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A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances


This study examined, for the first time, whether a high CYP2D6-CYP2C19 metabolic capacity combination increases the likelihood of suicidal intent severity in a large study cohort. Survivors of a suicide attempt (n=587; 86.8% women) were genotyped for CYP2C19 (*2, *17) and CYP2D6 (*3, *4, *4xN, *5, *6, *10, wtxN) genetic variation and evaluated with the Beck Suicide Intent Scale (SIS). Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt (P<0.01) as measured by the SIS-objective circumstance subscale (odds ratio (OR)=1.37; 95% confidence interval (CI)=1.05–1.78; P=0.02) after adjusting for confounders (gender, age, level of studies, marital status, mental disorders, tobacco use, family history of suicide, personal history of attempts and violence of the attempt). Importantly, the risk was greater in those without a family history of suicide (OR=1.82; CI=1.19–2.77; P=0.002). Further research is warranted to evaluate whether the observed relationship is mediated by the role of CYP2D6 and CYP2C19 involvement in the endogenous physiology or drug metabolism or both.

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  1. Zackrisson AL, Lindblom B, Ahlner J . High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther 2010; 88: 354–359.

    CAS  Article  Google Scholar 

  2. Peñas-Lledó EM, Dorado P, Aguera Z, Gratacos M, Estivill X, Fernandez-Aranda F et al. High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders. Mol Psychiatry 2011; 16: 691–692.

    Article  Google Scholar 

  3. Stingl JC, Viviani R . CYP2D6 in the brain: impact on suicidality. Clin Pharmacol Ther 2011; 89: 352–353.

    CAS  Article  Google Scholar 

  4. Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, Vaquero-Lorenzo C, Baca-Garcia E, Llerena A . CYP2D6 and the severity of suicide attempts. Pharmacogenomics 2012; 13: 179–184.

    Article  Google Scholar 

  5. Llerena A, Dorado P, Peñas-Lledó EM . Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity. Pharmacogenomics 2009; 10: 17–28.

    CAS  Article  Google Scholar 

  6. Peñas-Lledó EM, Llerena A . CYP2D6 variation, behavior and psychopathology: implications for pharmacogenomics-guided clinical trials. Br J Clin Pharmacol 77: 673–683.

  7. Stingl JC, Brockmoller J, Viviani R . Genetic variability of drug metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 2012; 18: 273–287.

    Article  Google Scholar 

  8. Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther 2004; 75: 386–393.

    CAS  Article  Google Scholar 

  9. Kawanishi C, Lundgren S, Agren H, Bertilsson L . Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol 2004; 59: 803–807.

    CAS  Article  Google Scholar 

  10. Lobello KW, Preskorn SH, Guico-Pabia CJ, Jiang Q, Paul J, Nichols AI et al. Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder. J Clin Psychiatry 2010; 71: 1482–1487.

    CAS  Article  Google Scholar 

  11. Tsai MH, Lin KM, Hsiao MC, Shen WW, Lu ML, Tang HS et al. Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response. Pharmacogenomics 2010; 11: 537–546.

    CAS  Article  Google Scholar 

  12. Peñas-Lledó EM, Trejo HD, Dorado P, Ortega A, Jung H, Alonso E et al. CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients. Mol Psychiatry 2013; 18: 8–9.

    Article  Google Scholar 

  13. Gex-Fabry M, Eap CB, Oneda B, Gervasoni N, Aubry JM, Bondolfi G et al. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit 2008; 30: 474–482.

    CAS  PubMed  Google Scholar 

  14. Serretti A, Calati R, Massat I, Linotte S, Kasper S, Lecrubier Y et al. Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes are not associated with response and remission in a sample of depressive patients. Int Clin Psychopharmacol 2009; 24: 250–256.

    Article  Google Scholar 

  15. Kobylecki CJ, Hansen T, Timm S, Wang A, Jakobsen KD, Sørensen HJ et al. The impact of CYP2D6 and CYP2C19 polymorphisms on suicidal behavior and substance abuse disorder among patients with schizophrenia: a retrospective study. Ther Drug Monit 2008; 30: 265–270.

    CAS  Article  Google Scholar 

  16. Höfer P, Schosser A, Calati R, Serretti A, Massat I, Kocabas NA et al. The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk-a European multicentre study on treatment-resistant major depressive disorder. Eur Arch Psychiatry Clin Neurosci 2013; 263: 385–391.

    Article  Google Scholar 

  17. Peñas-Lledó EM, Naranjo ME, Llerena A . Impact of cytochrome P450 genes on suicide attempt and risk. Eur Arch Psychiatry Clin Neurosci 2013; 263: 703–704.

    Article  Google Scholar 

  18. Llerena A, Dorado P, Ramírez R, González I, Alvarez M, Peñas-Lledó EM et al. CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans. Pharmacogenomics 2012; 12: 176–183.

    CAS  Article  Google Scholar 

  19. Sachse C, Brockmoller J, Bauer S, Roots I . Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60: 284–295.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sim SC, Kacevska M, Ingelman-Sundberg M . Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics 2013; 13: 1–11.

    CAS  Article  Google Scholar 

  21. Persson A, Sim SC, Virding S, Onishchenko N, Schulte G, Ingelman-Sundberg M . Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 2013; 19: 733–741.

    Article  Google Scholar 

  22. Sim SC, Nordin L, Andersson TM, Virding S, Olsson M, Pedersen NL et al. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1160–1166.

    CAS  PubMed  Google Scholar 

  23. Beck AT, Schuyler D, Herman I . Development of Suicidal Intent Scales. In: Beck AT (ed). The Prediction of Suicide. Charles Press: Pennsylvania, PA, USA, 1974, pp 45–56.

    Google Scholar 

  24. Dorado P, Cáceres M, Pozo-Guisado E, Wong ML, Licinio J, Llerena A . Development of a PCR-based strategy for CYP2D6 genotyping including gene multiplication of worldwide potential use. Biotechniques 2005; 39: 571–574.

    Article  Google Scholar 

  25. Pedersen RS, Brasch-Andersen C, Sim SC, Bergmann TK, Halling J, Petersen MS et al. Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. Eur J Clin Pharmacol 2010; 66: 1199–1205.

    Article  Google Scholar 

  26. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS . The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 2008; 83: 34–42.

    Article  Google Scholar 

  27. Mrazek DA, Biernacka JM, O'Kane DJ, Black JL, Cunningham JM, Drews MS et al. CYP2C19 variation and citalopram response. Pharmacogenet Genomics 2011; 21: 1–9.

    CAS  Article  Google Scholar 

  28. Villagra D, Goethe J, Schwartz HI, Szarek B, Kocherla M, Gorowski K et al. Novel drug metabolism indices for pharmacogenetic functional status based on combinatory genotyping of CYP2C9, CYP2C19 and CYP2D6 genes. Biomark Med 2011; 5: 427–438.

    CAS  Article  Google Scholar 

  29. Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, Dorado P, Saiz-Ruiz J, Llerena A et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters. J Personal Disord advance online publication, 11 February 2013 (e-pub ahead of print).

  30. Schenk PW, van Fessem MA, Verploegh-Van Rij S, Mathot RA, van Gelder T, Vulto AG et al. Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients. Mol Psychiatry 2008; 13: 597–605.

    CAS  Article  Google Scholar 

  31. Huezo-Diaz P, Perroud N, Spencer EP, Smith R, Sim S, Virding S et al. CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. J Psychopharmacol 2012; 26: 398–407.

    CAS  Article  Google Scholar 

  32. de Vos A, van der Weide J, Loovers HM . Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients. Pharmacogenomics J 2011; 11: 359–367.

    CAS  Article  Google Scholar 

  33. Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E . Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 2008a; 83: 322–327.

    CAS  Article  Google Scholar 

  34. Rudberg I, Hermann M, Refsum H, Molden E . Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Eur J Clin Pharmacol 2008b; 6: 1181–1188.

    Article  Google Scholar 

  35. Schenk PW, van Vliet M, Mathot RA, van Gelder T, Vulto AG, van Fessem MA et al. The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients. Pharmacogenomics J 2010; 10: 219–225.

    CAS  Article  Google Scholar 

  36. Lopez-Castroman J, Jaussent I, Beziat S, Genty C, Olie E, de Leon-Martinez V et al. Suicidal phenotypes associated withfamily history of suicidal behavior and early traumatic experiences. J Affect Disord 142: 193–199.

  37. Mann JJ, Waternaux C, Haas GL, Malone KM . Toward a clinical model of suicidal behavior in psychiatric patients. Am J Psych 1999; 156: 181–1899.

    CAS  Google Scholar 

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This work was supported in part by the Union Europea Fondo Social Europeo (FEDER), Instituto de Salud Carlos III-FIS (PI10/02758) and Gobierno de Extremadura Consejería de Empleo, Empresa e Innovación, FSE (IB13186 and PD10199), CHU Montpellier (PHRC UF 7653), Agence Nationale de la Recherche (ANR NEURO 2007 ‘GENESIS’).

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Correspondence to E Peñas-Lledó.

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Competing interests

Dr Blasco-Fontecilla has received lecture fees from Eli Lilly, AB-Biotics and Shire. The remaining authors declare no conflict of interest.

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Peñas-Lledó, E., Guillaume, S., Naranjo, M. et al. A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances. Pharmacogenomics J 15, 172–176 (2015).

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