Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter November 28, 2016

Pharmacogenetic studies: a tool to improve antidepressant therapy

  • Marta Ramos , Cecilia Berrogain , Julia Concha , Laura Lomba , Cristina Belén García and Mª Pilar Ribate EMAIL logo

Abstract

The World Health Organization (WHO) predicts that major depressive disorder (MDD) will be the second leading cause of death and disability by 2020. Nowadays, approximately 60–70% of patients with this disorder have shown the lack of effectiveness and tolerability of the therapy with antidepressants. The US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) are including pharmacogenetic information in the labeling of several antidepressants. The presence of this information represents the relevance of genetic polymorphisms in drug response. These pharmacogenetic studies have been based on the knowledge of genes involved in pharmacokinetic (CYP2D6, CYP2C19 and ABCB1) and pharmacodynamic (SLC6A4, HTR2A, BDNF, GNB3 and FKBP5) processes of antidepressant medications. The knowledge of the genotype of patients with MDD is an important tool for personalized therapy that can improve their clinical response to treatment. In this review, we highlight the most relevant genes involved in the metabolism of antidepressants (ADs) or the genes related to the presence of adverse reactions.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: GreenLife Research Group (Universidad San Jorge) is funded by DGA (Spain): E105.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Porcelli S, Drago A, Fabbri C, Gibiino S, Calati R, Serretti A. Pharmacogenetics of antidepressant response. J Psychiatry Neurosci 2011;36:87–113.10.1503/jpn.100059Search in Google Scholar PubMed PubMed Central

2. Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, De Ronchi D, et al. Pharmacogenetics of antidepressants. Front Pharmacol 2011;2:6.10.3389/fphar.2011.00006Search in Google Scholar PubMed PubMed Central

3. Fabbri C, Serretti A. Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical applications. Curr Psychiatry Rep 2015;17:50.10.1007/s11920-015-0594-9Search in Google Scholar PubMed

4. Gray IC, Nobile C, Muresu R, Ford S, Spurr NK. A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 1995;28:328–32.10.1006/geno.1995.1149Search in Google Scholar PubMed

5. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;41:913–58.10.2165/00003088-200241120-00002Search in Google Scholar PubMed

6. Martis S, Peter I, Hulot JS, Kornreich R, Desnick RJ, Scott SA. Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes. Pharmacogenomics J 2013;13:369–77.10.1038/tpj.2012.10Search in Google Scholar PubMed PubMed Central

7. Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 2015;98:127–34.10.1002/cpt.147Search in Google Scholar PubMed PubMed Central

8. Payan M, Tajik N, Rouini MR, Ghahremani MH. Genotype and allele frequency of CYP2C19*17 in a healthy Iranian population. Med J Islam Repub Iran 2015;29:269.Search in Google Scholar

9. Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013;93:402–8.10.1038/clpt.2013.2Search in Google Scholar PubMed PubMed Central

10. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138:103–41.10.1016/j.pharmthera.2012.12.007Search in Google Scholar PubMed

11. Licinio J, Wong ML. Pharmacogenomics of antidepressant treatment effects. Dialogues Clin Neurosci 2011;13:63–71.10.31887/DCNS.2011.13.1/jlicinioSearch in Google Scholar

12. Breitenstein B, Brückl TM, Ising M, Müller-Myhsok B, Holsboer F, Czamara D. ABCB1 gene variants and antidepressant treatment outcome: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2015;168B:274–83.10.1002/ajmg.b.32309Search in Google Scholar PubMed

13. Sarginson JE, Lazzeroni LC, Ryan HS, Ershoff BD, Schatzberg AF, Murphy GM. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression. Pharmacogenet Genomics 2010;20:467–75.10.1097/FPC.0b013e32833b593aSearch in Google Scholar PubMed

14. Breitenstein B, Scheuer S, Pfister H, Uhr M, Lucae S, Holsboer F, et al. The clinical application of ABCB1 genotyping in antidepressant treatment: a pilot study. CNS Spectr 2014;19:165–75.10.1017/S1092852913000436Search in Google Scholar PubMed

15. Niitsu T, Fabbri C, Bentini F, Serretti A. Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2013;45:183–94.10.1016/j.pnpbp.2013.05.011Search in Google Scholar PubMed

16. Stamm TJ, Rampp C, Wiethoff K, Stingl J, Mössner R, O Malley G, et al. The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression. J Psychopharmacol 2016;30:40–7.10.1177/0269881115620459Search in Google Scholar PubMed

17. Tsai SJ, Hong CJ, Liou YJ. Effects of BDNF polymorphisms on antidepressant action. Psychiatry Investig 2010;7:236–42.10.4306/pi.2010.7.4.236Search in Google Scholar PubMed PubMed Central

18. Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 2010;7:231–5.10.4306/pi.2010.7.4.231Search in Google Scholar PubMed PubMed Central

19. Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol 2012;22:239–58.10.1016/j.euroneuro.2011.10.003Search in Google Scholar PubMed

20. Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, et al. Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline. Int J Neuropsychopharmacol 2003;6:339–46.10.1017/S1461145703003663Search in Google Scholar PubMed

21. Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 2010;15:473–500.10.1038/mp.2008.116Search in Google Scholar PubMed

22. Serretti A, Fabbri C, Pellegrini S, Porcelli S, Politi P, Bellino S, et al. No effect of serotoninergic gene variants on response to interpersonal counseling and antidepressants in major depression. Psychiatry Investig 2013;10:180–9.10.4306/pi.2013.10.2.180Search in Google Scholar PubMed PubMed Central

23. Basu A, Chadda RK, Sood M, Kaur H, Kukreti R. Association of serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms with response to treatment with escitalopram in patients with major depressive disorder: a preliminary study. Indian J Med Res 2015;142:40–5.10.4103/0971-5916.162094Search in Google Scholar PubMed PubMed Central

24. Huezo-Diaz P, Uher R, Smith R, Rietschel M, Henigsberg N, Marusic A, et al. Moderation of antidepressant response by the serotonin transporter gene. Br J Psychiatry 2009;195:30–8.10.1192/bjp.bp.108.062521Search in Google Scholar PubMed

25. Illi A, Poutanen O, Setälä-Soikkeli E, Kampman O, Viikki M, Huhtala H, et al. Is 5-HTTLPR linked to the response of selective serotonin reuptake inhibitors in MDD? Eur Arch Psychiatry Clin Neurosci 2011;261:95–102.10.1007/s00406-010-0126-xSearch in Google Scholar PubMed

26. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66:2621–4.10.1046/j.1471-4159.1996.66062621.xSearch in Google Scholar PubMed

27. Serretti A, Artioli P. The pharmacogenomics of selective serotonin reuptake inhibitors. Pharmacogenomics J 2004;4:233–44.10.1038/sj.tpj.6500250Search in Google Scholar PubMed

28. Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T, et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 1997;2:457–62.10.1038/sj.mp.4000334Search in Google Scholar PubMed

29. Schürks M, Frahnow A, Diener HC, Kurth T, Rosskopf D, Grabe HJ. Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache. J Headache Pain 2014;15:46.10.1186/1129-2377-15-46Search in Google Scholar PubMed PubMed Central

30. Ramos Neto ES, Mágulas JO, Sousa JJ, Moura AC, Pinto GR, Yoshioka FK, et al. Study of polymorphic variants of the serotonin 2A receptor gene (5-HT2A) and its possible effects on smoking habits of a population from northeastern Brazil. Genet Mol Res 2014;13:8268–77.10.4238/2014.October.20.3Search in Google Scholar PubMed

31. Choi MJ, Kang RH, Ham BJ, Jeong HY, Lee MS. Serotonin receptor 2A gene polymorphism (-1438A/G) and short-term treatment response to citalopram. Neuropsychobiology 2005;52:155–62.10.1159/000087847Search in Google Scholar PubMed

32. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 2007;12:247–57.10.1038/sj.mp.4001926Search in Google Scholar PubMed

33. Benedetti F, Dallaspezia S, Colombo C, Lorenzi C, Pirovano A, Smeraldi E. Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant efficacy of fluvoxamine. Eur Psychiatry 2010;25:476–8.10.1016/j.eurpsy.2009.12.007Search in Google Scholar PubMed

34. Spronk D, Arns M, Barnett KJ, Cooper NJ, Gordon E. An investigation of EEG, genetic and cognitive markers of treatment response to antidepressant medication in patients with major depressive disorder: a pilot study. J Affect Disord 2011;128:41–8.10.1016/j.jad.2010.06.021Search in Google Scholar PubMed

35. Matsumoto Y, Fabbri C, Pellegrini S, Porcelli S, Politi P, Bellino S, et al. Serotonin transporter gene: a new polymorphism may affect response to antidepressant treatments in major depressive disorder. Mol Diagn Ther 2014;18:567–77.10.1007/s40291-014-0110-7Search in Google Scholar PubMed

36. Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP. Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 2004;9:879–89.10.1038/sj.mp.4001502Search in Google Scholar PubMed

37. Conrado DJ, Rogers HL, Zineh I, Pacanowski MA. Consistency of drug-drug and gene-drug interaction information in US FDA-approved drug labels. Pharmacogenomics 2013;14:215–23.10.2217/pgs.12.203Search in Google Scholar PubMed

38. Molden E, Braathen P. Celecoxib is often combined with cytochrome P450 2D6 substrates in general clinical practice. Clin Pharmacol Ther 2005;78:93.10.1016/j.clpt.2005.04.009Search in Google Scholar PubMed

39. Quinn GR, Singer DE, Chang Y, Go AS, Borowsky LH, Udaltsova N, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014;114:583–6.10.1016/j.amjcard.2014.05.037Search in Google Scholar PubMed PubMed Central

40. Haufroid V, Hantson P. CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants. Clin Toxicol (Phila) 2015;53:501–10.10.3109/15563650.2015.1049355Search in Google Scholar PubMed

Received: 2016-6-24
Accepted: 2016-10-20
Published Online: 2016-11-28
Published in Print: 2016-12-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 26.4.2024 from https://www.degruyter.com/document/doi/10.1515/dmpt-2016-0019/html
Scroll to top button