinez V et al. Suicidal phenotypes associated with family history of suicidal behavior and early traumatic experiences. J Affect Disord 2012; 142: 193–199.
Lopez-Castroman J, Melhem N, Birmaher B, Greenhill L, Kolko D, Stanley B et al. Early childhood sexual abuse increases suicidal intent. World Psychiatry 2013; 12: 149–154.
Turecki G, Ota VK, Belangero SI, Jackowski A, Kaufman J . Early life adversity, genomic plasticity, and psychopathology. Lancet Psychiatry 2014; 1: 461–466.
Labonte B, Suderman M, Maussion G, Lopez JP, Navarro-Sanchez L, Yerko V et al. Genome-wide methylation changes in the brains of suicide completers. Am J Psychiatry 2013; 170: 511–520.
Schneider E, El Hajj N, Muller F, Navarro B, Haaf T . Epigenetic dysregulation in the prefrontal cortex of suicide completers. Cytogenet Genome Res 2015; 146: 19–27.
Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C et al. Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Mol Psychiatry 2015; 20: 320–328.
Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V . ‘Serotonin depression’—a biochemical subgroup within the affective disorders? Science 1976; 191: 478–480.
Boldrini M, Underwood MD, Mann JJ, Arango V . Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. J Psychiatr Res 2008; 42: 433–442.
Bach H, Arango V . Neuroanatomy of serotonergic abnormalities in suicide. In: Dwivedi Y (ed). The Neurobiological Basis of Suicide. Boca Raton (FL), USA, 2012.
Kaufman J, Sullivan GM, Yang J, Ogden RT, Miller JM, Oquendo MA et al. Quantification of the serotonin 1A receptor using PET: identification of a potential biomarker of major depression in males. Neuropsychopharmacology 2015; 40: 1692–1699.
Antypa N, Serretti A, Rujescu D . Serotonergic genes and suicide: a systematic review. Eur Neuropsychopharmacol 2013; 23: 1125–1142.
Sudol K, Mann JJ . Biomarkers of suicide attempt behavior: towards a biological model of risk. Curr Psychiatry Rep 2017; 19: 31.
Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S et al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001; 25: 892–903.
Boldrini M, Underwood MD, Mann JJ, Arango V . More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res 2005; 1041: 19–28.
Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H et al. Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 2006; 31: 814–824.
Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ et al. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 2007; 34: 865–877.
Bach-Mizrachi H, Underwood MD, Tin A, Ellis SP, Mann JJ, Arango V . Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides. Mol Psychiatry 2008; 13: 507–513, 465.
Sullivan GM, Oquendo MA, Milak M, Miller JM, Burke A, Ogden RT et al. Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. JAMA Psychiatry 2015; 72: 169–178.
Wang L, Zhou C, Zhu D, Wang X, Fang L, Zhong J et al. Serotonin-1A receptor alterations in depression: a meta-analysis of molecular imaging studies. BMC Psychiatry 2016; 16: 319.
Jokinen J, Nordstrom AL, Nordstrom P . CSF 5-HIAA and DST non-suppression—orthogonal biologic risk factors for suicide in male mood disorder inpatients. Psychiatry Res 2009; 165: 96–102.
Miller JM, Hesselgrave N, Ogden RT, Sullivan GM, Oquendo MA, Mann JJ et al. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol Psychiatry 2013; 74: 287–295.
Arango V, Underwood MD, Mann JJ . Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 2002; 136: 443–453.
Lopez-Castroman J, Jaussent I, Beziat S, Guillaume S, Baca-Garcia E, Genty C et al. Increased severity of suicidal behavior in impulsive aggressive patients exposed to familial adversities. Psychol Med 2014; 44: 3059–3068.
Dracheva S, Patel N, Woo DA, Marcus SM, Siever LJ, Haroutunian V . Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. Mol Psychiatry 2008; 13: 1001–1010.
Schmauss C . Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing. Neuroscientist 2003; 9: 237–242.
Bjork K, Svenningsson P . Modulation of monoamine receptors by adaptor proteins and lipid rafts: role in some effects of centrally acting drugs and therapeutic agents. Annu Rev Pharmacol Toxicol 2011; 51: 211–242.
Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N . Identification of the cortical neurons that mediate antidepressant responses. Cell 2012; 149: 1152–1163.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006; 311: 77–80.
Lutz PE . Multiple serotonergic paths to antidepressant efficacy. J Neurophysiol 2013; 109: 2245–2249.
Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 2007; 55: 712–725.
Schildkraut JJ . The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122: 509–522.
Ordway GA, Smith KS, Haycock JW . Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims. J Neurochem 1994; 62: 680–685.
Zhu MY, Klimek V, Dilley GE, Haycock JW, Stockmeier C, Overholser JC et al. Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry 1999; 46: 1275–1286.
Biegon A, Fieldust S . Reduced tyrosine hydroxylase immunoreactivity in locus coeruleus of suicide victims. Synapse 1992; 10: 79–82.
Arango V, Underwood MD, Mann JJ . Fewer pigmented locus coeruleus neurons in suicide victims: preliminary results. Biol Psychiatry 1996; 39: 112–120.
Baumann B, Danos P, Diekmann S, Krell D, Bielau H, Geretsegger C et al. Tyrosine hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed non-suicidal patients but normal in depressed suicide patients. Eur Arch Psychiatry Clin Neurosci 1999; 249: 212–219.
Syed A, Chatfield M, Matthews F, Harrison P, Brayne C, Esiri MM . Depression in the elderly: pathological study of raphe and locus ceruleus. Neuropathol Appl Neurobiol 2005; 31: 405–413.
Chandley MJ, Szebeni K, Szebeni A, Crawford J, Stockmeier CA, Turecki G et al. Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder. J Psychiatry Neurosci 2013; 38: 276–284.
Chandley MJ, Szebeni A, Szebeni K, Crawford JD, Stockmeier CA, Turecki G et al. Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int J Neuropsychopharmacol 2014; 17: 1569–1578.
Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 2004; 56: 640–650.
Videbech P, Ravnkilde B . Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004; 161: 1957–1966.
Sheline YI, Gado MH, Kraemer HC . Untreated depression and hippocampal volume loss. Am J Psychiatry 2003; 160: 1516–1518.
Dranovsky A, Hen R . Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 2006; 59: 1136–1143.
Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci 2007; 27: 4894–4901.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.
Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry 2011; 16: 1177–1188.
Hill AS, Sahay A, Hen R . Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology 2015; 40: 2368–2378.
Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 2009; 34: 2376–2389.
Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 2012; 72: 562–571.
Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology 2013; 38: 1068–1077.
Bielau H, Steiner J, Mawrin C, Trubner K, Brisch R, Meyer-Lotz G et al. Dysregulation of GABAergic neurotransmission in mood disorders: a postmortem study. Ann NY Acad Sci 2007; 1096: 157–169.
Law AJ, Harrison PJ . The distribution and morphology of prefrontal cortex pyramidal neurons identified using anti-neurofilament antibodies SMI32, N200 and FNP7. Normative data and a comparison in subjects with schizophrenia, bipolar disorder or major depression. J Psychiatr Res 2003; 37: 487–499.
Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 1999; 45: 1085–1098.
Rajkowska G, O'Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ . GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 2007; 32: 471–482.
Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 2009; 4: e6585.
Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 2005; 102: 15653–15658.
Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, ffrench-Mullen J et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry 2009; 14: 175–189.
Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F . Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 2000; 47: 305–313.
Mirza Y, Tang J, Russell A, Banerjee SP, Bhandari R, Ivey J et al. Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. J Am Acad Child Adolesc Psychiatry 2004; 43: 341–348.
Frye MA, Watzl J, Banakar S, O'Neill J, Mintz J, Davanzo P et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology 2007; 32: 2490–2499.
Ballmaier M, Toga AW, Blanton RE, Sowell ER, Lavretsky H, Peterson J et al. Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. Am J Psychiatry 2004; 161: 99–108.
Coryell W, Nopoulos P, Drevets W, Wilson T, Andreasen NC . Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. Am J Psychiatry 2005; 162: 1706–1712.
Konarski JZ, McIntyre RS, Kennedy SH, Rafi-Tari S, Soczynska JK, Ketter TA . Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord 2008; 10: 1–37.
Bremner JD, Vythilingam M, Vermetten E, Vaccarino V, Charney DS . Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression. Am J Psychiatry 2004; 161: 637–645.
Mannie ZN, Norbury R, Murphy SE, Inkster B, Harmer CJ, Cowen PJ . Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression. Br J Psychiatry 2008; 192: 356–361.
Holmes AJ, Pizzagalli DA . Response conflict and frontocingulate dysfunction in unmedicated participants with major depression. Neuropsychologia 2008; 46: 2904–2913.
Bunge SA, Klingberg T, Jacobsen RB, Gabrieli JD . A resource model of the neural basis of executive working memory. Proc Natl Acad Sci USA 2000; 97: 3573–3578.
Zhang JX, Leung HC, Johnson MK . Frontal activations associated with accessing and evaluating information in working memory: an fMRI study. Neuroimage 2003; 20: 1531–1539.
Herman JP, Ostrander MM, Mueller NK, Figueiredo H . Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1201–1213.
Drevets WC . Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48: 813–829.
Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord 2009; 112: 206–211.
Vasic N, Walter H, Sambataro F, Wolf RC . Aberrant functional connectivity of dorsolateral prefrontal and cingulate networks in patients with major depression during working memory processing. Psychol Med 2009; 39: 977–987.
Grieve SM, Korgaonkar MS, Koslow SH, Gordon E, Williams LM . Widespread reductions in gray matter volume in depression. Neuroimage Clin 2013; 3: 332–339.
Hercher C, Canetti L, Turecki G, Mechawar N . Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides. J Psychiatr Res 2010; 44: 286–293.
Poulter MO, Du L, Zhurov V, Palkovits M, Faludi G, Merali Z et al. Altered organization of GABA(A) receptor mRNA expression in the depressed suicide brain. Front Mol Neurosci 2010; 3: 3.
Yin H, Pantazatos SP, Galfalvy H, Huang YY, Rosoklija GB, Dwork AJ et al. A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 2016; 171b: 414–426.
Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry 2008; 64: 645–652.
Gray AL, Hyde TM, Deep-Soboslay A, Kleinman JE, Sodhi MS . Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry 2015; 20: 1057–1068.
Zhao J, Verwer RW, van Wamelen DJ, Qi XR, Gao SF, Lucassen PJ et al. Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide. J Psychiatr Res 2016; 82: 8–15.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354.
McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW . A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2015; 45: 693–704.
Zarate CA Jr ., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856–864.
Price RB, Nock MK, Charney DS, Mathew SJ . Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66: 522–526.
Rajkumar R, Fam J, Yeo EY, Dawe GS . Ketamine and suicidal ideation in depression: jumping the gun? Pharmacol Res 2015; 99: 23–35.
Ionescu DF, Swee MB, Pavone KJ, Taylor N, Akeju O, Baer L et al. Rapid and sustained reductions in current suicidal ideation following repeated doses of intravenous ketamine: secondary analysis of an open-label study. J Clin Psychiatry 2016; 77: e719–e725.
Stenovec M, Lasic E, Bozic M, Bobnar ST, Stout RF Jr ., Grubisic V et al. Ketamine inhibits ATP-evoked exocytotic release of brain-derived neurotrophic factor from vesicles in cultured rat astrocytes. Mol Neurobiol 2015; 53: 6882–6896.
Grieco SF, Cheng Y, Eldar-Finkelman H, Jope RS, Beurel E . Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition. Prog Neuropsychopharmacol Biol Psychiatry 2017; 72: 49–54.
Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry 2016; 80: 457–468.
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533: 481–486.
Beurel E, Grieco SF, Amadei C, Downey K, Jope RS . Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord 2016; 18: 473–480.
Grieco SF, Velmeshev D, Magistri M, Eldar-Finkelman H, Faghihi MA, Jope RS et al. Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3. World J Biol Psychiatry e-pub ahead of print 10 October 2016.
Janak PH, Tye KM . From circuits to behaviour in the amygdala. Nature 2015; 517: 284–292.
Sheline YI, Gado MH, Price JL . Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport 1998; 9: 2023–2028.
Monkul ES, Hatch JP, Nicoletti MA, Spence S, Brambilla P, Lacerda AL et al. Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Mol Psychiatry 2007; 12: 360–366.
Rubinow MJ, Mahajan G, May W, Overholser JC, Jurjus GJ, Dieter L et al. Basolateral amygdala volume and cell numbers in major depressive disorder: a postmortem stereological study. Brain Struct Funct 2016; 221: 171–184.
Maheu ME, Davoli MA, Turecki G, Mechawar N . Amygdalar expression of proteins associated with neuroplasticity in major depression and suicide. J Psychiatr Res 2013; 47: 384–390.
Douillard-Guilloux G, Lewis D, Seney ML, Sibille E . Decrease in somatostatin-positive cell density in the amygdala of females with major depression. Depress Anxiety 2016; 34: 68–78.
Cotter D, Landau S, Beasley C, Stevenson R, Chana G, MacMillan L et al. The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia. Biol Psychiatry 2002; 51: 377–386.
Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI . Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 2004; 67: 269–275.
Rajkowska G, Mahajan G, Maciag D, Sathyanesan M, Iyo AH, Moulana M et al. Oligodendrocyte morphometry and expression of myelin-related mRNA in ventral prefrontal white matter in major depressive disorder. J Psychiatr Res 2015; 65: 53–62.
Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 2008; 42: 151–157.
Ongur D, Drevets WC, Price JL . Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998; 95: 13290–13295.
Hercher C, Parent M, Flores C, Canetti L, Turecki G, Mechawar N . Alcohol dependence-related increase of glial cell density in the anterior cingulate cortex of suicide completers. J Psychiatry Neurosci 2009; 34: 281–288.
Bowley MP, Drevets WC, Ongur D, Price JL . Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 2002; 52: 404–412.
Hamidi M, Drevets WC, Price JL . Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry 2004; 55: 563–569.
Maheu M, Lopez JP, Crapper L, Davoli MA, Turecki G, Mechawar N . MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression. Transl Psychiatry 2015; 5: e511.
Wilkins A, Majed H, Layfield R, Compston A, Chandran S . Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci 2003; 23: 4967–4974.
Colombo E, Farina C . Astrocytes: key regulators of neuroinflammation. Trends Immunol 2016; 37: 608–620.
Oberheim NA, Goldman SA, Nedergaard M . Heterogeneity of astrocytic form and function. Methods Mol Biol 2012; 814: 23–45.
Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman RS, Behar KL 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 2010; 15: 501–511.
Czeh B, Fuchs E, Flugge G . Altered glial plasticity in animal models for mood disorders. Curr Drug Targets 2013; 14: 1249–1261.
Torres-Platas SG, Cruceanu C, Chen GG, 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 2014; 42: 50–59.
Schnieder TP, Trencevska I, Rosoklija G, Stankov A, Mann JJ, Smiley J et al. Microglia of prefrontal white matter in suicide. J Neuropathol Exp Neurol 2014; 73: 880–890.
Torres-Platas SG, Hercher C, Davoli MA, Maussion G, Labonte B, Turecki G et al. Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology 2011; 36: 2650–2658.
Mechawar N, Savitz J . Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry 2016; 6: e946.
Torres-Platas SG, Nagy C, Wakid M, Turecki G, Mechawar N . Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry 2016; 21: 509–515.
Ernst C, Nagy C, Kim S, Yang JP, Deng X, Hellstrom IC et al. Dysfunction of astrocyte connexins 30 and 43 in dorsal lateral prefrontal cortex of suicide completers. Biol Psychiatry 2011; 70: 312–319.
Ezan P, Andre P, Cisternino S, Saubamea B, Boulay AC, Doutremer S et al. Deletion of astroglial connexins weakens the blood-brain barrier. J Cereb Blood Flow Metab 2012; 32: 1457–1467.
Ventorp F, Barzilay R, Erhardt S, Samuelsson M, Traskman-Bendz L, Janelidze S et al. The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability. J Affect Disord 2016; 193: 349–354.
Muller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ, Holsboer F, Swaab DF . Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci 2001; 14: 1603–1612.
Cobb JA, O'Neill K, Milner J, Mahajan GJ, Lawrence TJ, May WL et al. Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience 2016; 316: 209–220.
Brundin L, Bryleva EY, Thirtamara Rajamani K . Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacology 2016; 42: 271–283.
Courtet P, Giner L, Seneque M, Guillaume S, Olie E, Ducasse D . Neuroinflammation in suicide: toward a comprehensive model. World J Biol Psychiatry 2015; 1–23.
Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.
Kayser MS, Dalmau J . The emerging link between autoimmune disorders and neuropsychiatric disease. J Neuropsychiatry Clin Neurosci 2011; 23: 90–97.
Egeberg A, Hansen PR, Gislason GH, Skov L, Mallbris L . Risk of self-harm and nonfatal suicide attempts, and completed suicide in patients with psoriasis: a population-based cohort study. Br J Dermatol 2016; 175: 493–500.
Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58: 445–452.
Capuron L, Miller AH . Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56: 819–824.
Lindqvist D, Janelidze S, Hagell P, Erhardt S, Samuelsson M, Minthon L et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry 2009; 66: 287–292.
Janelidze S, Suchankova P, Ekman A, Erhardt S, Sellgren C, Samuelsson M et al. Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels. Acta Psychiatr Scand 2014; 131: 269–278.
Black C, Miller BJ . Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients. Biol Psychiatry 2015; 78: 28–37.
Janelidze S, Mattei D, Westrin A, Traskman-Bendz L, Brundin L . Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav Immun 2011; 25: 335–339.
Serafini G, Pompili M, Elena Seretti M, Stefani H, Palermo M, Coryell W et al. The role of inflammatory cytokines in suicidal behavior: a systematic review. Eur Neuropsychopharmacol 2013; 23: 1672–1686.
Isung J, Mobarrez F, Nordstrom P, Asberg M, Jokinen J . Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide. World J Biol Psychiatry 2012; 13: 468–473.
Erhardt S, Lim CK, Linderholm KR, Janelidze S, Lindqvist D, Samuelsson M et al. Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology 2013; 38: 743–752.
Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun 2011; 25: 1272–1278.
Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT . Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen Psychiatry 2012; 69: 1123–1130.
Arling TA, Yolken RH, Lapidus M, Langenberg P, Dickerson FB, Zimmerman SA et al. Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders. J Nerv Mental Dis 2009; 197: 905–908.
Cook TB, Brenner LA, Cloninger CR, Langenberg P, Igbide A, Giegling I et al. ‘Latent’ infection with Toxoplasma gondii: association with trait aggression and impulsivity in healthy adults. J Psychiatr Res 2015; 60: 87–94.
Flegr J . How and why Toxoplasma makes us crazy. Trends Parasitol 2013; 29: 156–163.
Okusaga O, Duncan E, Langenberg P, Brundin L, Fuchs D, Groer MW et al. Combined Toxoplasma gondii seropositivity and high blood kynurenine—linked with nonfatal suicidal self-directed violence in patients with schizophrenia. J Psychiatr Res 2016; 72: 74–81.
Sugden K, Moffitt TE, Pinto L, Poulton R, Williams BS, Caspi A . Is Toxoplasma gondii infection related to brain and behavior impairments in humans? Evidence from a population-representative birth cohort. PLoS ONE 2016; 11: e0148435.
Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Traskman-Bendz L, Guillemin GJ et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality. Brain Behav Immun 2014; 43: 110–117.
Pandey GN, Rizavi HS, Ren X, Fareed J, Hoppensteadt DA, Roberts RC et al. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res 2012; 46: 57–63.
Tonelli LH, Stiller J, Rujescu D, Giegling I, Schneider B, Maurer K et al. Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatr Scand 2008; 117: 198–206.
Ossipov MH, Dussor GO, Porreca F . Central modulation of pain. J Clin Invest 2010; 120: 3779–3787.
Russo SJ, Nestler EJ . The brain reward circuitry in mood disorders. Nat Rev Neurosci 2013; 14: 609–625.
Lutz PE, Kieffer BL . Opioid receptors: distinct roles in mood disorders. Trends Neurosci 2013; 36: 195–206.
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: 1512–1521.
Gabilondo AM, Meana JJ, Garcia-Sevilla JA . Increased density of mu-opioid receptors in the postmortem brain of suicide victims. Brain Res 1995; 682: 245–250.
Gross-Isseroff R, Dillon KA, Israeli M, Biegon A . Regionally selective increases in mu opioid receptor density in the brains of suicide victims. Brain Res 1990; 530: 312–316.
Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA et al. Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Arch Gen Psychiatry 2003; 60: 1145–1153.
Kennedy SE, Koeppe RA, Young EA, Zubieta JK . Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry 2006; 63: 1199–1208.
Hurd YL, Herman MM, Hyde TM, Bigelow LB, Weinberger DR, Kleinman JE . Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects. Mol Psychiatry 1997; 2: 495–500.
Hurd YL . Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex. Mol Psychiatry 2002; 7: 75–81.
Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng MQ, Stein MB et al. Association of in vivo kappa-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry 2014; 71: 1262–1270.
Lutz PE, Zhou Y, Labbe A, Mechawar N, Turecki G . Decreased expression of nociceptin/orphanin FQ in the dorsal anterior cingulate cortex of suicides. Eur Neuropsychopharmacol 2015; 25: 2008–2014.
Eisenberger NI . The pain of social disconnection: examining the shared neural underpinnings of physical and social pain. Nat Rev Neurosci 2012; 13: 421–434.
Elman I, Borsook D, Volkow ND . Pain and suicidality: Insights from reward and addiction neuroscience. Prog Neurobiol 2013; 109C: 1–27.
Stanley B, Sher L, Wilson S, Ekman R, Huang YY, Mann JJ . Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters. J Affect Disord 2010; 124: 134–140.
Kirtley OJ, O'Carroll RE, O'Connor RC . The role of endogenous opioids in non-suicidal self-injurious behavior: methodological challenges. Neurosci Biobehav Rev 2015; 48: 186–189.
Sher L, Stanley BH . The role of endogenous opioids in the pathophysiology of self-injurious and suicidal behavior. Arch Suicide Res 2008; 12: 299–308.
Yovell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry 2015; 173: 491–498.
Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer M et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry 2016; 173: 499–508.
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN . Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60: 804–815.
Banerjee R, Ghosh AK, Ghosh B, Bhattacharyya S, Mondal AC . 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 2013; 6: 1–11.
Eisen RB, Perera S, Banfield L, Anglin R, Minuzzi L, Samaan Z . Association between BDNF levels and suicidal behaviour: a systematic review and meta-analysis. Syst Rev 2015; 4: 187.
Eisen RB, Perera S, Bawor M, Dennis BB, El-Sheikh W, DeJesus J et al. Exploring the association between serum BDNF and attempted suicide. Sci Rep 2016; 6: 25229.
Grah M, Mihanovic M, Ruljancic N, Restek-Petrovic B, Molnar S, Jelavic S . Brain-derived neurotrophic factor as a suicide factor in mental disorders. Acta Neuropsychiatr 2014; 26: 356–363.
Keller S, Sarchiapone M, Zarrilli F, Videtic A, Ferraro A, Carli V et al. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch Gen Psychiatry 2010; 67: 258–267.
Kang HJ, Kim JM, Lee JY, Kim SY, Bae KY, Kim SW et al. BDNF promoter methylation and suicidal behavior in depressive patients. J Affect Disord 2013; 151: 679–685.
Roth TL, Lubin FD, Funk AJ, Sweatt JD . Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 2009; 65: 760–769.
Chen ES, Ernst C, Turecki G . The epigenetic effects of antidepressant treatment on human prefrontal cortex BDNF expression. Int J Neuropsychopharmacol 2011; 14: 427–429.
Ernst C, Chen ES, Turecki G . Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers. Mol Psychiatry 2009; 14: 830–832.
Maussion G, Yang J, Suderman M, Diallo A, Nagy C, Arnovitz M et al. Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide. Epigenetics 2014; 9: 1061–1070.
Maussion G, Yang J, Yerko V, Barker P, Mechawar N, Ernst C et al. Regulation of a truncated form of tropomyosin-related kinase B (TrkB) by Hsa-miR-185* in frontal cortex of suicide completers. PLoS ONE 2012; 7: e39301.
Perroud N, Courtet P, Vincze I, Jaussent I, Jollant F, Bellivier F et al. Interaction between BDNF Val66Met and childhood trauma on adult's violent suicide attempt. Genes Brain Behav 2008; 7: 314–322.
Sarchiapone M, Carli V, Roy A, Iacoviello L, Cuomo C, Latella MC et al. Association of polymorphism (Val66Met) of brain-derived neurotrophic factor with suicide attempts in depressed patients. Neuropsychobiology 2008; 57: 139–145.
Pregelj P, Nedic G, Paska AV, Zupanc T, Nikolac M, Balazic J et al. The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide. J Affect Disord 2011; 128: 287–290.
Zarrilli F, Angiolillo A, Castaldo G, Chiariotti L, Keller S, Sacchetti S et al. Brain derived neurotrophic factor (BDNF) genetic polymorphism (Val66Met) in suicide: a study of 512 cases. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 599–600.
Gonzalez-Castro TB, Nicolini H, Lanzagorta N, Lopez-Narvaez L, Genis A, Pool Garcia S et al. The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects. Bipolar Disord 2015; 17: 27–38.
Bresin K, Sima Finy M, Verona E . Childhood emotional environment and self-injurious behaviors: the moderating role of the BDNF Val66Met polymorphism. J Affect Disord 2013; 150: 594–600.
Schenkel LC, Segal J, Becker JA, Manfro GG, Bianchin MM, Leistner-Segal S . The BDNF Val66Met polymorphism is an independent risk factor for high lethality in suicide attempts of depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 940–944.
Cantarelli Mda G, Tramontina AC, Leite MC, Goncalves CA . Potential neurochemical links between cholesterol and suicidal behavior. Psychiatry Res 2014; 220: 745–751.
Lalovic A, Levy E, Luheshi G, Canetti L, Grenier E, Sequeira A et al. Cholesterol content in brains of suicide completers. Int J Neuropsychopharmacol 2007; 10: 159–166.
Jokinen J, Nordstrom AL, Nordstrom P . Cholesterol, CSF 5-HIAA, violence and intent in suicidal men. Psychiatry Res 2010; 178: 217–219.
Lalovic A, Merkens L, Russell L, Arsenault-Lapierre G, Nowaczyk MJ, Porter FD et al. Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers. Am J Psychiatry 2004; 161: 2123–2126.
Freemantle E, Mechawar N, Turecki G . Cholesterol and phospholipids in frontal cortex and synaptosomes of suicide completers: relationship with endosomal lipid trafficking genes. J Psychiatr Res 2013; 47: 272–279.
Tanskanen A, Vartiainen E, Tuomilehto J, Viinamaki H, Lehtonen J, Puska P . High serum cholesterol and risk of suicide. Am J Psychiatry 2000; 157: 648–650.
Shakeri J, Farnia V, Valinia K, Hashemian AH, Bajoghli H, Holsboer-Trachsler E et al. The relationship between lifetime suicide attempts, serum lipid levels, and metabolic syndrome in patients with bipolar disorders. Int J Psychiatry Clin Pract 2015; 19: 124–131.
Misiak B, Kiejna A, Frydecka D . Higher total cholesterol level is associated with suicidal ideation in first-episode schizophrenia females. Psychiatry Res 2015; 226: 383–388.
Dietschy JM . Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 2009; 390: 287–293.
Koudinov AR, Koudinova NV . Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 2001; 15: 1858–1860.
Roaldset JO, Linaker OM, Bjorkly S . Triglycerides as a biological marker of repeated re-hospitalization resulting from deliberate self-harm in acute psychiatry patients: a prospective observational study. BMC Psychiatry 2014; 14: 54.
Shin HY, Kang G, Kang HJ, Kim SW, Shin IS, Yoon JS et al. Associations between serum lipid levels and suicidal ideation among Korean older people. J Affect Disord 2016; 189: 192–198.
Lalovic A, Klempan T, Sequeira A, Luheshi G, Turecki G . Altered expression of lipid metabolism and immune response genes in the frontal cortex of suicide completers. J Affect Disord 2010; 120: 24–31.
Haghighi F, Galfalvy H, Chen S, Huang YY, Cooper TB, Burke AK et al. DNA methylation perturbations in genes involved in polyunsaturated fatty acid biosynthesis associated with depression and suicide risk. Front Neurol 2015; 6: 92.
Lalovic A, Levy E, Canetti L, Sequeira A, Montoudis A, Turecki G . Fatty acid composition in postmortem brains of people who completed suicide. J Psychiatry Neurosci 2007; 32: 363–370.
Evans SJ, Prossin AR, Harrington GJ, Kamali M, Ellingrod VL, Burant CF et al. Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects. PLoS ONE 2012; 7: e29297.
Limon A, Mamdani F, Hjelm BE, Vawter MP, Sequeira A . Targets of polyamine dysregulation in major depression and suicide: activity-dependent feedback, excitability, and neurotransmission. Neurosci Biobehav Rev 2016; 66: 80–91.
Goracke-Postle CJ, Overland AC, Riedl MS, Stone LS, Fairbanks CA . Potassium- and capsaicin-induced release of agmatine from spinal nerve terminals. J Neurochem 2007; 102: 1738–1748.
Wang G, Gorbatyuk OS, Dayanithi G, Ouyang W, Wang J, Milner TA et al. Evidence for endogenous agmatine in hypothalamo-neurohypophysial tract and its modulation on vasopressin release and Ca2+ channels. Brain Res 2002; 932: 25–36.
Hiasa M, Miyaji T, Haruna Y, Takeuchi T, Harada Y, Moriyama S et al. Identification of a mammalian vesicular polyamine transporter. Sci Rep 2014; 4: 6836.
Gilad GM, Gilad VH . Overview of the brain polyamine-stress-response: regulation, development, and modulation by lithium and role in cell survival. Cell Mol Neurobiol 2003; 23: 637–649.
Karssen AM, Her S, Li JZ, Patel PD, Meng F, Bunney WE Jr . et al. Stress-induced changes in primate prefrontal profiles of gene expression. Mol Psychiatry 2007; 12: 1089–1102.
Shopsin B . The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta Neuropsychiatr 2013; 25: 113–118.
Gawali NB, Bulani VD, Chowdhury AA, Deshpande PS, Nagmoti DM, Juvekar AR . Agmatine ameliorates lipopolysaccharide induced depressive-like behaviour in mice by targeting the underlying inflammatory and oxido-nitrosative mediators. Pharmacol Biochem Behav 2016; 149: 1–8.
Neis VB, Manosso LM, Moretti M, Freitas AE, Daufenbach J, Rodrigues AL . Depressive-like behavior induced by tumor necrosis factor-alpha is abolished by agmatine administration. Behav Brain Res 2014; 261: 336–344.
Kotagale NR, Tripathi SJ, Aglawe MM, Chopde CT, Umekar MJ, Taksande BG . Evidences for the agmatine involvement in antidepressant like effect of bupropion in mouse forced swim test. Pharmacol Biochem Behav 2013; 107: 42–47.
Taksande BG, Kotagale NR, Tripathi SJ, Ugale RR, Chopde CT . Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine. Neuropharmacology 2009; 57: 415–424.
Neis VB, Moretti M, Manosso LM, Lopes MW, Leal RB, Rodrigues AL . Agmatine enhances antidepressant potency of MK-801 and conventional antidepressants in mice. Pharmacol Biochem Behav 2015; 130: 9–14.
Pantazatos SP, Andrews SJ, Dunning-Broadbent J, Pang J, Huang YY, Arango V et al. Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 (SAT1) gene in major depression and suicide. Neurobiol Dis 2015; 79: 123–134.
Fiori LM, Turecki G . Implication of the polyamine system in mental disorders. J Psychiatry Neurosci 2008; 33: 102–110.
Sequeira A, Gwadry FG, Ffrench-Mullen JM, Canetti L, Gingras Y, Casero RA Jr. et al. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Arch Gen Psychiatry 2006; 63: 35–48.
Klempan TA, Rujescu D, Merette C, Himmelman C, Sequeira A, Canetti L et al. Profiling brain expression of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene in suicide. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 934–943.
Chen GG, Fiori LM, Moquin L, Gratton A, Mamer O, Mechawar N et al. Evidence of altered polyamine concentrations in cerebral cortex of suicide completers. Neuropsychopharmacology 2010; 35: 1477–1484.
Gross JA, Turecki G . Suicide and the polyamine system. CNS Neurol Disord Drug Targets 2013; 12: 980–988.
Sequeira A, Klempan T, Canetti L, ffrench-Mullen J, Benkelfat C, Rouleau GA et al. Patterns of gene expression in the limbic system of suicides with and without major depression. Mol Psychiatry 2007; 12: 640–655.
Fiori LM, Mechawar N, Turecki G . Identification and characterization of spermidine/spermine N1-acetyltransferase promoter variants in suicide completers. Biol Psychiatry 2009; 66: 460–467.
Pantazatos SP, Huang YY, Rosoklija GB, Dwork AJ, Arango V, Mann JJ . Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity. Mol Psychiatry 2017; 22: 760–773.
Lopez JP, Fiori LM, Gross JA, Labonte B, Yerko V, Mechawar N et al. Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int J Neuropsychopharmacol 2014; 17: 23–32.
Fiori LM, Turecki G . Epigenetic regulation of spermidine/spermine N1-acetyltransferase (SAT1) in suicide. J Psychiatr Res 2011; 45: 1229–1235.
Gross JA, Fiori LM, Labonte B, Lopez JP, Turecki G . Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide. J Psychiatr Res 2013; 47: 513–519.
Fiori LM, Gross JA, Turecki G . Effects of histone modifications on increased expression of polyamine biosynthetic genes in suicide. Int J neuropsychopharmacol 2012; 15: 1161–1166.
Niculescu AB, Levey DF, Phalen PL, Le-Niculescu H, Dainton HD, Jain N et al. Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach. Mol Psychiatry 2015; 20: 1266–1285.
Niculescu AB, Levey D, Le-Niculescu H, Niculescu E, Kurian SM, Salomon D . Psychiatric blood biomarkers: avoiding jumping to premature negative or positive conclusions. Mol Psychiatry 2015; 20: 286–288.
Le-Niculescu H, Levey DF, Ayalew M, Palmer L, Gavrin LM, Jain N et al. Discovery and validation of blood biomarkers for suicidality. Mol Psychiatry 2013; 18: 1249–1264.
Raison CL, Miller AH . When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003; 160: 1554–1565.
Heim C, Shugart M, Craighead WE, Nemeroff CB . Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol 2010; 52: 671–690.
Francis D, Diorio J, Liu D, Meaney MJ . Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 1999; 286: 1155–1158.
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997; 277: 1659–1662.
Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004; 7: 847–854.
McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009; 12: 342–348.
Turecki G, Meaney MJ . Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry 2014; 79: 87–96.
Brent D, Melhem N, Ferrell R, Emslie G, Wagner KD, Ryan N et al. Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am J Psychiatry 2010; 167: 190–197.
Leszczynska-Rodziewicz A, Szczepankiewicz A, Narozna B, Skibinska M, Pawlak J, Dmitrzak-Weglarz M 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 2014; 10: 243–248.
Perroud N, Bondolfi G, Uher R, Gex-Fabry M, Aubry JM, Bertschy G et al. Clinical and genetic correlates of suicidal ideation during antidepressant treatment in a depressed outpatient sample. Pharmacogenomics 2011; 12: 365–377.
Supriyanto I, Sasada T, Fukutake M, Asano M, Ueno Y, Nagasaki Y et al. Association of FKBP5 gene haplotypes with completed suicide in the Japanese population. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 252–256.
Willour VL, Chen H, Toolan J, Belmonte P, Cutler DJ, Goes FS et al. Family-based association of FKBP5 in bipolar disorder. Mol Psychiatry 2009; 14: 261–268.
Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 2013; 16: 33–41.
Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA . Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology 2010; 35: 1674–1683.
Roy A, Hodgkinson CA, Deluca V, Goldman D, Enoch MA . Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior. J Psychiatr Res 2012; 46: 72–79.
Lahti J, Ala-Mikkula H, Kajantie E, Haljas K, Eriksson JG, Raikkonen K . Associations between self-reported and objectively recorded early life stress, FKBP5 polymorphisms, and depressive symptoms in midlife. Biol Psychiatry 2015; 80: 869–877.
Rice L, Waters CE, Eccles J, Garside H, Sommer P, Kay P et al. Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor. J Endocrinol 2008; 198: 499–509.
Kaminsky Z, Wilcox HC, Eaton WW, Van Eck K, Kilaru V, Jovanovic T et al. Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl Psychiatry 2015; 5: e627.
Guintivano J, Brown T, Newcomer A, Jones M, Cox O, Maher BS et al. Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors. Am J Psychiatry 2014; 171: 1287–1296.
He Y, Ecker JR . Non-CG methylation in the human genome. Annu Rev Genomics Hum Genet 2015; 16: 55–77.
Kriaucionis S, Heintz N . The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 2009; 324: 929–930.
Frye M, Jaffrey SR, Pan T, Rechavi G, Suzuki T . RNA modifications: what have we learned and where are we headed? Nat Rev Genet 2016; 17: 365–372.
Nestler EJ . Transgenerational epigenetic contributions to stress responses: fact or fiction? PLoS Biol 2016; 14: e1002426.
Sweatt JD . Neural plasticity & behavior—sixty years of conceptual advances. J Neurochem 2016; 139 (Suppl 2): 179–199.
Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R . Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci USA 2000; 97: 5237–5242.
Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 2013; 17: 215–222.
Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND et al. Global epigenomic reconfiguration during mammalian brain development. Science 2013; 341: 1237905.
Barkat TR, Polley DB, Hensch TK . A critical period for auditory thalamocortical connectivity. Nat Neurosci 2011; 14: 1189–1194.
Makinodan M, Rosen KM, Ito S, Corfas G . A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 2012; 337: 1357–1360.
Lutz PE, Turecki G . DNA methylation and childhood maltreatment: from animal models to human studies. Neuroscience 2014; 264: 142–156.
Jin J, Lian T, Gu C, Yu K, Gao YQ, Su XD . The effects of cytosine methylation on general transcription factors. Sci Rep 2016; 6: 29119.
Chen L, Chen K, Lavery LA, Baker SA, Shaw CA, Li W et al. MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc Natl Acad Sci USA 2015; 112: 5509–5514.
Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 2015; 522: 89–93.
Luo C, Ecker JR . Epigenetics. Exceptional epigenetics in the brain. Science 2015; 348: 1094–1095.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930–935.
Bachman M, Uribe-Lewis S, Yang X, Williams M, Murrell A, Balasubramanian S . 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat Chem 2014; 6: 1049–1055.
Nestor CE, Ottaviano R, Reddington J, Sproul D, Reinhardt D, Dunican D et al. Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 2012; 22: 467–477.
Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F, Reik W et al. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 2012; 336: 934–937.
Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 2012; 149: 1368–1380.
Sun Z, Terragni J, Borgaro JG, Liu Y, Yu L, Guan S et al. High-resolution enzymatic mapping of genomic 5-hydroxymethylcytosine in mouse embryonic stem cells. Cell Rep 2013; 3: 567–576.
Gross JA, Pacis A, Chen GG, Barreiro LB, Ernst C, Turecki G . Characterizing 5-hydroxymethylcytosine in human prefrontal cortex at single base resolution. BMC Genomics 2015; 16: 672.
Jones PA . Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484–492.
Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N . MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 2012; 151: 1417–1430.
Pacis A, Tailleux L, Morin AM, Lambourne J, MacIsaac JL, Yotova V et al. Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res 2015; 25: 1801–1811.
Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev 2011; 25: 679–684.
Kinde B, Gabel HW, Gilbert CS, Griffith EC, Greenberg ME . Reading the unique DNA methylation landscape of the brain: non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci USA 2015; 112: 6800–6806.
Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M . Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain. Neurobiol Aging 2014; 35: 1334–1344.
Villar-Menendez I, Blanch M, Tyebji S, Pereira-Veiga T, Albasanz JL, Martin M et al. Increased 5-methylcytosine and decreased 5-hydroxymethylcytosine levels are associated with reduced striatal A2AR levels in Huntington's disease. Neuromolecular Med 2013; 15: 295–309.
Nainar S, Marshall PR, Tyler CR, Spitale RC, Bredy TW . Evolving insights into RNA modifications and their functional diversity in the brain. Nat Neurosci 2016; 19: 1292–1298.
Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J et al. Global quantification of mammalian gene expression control. Nature 2011; 473: 337–342.
Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR . Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012; 149: 1635–1646.
Widagdo J, Zhao QY, Kempen MJ, Tan MC, Ratnu VS, Wei W et al. Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. J Neurosci 2016; 36: 6771–6777.
Du T, Rao S, Wu L, Ye N, Liu Z, Hu H et al. An association study of the m6A genes with major depressive disorder in Chinese Han population. J Affect Disord 2015; 183: 279–286.
Samaan Z, Anand SS, Zhang X, Desai D, Rivera M, Pare G et al. The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression. Mol Psychiatry 2013; 18: 1281–1286.
Li X, Zhu P, Ma S, Song J, Bai J, Sun F et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat Chem Biol 2015; 11: 592–597.
Schwartz S, Bernstein DA, Mumbach MR, Jovanovic M, Herbst RH, Leon-Ricardo BX et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 2014; 159: 148–162.
Behm M, Ohman M . RNA editing: a contributor to neuronal dynamics in the mammalian brain. Trends Genet 2016; 32: 165–175.
Li JB, Church GM . Deciphering the functions and regulation of brain-enriched A-to-I RNA editing. Nat Neurosci 2013; 16: 1518–1522.
Karanovic J, Svikovic S, Pantovic M, Durica S, Brajuskovic G, Damjanovic A et al. Joint effect of ADARB1 gene, HTR2C gene and stressful life events on suicide attempt risk in patients with major psychiatric disorders. World J Biol Psychiatry 2015; 16: 261–271.
Di Narzo AF, Kozlenkov A, Roussos P, Hao K, Hurd Y, Lewis DA et al. A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum Mol Genet 2014; 23: 4801–4813.
Bhansali P, Dunning J, Singer SE, David L, Schmauss C . Early life stress alters adult serotonin 2C receptor pre-mRNA editing and expression of the alpha subunit of the heterotrimeric G-protein G q. J Neurosci 2007; 27: 1467–1473.
Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G . Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron 2015; 88: 861–877.
Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 2012; 22: 1775–1789.
Aprea J, Prenninger S, Dori M, Ghosh T, Monasor LS, Wessendorf E et al. Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment. EMBO J 2013; 32: 3145–3160.
Spadaro PA, Flavell CR, Widagdo J, Ratnu VS, Troup M, Ragan C et al. Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice. Biol Psychiatry 2015; 78: 848–859.
Serafini G, Pompili M, Hansen KF, Obrietan K, Dwivedi Y, Shomron N et al. The involvement of microRNAs in major depression, suicidal behavior, and related disorders: a focus on miR-185 and miR-491-3p. Cell Mol Neurobiol 2014; 34: 17–30.
Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcao A, Xiao L et al. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 2016; 352: 1326–1329.
Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 2015; 347: 1138–1142.
Mo A, Mukamel EA, Davis FP, Luo C, Henry GL, Picard S et al. Epigenomic signatures of neuronal diversity in the mammalian brain. Neuron 2015; 86: 1369–1384.
Okaty BW, Sugino K, Nelson SB . Cell type-specific transcriptomics in the brain. J Neurosci 2011; 31: 6939–6943.
Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA 2012; 109: 11360–11365.
Lake BB, Ai R, Kaeser GE, Salathia NS, Yung YC, Liu R et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 2016; 352: 1586–1590.
Tagliafierro L, Bonawitz K, Glenn OC, Chiba-Falek O . Gene expression analysis of neurons and astrocytes isolated by laser capture microdissection from frozen human brain tissues. Front Mol Neurosci 2016; 9: 72.
Wang C, Schroeder FA, Hooker JM . Visualizing epigenetics: current advances and advantages in HDAC PET imaging techniques. Neuroscience 2013; 264: 186–197.
Wey HY, Gilbert TM, Zurcher NR, She A, Bhanot A, Taillon BD et al. Insights into neuroepigenetics through human histone deacetylase PET imaging. Sci Transl Med 2016; 8: 351ra106.
Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E . A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012; 337: 816–821.
Vojta A, Dobrinic P, Tadic V, Bockor L, Korac P, Julg B et al. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res 2016; 44: 5615–5628.
Bernstein DL, Le Lay JE, Ruano EG, Kaestner KH . TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts. J Clin Invest 2015; 125: 1998–2006.
Heller EA, Cates HM, Pena CJ, Sun H, Shao N, Feng J et al. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat Neurosci 2014; 17: 1720–1727.
Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S et al. Editing DNA methylation in the mammalian genome. Cell 2016; 167: 233–247 e217.
Amabile A, Migliara A, Capasso P, Biffi M, Cittaro D, Naldini L et al. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 2016; 167: 219–232 e214.
Saraiva J, Nobre RJ, Pereira de Almeida L . Gene therapy for the CNS using AAVs: the impact of systemic delivery by AAV9. J Control Release 2016; 241: 94–109.
Mok PL, Pedersen CB, Springate D, Astrup A, Kapur N, Antonsen S et al. Parental psychiatric disease and risks of attempted suicide and violent criminal offending in offspring: a population-based cohort study. JAMA Psychiatry 2016; 73: 1015–1022.
Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339: b2880.
Perlis RH, Purcell S, Fava M, Fagerness J, Rush AJ, Trivedi MH 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: 689–697.
Klonsky ED, Qiu T, Saffer BY . Recent advances in differentiating suicide attempters from suicide ideators. Curr Opin Psychiatry 2016; 30: 15–20.
Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis. Cell Rep 2013; 3: 291–300.
Kozlenkov A, Wang M, Roussos P, Rudchenko S, Barbu M, Bibikova M et al. Substantial DNA methylation differences between two major neuronal subtypes in human brain. Nucleic Acids Res 2016; 44: 2593–2612.
Szulwach KE, Li X, Li Y, Song CX, Wu H, Dai Q et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 2011; 14: 1607–1616.
Li X, Wei W, Zhao QY, Widagdo J, Baker-Andresen D, Flavell CR et al. Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci USA 2014; 111: 7120–7125.
Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S et al. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res 2004; 14: 1719–1725.
Weissmann D, van der Laan S, Underwood MD, Salvetat N, Cavarec L, Vincent L et al. Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression. Transl Psychiatry 2016; 6: e878.
Acknowledgements
We thank Sylvanne Daniels for expert and essential help in the preparation of this review. P-EL is supported by scholarships from the Fondation Fyssen, the Fondation Bettencourt-Schueller, the Canadian Institute of Health Research, the American Foundation for Suicide Prevention, the Fondation pour la Recherche Médicale and the Fondation Deniker. NM is a CIHR New Investigator and is supported by the CIHR grant MOP-111022 and by an ERA-NET NEURON (FRQ-S) team grant. GT holds a Canada Research Chair (Tier 1), Fonds de Recherche du Québec—Santé (FRQS) Chercheur National salary award and a NARSAD Distinguished Investigator Award. He is supported by grants from the CIHR (FDN148374, MOP93775, MOP11260, MOP119429 and MOP119430), from the US National Institutes of Health (NIH) (1R01DA033684), by the FRQS through the Quebec Network on Suicide, Mood Disorders and Related Disorders and through an investigator-initiated research grant from Pfizer.
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GT has received investigator-initiated grants from Pfizer Canada. The other authors declare no conflict of interest.
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Lutz, PE., Mechawar, N. & Turecki, G. Neuropathology of suicide: recent findings and future directions. Mol Psychiatry 22, 1395–1412 (2017). https://doi.org/10.1038/mp.2017.141
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DOI: https://doi.org/10.1038/mp.2017.141
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