A Comparison of Genetic versus Non-Genetic Contribution of Serotonin to Suicide
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Published
Jul 31, 2023
Abstract
Suicide is a complex and multifaceted public health issue that has been intensively studied to identify its contributing factors. Serotonin, a neurotransmitter essential for affective regulation and mood control, has been linked to suicidal propensity. Understanding the relative contribution of serotonin’s genetic versus non-genetic influences is essential for the development of effective preventive measures, given that the etiology of suicide involves both genetic and non-genetic factors. This review seeks to compare the influence of genetic and non-genetic factors on the association between serotonin and suicide risk. Examining serotonin-related gene polymorphisms, with a focus on the serotonin transporter gene, the serotonin receptor 1A, and the serotonin receptor 2A, genetic contributions are investigated. This review emphasizes the complex interplay between genetic and non-genetic contributions to serotonin’s role in suicide by synthesizing existing literature. Understanding these complex interactions can provide a comprehensive framework for targeted interventions and individualized methods of suicide prevention and mental health promotion. Future research should incorporate large-scale genetic studies, genetic and non-genetic interaction analyses, and longitudinal designs in order to further elucidate the complex relationship between serotonin and suicide risk.
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Keywords
Suicide, Biology, Genetics, Non-Genetics, Serotonin, Prevention
References
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6. Brent DA, Melhem N. Familial transmission of suicidal behavior. Psychiatr Clin North Am 2008; 31(2):157-177. DOI: https://doi.org/10.1016/j.psc.2008.02.001
7. Pedersen JH, Skytthe A, Bybjerg-Grauholm J, Kucukyildiz AS, Skov L, Debes NM, Tümer Z. Concordance and comorbidities among monozygotic twins with tic disorders. J Psychiatr Res 2022; 146:297-303. DOI: https://doi.org/10.1016/j.jpsychires.2021.11.019
8. Voracek M, Loibl LM. Genetics of suicide: A systematic review of twin studies. Wien Klin Wochenschr 2007; 119(15-16):463-475. DOI: https://doi.org/10.1007/s00508-007-0823-2
9. Keyes MA, Malone SM, Sharma A, Iacono WG, McGue M. Risk of suicide attempt in adopted and nonadopted offspring. Pediatrics 2013; 132(4):639-646. DOI: https://doi.org/10.1542/peds.2012-3251
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14. Yokoyama JS, Bonham LW, Sturm VE, Adhimoolam B, Karydas A, Coppola G, Miller BL, Rankin KP. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia. Neuroimage Clin 2015; 9:283-290. DOI: https://doi.org/10.1016/j.nicl.2015.07.017
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18. Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry 1997; 154(10):1451-1453. DOI: https://doi.org/10.1176/ajp.154.10.1451
19. Bellivier F, Chaste P, Malafosse A. Association between the TPH gene A218C polymorphism and suicidal behavior: A meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2004; 124B(1):87-91. DOI: https://doi.org/10.1002/ajmg.b.20015
20. Cooper SJ, Kelly CB, King DJ. 5-Hydroxyindoleacetic acid in cerebrospinal fluid and prediction of suicidal behaviour in schizophrenia. Lancet 1992; 340(8825):940-941. DOI: https://doi.org/10.1016/0140-6736(92)92819-2
21. Williams MS. Platelets and depression in cardiovascular disease: A brief review of the current literature. World J Psychiatry 2012; 2(6):114-123. DOI: https://doi.org/10.5498/wjp.v2.i6.114
22. Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 2000; 57(8):729-738. DOI: https://doi.org/10.1001/archpsyc.57.8.729
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24. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23(25):8788-8799. DOI: https://doi.org/10.1523/JNEUROSCI.23-25-08788.2003
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35. Doudet D, Hommer D, Higley JD, Andreason PJ, Moneman R, Suomi SJ, Linnoila M. Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys. Am J Psychiatry 1995; 152(12):1782-1787. DOI: https://doi.org/10.1176/ajp.152.12.1782
36. Jayamohananan H, Manoj Kumar MK, T P A. 5-HIAA as a potential biological marker for neurological and psychiatric disorders. Adv Pharm Bull 2019; 9(3):374-381. DOI: https://doi.org/10.15171/apb.2019.044
37. Wisłowska-Stanek A, Kołosowska K, Maciejak P. Neurobiological basis of increased risk for suicidal behaviour. Cells 2021; 10(10):2519. DOI: https://doi.org/10.3390/cells10102519
38. Malone KM, Corbitt EM, Li S, Mann JJ. Prolactin response to fenfluramine and suicide attempt lethality in major depression. Br J Psychiatry 1996; 168(3):324-329. DOI: https://doi.org/10.1192/bjp.168.3.324
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2. Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci 2013; 368(1615):20120537. DOI: https://doi.org/10.1098/rstb.2012.0537
3. Pandey GN, Dwivedi Y. What can post-mortem studies tell us about the pathoetiology of suicide? Future Neurol 2010; 5(5):701-720. DOI: https://doi.org/10.2217/fnl.10.49
4. Mann JJ, Malone KM, Sweeney JA, Brown RP, Linnoila M, Stanley B, Stanley M. Attempted suicide characteristics and cerebrospinal fluid amine metabolites in depressed inpatients. Neuropsychopharmacology 1996; 15(6):576-586. DOI: https://doi.org/10.1016/S0893-133X(96)00102-9
5. Sadkowski M, Dennis B, Clayden RC, Elsheikh W, Rangarajan S, Dejesus J, Samaan Z. The role of the serotonergic system in suicidal behavior. Neuropsychiatr Dis Treat 2013; 9:1699-1716. DOI: https://doi.org/10.2147/NDT.S50300
6. Brent DA, Melhem N. Familial transmission of suicidal behavior. Psychiatr Clin North Am 2008; 31(2):157-177. DOI: https://doi.org/10.1016/j.psc.2008.02.001
7. Pedersen JH, Skytthe A, Bybjerg-Grauholm J, Kucukyildiz AS, Skov L, Debes NM, Tümer Z. Concordance and comorbidities among monozygotic twins with tic disorders. J Psychiatr Res 2022; 146:297-303. DOI: https://doi.org/10.1016/j.jpsychires.2021.11.019
8. Voracek M, Loibl LM. Genetics of suicide: A systematic review of twin studies. Wien Klin Wochenschr 2007; 119(15-16):463-475. DOI: https://doi.org/10.1007/s00508-007-0823-2
9. Keyes MA, Malone SM, Sharma A, Iacono WG, McGue M. Risk of suicide attempt in adopted and nonadopted offspring. Pediatrics 2013; 132(4):639-646. DOI: https://doi.org/10.1542/peds.2012-3251
10. Forum on Global Violence Prevention; Board on Global Health; Institute of Medicine; National Research Council. Contagion of Violence: Workshop Summary. Washington (DC): National Academies Press (US); 2013 Feb 6. II.4, The Contagion of Suicidal Behavior. Available at: https://www.ncbi.nlm.nih.gov/books/NBK207262/
11. Zai CC, de Luca V, Strauss J, Tong RP, Sakinofsky I, Kennedy JL. Genetic Factors and Suicidal Behavior. In: Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012. Chapter 11. Available at: https://www.ncbi.nlm.nih.gov/books/NBK107191/
12. Andriessen K, Videtic-Paska A. Genetic vulnerability as a distal risk factor for suicidal behaviour: Historical perspective and current knowledge. Zdr Varst 2015; 54(3):238-251. DOI: https://doi.org/10.1515/sjph-2015-0026
13. Jacobsen JP, Medvedev IO, Caron MG. The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. Philos Trans R Soc Lond B Biol Sci 2012; 367(1601):2444-2459. DOI: https://doi.org/10.1098/rstb.2012.0109
14. Yokoyama JS, Bonham LW, Sturm VE, Adhimoolam B, Karydas A, Coppola G, Miller BL, Rankin KP. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia. Neuroimage Clin 2015; 9:283-290. DOI: https://doi.org/10.1016/j.nicl.2015.07.017
15. Höfer P, Schosser A, Calati R, Serretti A, Massat I, Kocabas NA, Konstantinidis A, Mendlewicz J, Souery D, Zohar J, Juven-Wetzler A, Montgomery S, Kasper S. The impact of serotonin receptor 1A and 2A gene polymorphisms and interactions on suicide attempt and suicide risk in depressed patients with insufficient response to treatment-A European multicentre study. Int Clin Psychopharmacol 2016; 31(1):1-7. DOI: https://doi.org/10.1097/YIC.0000000000000101
16. Nielsen DA, Virkkunen M, Lappalainen J, Eggert M, Brown GL, Long JC, Goldman D, Linnoila M. A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch Gen Psychiatry 1998; 55(7):593-602. DOI: https://doi.org/10.1001/archpsyc.55.7.593
17. Zhang Y, Zhang C, Yuan G, Yao J, Cheng Z, Liu C, Liu Q, Wan G, Shi G, Cheng Y, Ling Y, Li K. Effect of tryptophan hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression. Behav Brain Funct 2010; 6:49. DOI: https://doi.org/10.1186/1744-9081-6-49
18. Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry 1997; 154(10):1451-1453. DOI: https://doi.org/10.1176/ajp.154.10.1451
19. Bellivier F, Chaste P, Malafosse A. Association between the TPH gene A218C polymorphism and suicidal behavior: A meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2004; 124B(1):87-91. DOI: https://doi.org/10.1002/ajmg.b.20015
20. Cooper SJ, Kelly CB, King DJ. 5-Hydroxyindoleacetic acid in cerebrospinal fluid and prediction of suicidal behaviour in schizophrenia. Lancet 1992; 340(8825):940-941. DOI: https://doi.org/10.1016/0140-6736(92)92819-2
21. Williams MS. Platelets and depression in cardiovascular disease: A brief review of the current literature. World J Psychiatry 2012; 2(6):114-123. DOI: https://doi.org/10.5498/wjp.v2.i6.114
22. Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 2000; 57(8):729-738. DOI: https://doi.org/10.1001/archpsyc.57.8.729
23. Seo D, Patrick CJ, Kennealy PJ. Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders. Aggress Violent Behav 2008; 13(5):383-395. DOI: https://doi.org/10.1016/j.avb.2008.06.003
24. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23(25):8788-8799. DOI: https://doi.org/10.1523/JNEUROSCI.23-25-08788.2003
25. Tiger M, Varnäs K, Okubo Y, Lundberg J. The 5-HT1B receptor - A potential target for antidepressant treatment. Psychopharmacology (Berl) 2018; 235(5):1317-1334. DOI: https://doi.org/10.1007/s00213-018-4872-1
26. McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJM, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 2006; 78(5):804-814. DOI: https://doi.org/10.1086/503820
27. Zhang X, Li J, Yu H, et al. Association between a serotonin transporter gene promoter polymorphism and mood disorders. Biol Psychiatry 1997; 41(1):32-38. DOI: https://doi.org/10.1016/S0006-3223(96)00091-3
28. Du L, Faludi G, Palkovits M, Bakish D, Hrdina PD. Tryptophan hydroxylase gene 218A/C polymorphism is not associated with depressed suicide. Int J Neuropsychopharmacol 2000; 3(3):215-220. DOI: https://doi.org/10.1017/S1461145700001954
29. Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L. Association between suicidal behavior, serotonin transporter protein, and serotonin 1A receptor gene polymorphisms in patients with major depression: A preliminary study. Neuropsychobiology 2001; 43(1):19-23. DOI: https://doi.org/10.1159/000054865
30. González-Castro TB, Tovilla-Zárate C, Juárez-Rojop I, Pool García S, Velázquez-Sánchez MP, Genis A, Nicolini H, López Narváez L. Association of the 5HTR2A gene with suicidal behavior: Case-control study and updated meta-analysis. BMC Psychiatry 2013; 13:25. DOI: https://doi.org/10.1186/1471-244X-13-25
31. Nishiguchi N, Shirakawa O, Ono H, Nishimura A, Nushida H, Ueno Y, Maeda K. Lack of an association between 5-HT1A receptor gene structural polymorphisms and suicide victims. Am J Med Genet 2002; 114(4):423-425. DOI: https://doi.org/10.1002/ajmg.10414
32. Lenchner JR, Santos C. Biochemistry, 5 Hydroxyindoleacetic Acid. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available at: https://www.ncbi.nlm.nih.gov/books/NBK551684/
33. Nordström P, Samuelsson M, Asberg M, Träskman-Bendz L, Aberg-Wistedt A, Nordin C, Bertilsson L. CSF 5-HIAA predicts suicide risk after attempted suicide. Suicide Life Threat Behav 1994; 24(1):1-9.
34. Coplan JD, Fulton SL, Reiner W, Jackowski A, Panthangi V, Perera TD, Gorman JM, Huang YY, Tang CY, Hof PR, Kaffman A, Dwork AJ, Mathew SJ, Kaufman J, Mann JJ. Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: Preliminary implications for serotonin-related function in mood and anxiety disorders. Front Behav Neurosci 2014; 8:440. DOI: https://doi.org/10.3389/fnbeh.2014.00440
35. Doudet D, Hommer D, Higley JD, Andreason PJ, Moneman R, Suomi SJ, Linnoila M. Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys. Am J Psychiatry 1995; 152(12):1782-1787. DOI: https://doi.org/10.1176/ajp.152.12.1782
36. Jayamohananan H, Manoj Kumar MK, T P A. 5-HIAA as a potential biological marker for neurological and psychiatric disorders. Adv Pharm Bull 2019; 9(3):374-381. DOI: https://doi.org/10.15171/apb.2019.044
37. Wisłowska-Stanek A, Kołosowska K, Maciejak P. Neurobiological basis of increased risk for suicidal behaviour. Cells 2021; 10(10):2519. DOI: https://doi.org/10.3390/cells10102519
38. Malone KM, Corbitt EM, Li S, Mann JJ. Prolactin response to fenfluramine and suicide attempt lethality in major depression. Br J Psychiatry 1996; 168(3):324-329. DOI: https://doi.org/10.1192/bjp.168.3.324
39. Bach H, Arango V. Neuroanatomy of Serotonergic Abnormalities in Suicide. In: Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012. Chapter 2. Available at: https://www.ncbi.nlm.nih.gov/books/NBK107204/
40. Bach H, Huang YY, Underwood MD, Dwork AJ, Mann JJ, Arango V. Elevated serotonin and 5-HIAA in the brainstem and lower serotonin turnover in the prefrontal cortex of suicides. Synapse 2014; 68(3):127-130. DOI: https://doi.org/10.1002/syn.21695
41. Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci. 2010; 12(4):471-487. DOI: https://doi.org/10.31887/DCNS.2010.12.4/ycharnay
42. Shelton RC, Sanders-Bush E, Manier DH, Lewis DA. Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 2009; 158(4):1406-1415. DOI: https://doi.org/10.1016/j.neuroscience.2008.11.036
43. Nelson EE, Guyer AE. The development of the ventral prefrontal cortex and social flexibility. Dev Cogn Neurosci 2011; 1(3):233-245. DOI: https://doi.org/10.1016/j.dcn.2011.01.002
44. Carballo JJ, Akamnonu CP, Oquendo MA. Neurobiology of suicidal behavior. An integration of biological and clinical findings. Arch Suicide Res 2008; 12(2):93-110. DOI: https://doi.org/10.1080/13811110701857004
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How to Cite
Lee, J. L. (2023). A Comparison of Genetic versus Non-Genetic Contribution of Serotonin to Suicide. Science Insights, 43(1), 995–1002. https://doi.org/10.15354/si.23.re611
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