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International Journal of Legal Medicine

, Volume 133, Issue 2, pp 353–363 | Cite as

Completed suicides of citalopram users—the role of CYP genotypes and adverse drug interactions

  • Anna-Liina RahikainenEmail author
  • P. Vauhkonen
  • H. Pett
  • J. U. Palo
  • J. Haukka
  • I. Ojanperä
  • M. Niemi
  • Antti SajantilaEmail author
Original Article

Abstract

Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides (n = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples (n = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31–0.41] vs. 0.265 [0.24–0.30] (p = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.

Keywords

Postmortem Suicide Citalopram CYP2C19 CYP2D6 Drug interactions 

Notes

Acknowledgements

We thank Professor Emeritus Erkki Vuori for sharing his expertise.

Funding information

This study is financially supported by the Doctoral Programme in Population Health, University of Helsinki, and the Medical Research Foundation of Juhani Aho.

Compliance with ethical standards

This study was approved by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District.

Supplementary material

414_2018_1927_MOESM1_ESM.docx (176 kb)
ESM 1 (DOCX 175 kb)

References

  1. 1.
    Official Statistics of Finland (2015) Number of suicides fell clearly. Available from: https://www.stat.fi/til/ksyyt/2015/ksyyt_2015_2016-12-30_kat_006_en.html [Access date: 21.08.2018]
  2. 2.
    Finnish Medicines Agency (Fimea) and Social Insurance Institution of Finland (Kela) (2016) The Finnish Statistics on Medicines, 29th edition. Available from: https://www.fimea.fi/documents/160140/1188389/Suomen_l%C3%A4%C3%A4ketilasto_2015.pdf/a813feac-1560-4cbf-80e1-44049449e0bf [Access date: 21.08.2018]
  3. 3.
    Henriksson MM, Aro HM, Marttunen MJ, Heikkinen ME, Isometsa ET, Kuoppasalmi KI et al (1993) Mental disorders and comorbidity in suicide. Am J Psychiatry 150(6):935–940CrossRefGoogle Scholar
  4. 4.
    Finnish Medicines Agency (Fimea) (2013) Essitalopraami ja sitalopraami masennuksen hoidossa (in Finnish). Arviointikooste, Fimea kehittää, arvioi ja informoi -julkaisusarja 6/2013Google Scholar
  5. 5.
    Barak Y, Swartz M, Baruch Y (2011) Venlafaxine or a second SSRI: switching after treatment failure with an SSRI among depressed inpatients: a retrospective analysis. Prog Neuro-Psychopharmacol Biol Psychiatry 35(7):1744–1747CrossRefGoogle Scholar
  6. 6.
    Jukic MM, Haslemo T, Molden E, Ingelman-Sundberg M (2018) Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: a retrospective study based on 2,087 patients. Am J Psychiatry 175(5):463–470CrossRefGoogle Scholar
  7. 7.
    Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E (2008) Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 83(2):322–327CrossRefGoogle Scholar
  8. 8.
    Ingelman-Sundberg M (2004) Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedeberg's Arch Pharmacol 369(1):89–104CrossRefGoogle Scholar
  9. 9.
    Hicks JK, Bishop JR, Sangkuhl K, Muller DJ, Ji Y, Leckband SG et al (2015) Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 98(2):127–134CrossRefGoogle Scholar
  10. 10.
    Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE, the PharmVar Steering Committee (2018) The Pharmacogene Variation (PharmVar) consortium: incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther 103(3):399–401CrossRefGoogle Scholar
  11. 11.
    Bertilsson L, Dahl ML, Sjoqvist F, Aberg-Wistedt A, Humble M, Johansson I et al (1993) Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341(8836):63CrossRefGoogle Scholar
  12. 12.
    Hamelin BA, Turgeon J, Vallee F, Belanger PM, Paquet F, LeBel M (1996) The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther 60(5):512–521CrossRefGoogle Scholar
  13. 13.
    Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH (1996) The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60(6):636–644CrossRefGoogle Scholar
  14. 14.
    Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S (2007) CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 17(2):93–101Google Scholar
  15. 15.
    Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS (2017) Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med 19(1):69–76CrossRefGoogle Scholar
  16. 16.
    Rasanen I, Kontinen I, Nokua J, Ojanpera I, Vuori E (2003) Precise gas chromatography with retention time locking in comprehensive toxicological screening for drugs in blood. J Chromatogr B Anal Technol Biomed Life Sci 788(2):243–250CrossRefGoogle Scholar
  17. 17.
    WHO Collaborating Centre for Drug Statistics Methodology (2018) ATC classification index with DDDs. Available from: https://www.whocc.no [Access date: 21.08.2018]
  18. 18.
    Haukka J, Kriikku P, Mariottini C, Partonen T, Ojanpera I (2018) Non-medical use of psychoactive prescription drugs is associated with fatal poisoning. Addiction 113(3):464–472CrossRefGoogle Scholar
  19. 19.
    Pietarinen P, Tornio A, Niemi M (2016) High frequency of CYP2D6 ultrarapid metabolizer genotype in the Finnish population. Basic Clin Pharmacol Toxicol 119(3):291–296CrossRefGoogle Scholar
  20. 20.
    Palo JU, Ulmanen I, Lukka M, Ellonen P, Sajantila A (2009) Genetic markers and population history: Finland revisited. Eur J Hum Genet 17(10):1336–1346CrossRefGoogle Scholar
  21. 21.
    Neuvonen AM, Putkonen M, Oversti S, Sundell T, Onkamo P, Sajantila A et al (2015) Vestiges of an ancient border in the contemporary genetic diversity of North-Eastern Europe. PLoS One 10(7):e0130331CrossRefGoogle Scholar
  22. 22.
    Launiainen T, Ojanpera I (2014) Drug concentrations in post-mortem femoral blood compared with therapeutic concentrations in plasma. Drug Test Anal 6(4):308–316CrossRefGoogle Scholar
  23. 23.
    Raymond M, Rousset F (1995) An exact test for population differentiation. Evolution 49(6):1280–1283CrossRefGoogle Scholar
  24. 24.
    Excoffier L, Lischer HE (2010) Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour 10(3):564–567CrossRefGoogle Scholar
  25. 25.
    Storey JD (2002) A direct approach to false discovery rates. J R Stat Soc Ser B 64:479–498CrossRefGoogle Scholar
  26. 26.
    Daly AK, Brockmoller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ, Huang JD, Idle JR, Ingelman-Sundberg M, Ishizaki T, Jacqz-Aigrain E, Meyer UA, Nebert DW, Steen VM, Wolf CR, Zanger UM (1996) Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6(3):193–201CrossRefGoogle Scholar
  27. 27.
    Ingelman-Sundberg M, Daly AK, Oscarson M, Nebert DW (2000) Human cytochrome P450 (CYP) genes: recommendations for the nomenclature of alleles. Pharmacogenetics 10(1):91–93CrossRefGoogle Scholar
  28. 28.
    Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE (2018) The Pharmacogene Variation (PharmVar) consortium: incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther 103(3):399–401CrossRefGoogle Scholar
  29. 29.
    RStudio Team 2016 (2016) RStudio: integrated development environment for R. Available from: www.rstudio.com [Access date: 21.08.2018]
  30. 30.
    Mrazek DA, Biernacka JM, O'Kane DJ, Black JL, Cunningham JM, Drews MS et al (2011) CYP2C19 variation and citalopram response. Pharmacogenet Genomics 21(1):1–9CrossRefGoogle Scholar
  31. 31.
    Chang M, Tybring G, Dahl ML, Lindh JD (2014) Impact of cytochrome P450 2C19 polymorphisms on citalopram/escitalopram exposure: a systematic review and meta-analysis. Clin Pharmacokinet 53(9):801–811CrossRefGoogle Scholar
  32. 32.
    Huezo-Diaz P, Perroud N, Spencer EP, Smith R, Sim S, Virding S, Uher R, Gunasinghe C, Gray J, Campbell D, Hauser J, Maier W, Marusic A, Rietschel M, Perez J, Giovannini C, Mors O, Mendlewicz J, McGuffin P, Farmer AE, Ingelman-Sundberg M, Craig IW, Aitchison KJ (2012) CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. J Psychopharmacol 26(3):398–407CrossRefGoogle Scholar
  33. 33.
    Zackrisson AL, Lindblom B, Ahlner J (2010) High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther 88(3):354–359CrossRefGoogle Scholar
  34. 34.
    Rahikainen AL, Majaharju S, Haukka J, Palo JU, Sajantila A (2017) Serotonergic 5HTTLPR/rs25531 s-allele homozygosity associates with violent suicides in male citalopram users. Am J Med Genet B Neuropsychiatr Genet 174:691–700CrossRefGoogle Scholar
  35. 35.
    Rahikainen AL, Palo JU, Haukka J, Sajantila A (2018) Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females. Pharmacogenet Genomics 28(4):99–106Google Scholar
  36. 36.
    Koskela L, Raatiniemi L, Bakke HK, Ala-Kokko T, Liisanantti J (2017) Do pre-hospital poisoning deaths differ from in-hospital deaths? A retrospective analysis. Scand J Trauma Resusc Emerg Med 25(1):48CrossRefGoogle Scholar
  37. 37.
    Launiainen T, Vuori E, Ojanpera I (2009) Prevalence of adverse drug combinations in a large post-mortem toxicology database. Int J Legal Med 123(2):109–115CrossRefGoogle Scholar
  38. 38.
    Koski A, Ojanpera I, Vuori E (2003) Interaction of alcohol and drugs in fatal poisonings. Hum Exp Toxicol 22(5):281–287CrossRefGoogle Scholar
  39. 39.
    Wendt FR, Sajantila A, Moura-Neto RS, Woerner AE, Budowle B (2018) Full-gene haplotypes refine CYP2D6 metabolizer phenotype inferences. Int J Legal Med 132(4):1007–1024CrossRefGoogle Scholar
  40. 40.
    Kroon LA (2007) Drug interactions with smoking. Am J Health Syst Pharm 64(18):1917–1921CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Forensic MedicineUniversity of HelsinkiHelsinkiFinland
  2. 2.Forensic Medicine UnitNational Institute for Health and WelfareHelsinkiFinland
  3. 3.Radboud Institute for Health SciencesRadboud University Medical CenterNijmegenthe Netherlands
  4. 4.Department of Clinical PharmacologyUniversity of Helsinki and Helsinki University Central HospitalHelsinkiFinland
  5. 5.Forensic Genetics UnitNational Institute for Health and WelfareHelsinkiFinland
  6. 6.Department of Public HealthUniversity of HelsinkiHelsinkiFinland
  7. 7.Forensic Toxicology UnitNational Institute for Health and WelfareHelsinkiFinland

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