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Pharmacogenetics of the Efficacy and Side Effects of Antidepressant Drugs

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Genetic Influences on Response to Drug Treatment for Major Psychiatric Disorders

Abstract

Both major depressive disorder (MDD) and antidepressant drug efficacy show an established evidence of being significantly affected by genetic polymorphisms. Thus, the pharmacogenetics of antidepressants has developed since the 1990s as a promising tool to produce tailored treatments of MDD.

Candidate gene studies were focused on a limited number of genes that were suggested to be involved in antidepressant mechanisms of action by preclinical evidence. Particularly, candidate studies provided quite replicated findings for the serotonin transporter gene (SLC6A4), brain-derived neurotrophic factor (BDNF), some subtypes of serotonin receptors (e.g., HTR2A), and genes involved in antidepressant metabolism and transport (e.g., ABCB1). Genome-wide association studies (GWAS) overcame the need of any a priori hypothesis and allowed the study of hundreds of thousands of polymorphisms throughout the whole genome. GWAS provided interesting signals in some individual genes (e.g., IL-11, NRG1, and RORA), but they also allowed to carry out more comprehensive analysis (e.g., pathway analysis), opening new perspectives.

Some pilot studies recently supported the clinical applicability of genotyping to tailor antidepressant treatments. A combinatorial categorization approach based on polymorphisms in cytochrome P450 genes (CYP2D6, CYP2C19, CYP2C9, and CYP1A2), SLC6A4 and HTR2A genes, was demonstrated to predict healthcare utilization and disability claims in patients treated with antidepressant drugs. Confirmations and further improvements of this tool are expected to receive recommendation for application in clinical practice according to specific guidelines.

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References

  1. Altar CA, Carhart JM, Allen JD, Hall-Flavin DK, Dechairo BM, Winner JG (2015) Clinical validity: combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. Pharmacogenomics J. doi:10.1038/tpj.2014.85

    PubMed  Google Scholar 

  2. Arias B, Fabbri C, Gressier F, Serretti A, Mitjans M, Gasto C, Catalan R, De Ronchi D, Fananas L (2013) TPH1, MAOA, serotonin receptor 2A and 2C genes in citalopram response: possible effect in melancholic and psychotic depression. Neuropsychobiology 67(1):41–47. doi:10.1159/000343388

    Article  CAS  PubMed  Google Scholar 

  3. Baune BT, Dannlowski U, Domschke K, Janssen DG, Jordan MA, Ohrmann P, Bauer J, Biros E, Arolt V, Kugel H, Baxter AG, Suslow T (2010) The interleukin 1 beta (IL1B) gene is associated with failure to achieve remission and impaired emotion processing in major depression. Biol Psychiatry 67(6):543–549. doi:10.1016/j.biopsych.2009.11.004

    Article  CAS  PubMed  Google Scholar 

  4. Bet PM, Verbeek EC, Milaneschi Y, Straver DB, Uithuisje T, Bevova MR, Hugtenburg JG, Heutink P, Penninx BW, Hoogendijk WJ (2015) A common polymorphism in the ABCB1 gene is associated with side effects of PGP-dependent antidepressants in a large naturalistic Dutch cohort. Pharmacogenomics J. doi:10.1038/tpj.2015.38

    PubMed  Google Scholar 

  5. Biernacka JM, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmoller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Baune BT, Kato M, Liu YL, Praphanphoj V, Stingl JC, Tsai SJ, Kubo M, Klein TE, Weinshilboum R (2015) The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response. Transl Psychiatry 5:e553. doi:10.1038/tp.2015.47

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Binder EB (2009) The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 34(Suppl 1):S186–S195. doi:10.1016/j.psyneuen.2009.05.021

    Article  CAS  PubMed  Google Scholar 

  7. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T, Muller N, Pfister H, Lieb R, Mueller JC, Lohmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B (2004) Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 36(12):1319–1325. doi:10.1038/ng1479

    Article  CAS  PubMed  Google Scholar 

  8. Blendy JA (2006) The role of CREB in depression and antidepressant treatment. Biol Psychiatry 59(12):1144–1150

    Article  CAS  PubMed  Google Scholar 

  9. Breitenstein B, Scheuer S, Pfister H, Uhr M, Lucae S, Holsboer F, Ising M, Bruckl TM (2014) The clinical application of ABCB1 genotyping in antidepressant treatment: a pilot study. CNS Spectr 19(2):165–175. doi:10.1017/S1092852913000436

    Article  PubMed  Google Scholar 

  10. Buist-Bouwman MA, De Graaf R, Vollebergh WA, Alonso J, Bruffaerts R, Ormel J (2006) Functional disability of mental disorders and comparison with physical disorders: a study among the general population of six European countries. Acta Psychiatr Scand 113(6):492–500

    Article  CAS  PubMed  Google Scholar 

  11. Bull SJ, Huezo-Diaz P, Binder EB, Cubells JF, Ranjith G, Maddock C, Miyazaki C, Alexander N, Hotopf M, Cleare AJ, Norris S, Cassidy E, Aitchison KJ, Miller AH, Pariante CM (2009) Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry 14(12):1095–1104. doi:10.1038/mp.2008.48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Calati R, Crisafulli C, Balestri M, Serretti A, Spina E, Calabro M, Sidoti A, Albani D, Massat I, Hofer P, Amital D, Juven-Wetzler A, Kasper S, Zohar J, Souery D, Montgomery S, Mendlewicz J (2013) Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 44:271–278. doi:10.1016/j.pnpbp.2013.03.005

    Article  CAS  PubMed  Google Scholar 

  13. Fabbri C, Crisafulli C, Gurwitz D, Stingl J, Calati R, Albani D, Forloni G, Calabrò M, Martines R, Kasper S, Zohar J, Juven-Wetzler A, Souery D, Montgomery S, Mendlewicz J, De Girolamo G, Serretti A (2015) Neuronal cell adhesion genes and antidepressant response in three independent samples. Pharmacogenomics J 15(6):538–548

    Google Scholar 

  14. Fabbri C, Di Girolamo G, Serretti A (2013) Pharmacogenetics of antidepressant drugs: an update after almost 20 years of research. Am J Med Genet B Neuropsychiatr Genet 162B(6):487–520. doi:10.1002/ajmg.b.32184

    Article  PubMed  Google Scholar 

  15. Fabbri C, Marsano A, Albani D, Chierchia A, Calati R, Drago A, Crisafulli C, Calabro M, Kasper S, Lanzenberger R, Zohar J, Juven-Wetzler A, Souery D, Montgomery S, Mendlewicz J, Serretti A (2014) PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway. Pharmacogenomics J 14(5):463–472. doi:10.1038/tpj.2014.15

    Article  CAS  PubMed  Google Scholar 

  16. Fabbri C, Serretti A (2015) Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical applications. Curr Psychiatry Rep 17(7):594. doi:10.1007/s11920-015-0594-9

    Article  Google Scholar 

  17. Garfield LD, Dixon D, Nowotny P, Lotrich FE, Pollock BG, Kristjansson SD, Dore PM, Lenze EJ (2014) Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial. Am J Geriatr Psychiatry 22(10):971–979. doi:10.1016/j.jagp.2013.07.003

    Article  PubMed Central  PubMed  Google Scholar 

  18. Garriock HA, Kraft JB, Shyn SI, Peters EJ, Yokoyama JS, Jenkins GD, Reinalda MS, Slager SL, McGrath PJ, Hamilton SP (2010) A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry 67(2):133–138. doi:10.1016/j.biopsych.2009.08.029

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. GENDEP Investigators; MARS Investigators; STAR*D Investigators (2013) Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies. Am J Psychiatry 170(2):207–217. doi:10.1176/appi.ajp.2012.12020237

    Article  Google Scholar 

  20. Guidotti G, Calabrese F, Anacker C, Racagni G, Pariante CM, Riva MA (2013) Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology 38(4):616–627. doi:10.1038/npp.2012.225

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36(12):2452–2459. doi:10.1038/npp.2011.132

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Hu XZ, Rush AJ, Charney D, Wilson AF, Sorant AJ, Papanicolaou GJ, Fava M, Trivedi MH, Wisniewski SR, Laje G, Paddock S, McMahon FJ, Manji H, Lipsky RH (2007) Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry 64(7):783–792

    Article  CAS  PubMed  Google Scholar 

  23. Hunter AM, Leuchter AF, Power RA, Muthen B, McGrath PJ, Lewis CM, Cook IA, Garriock HA, McGuffin P, Uher R, Hamilton SP (2013) A genome-wide association study of a sustained pattern of antidepressant response. J Psychiatr Res 47(9):1157–1165. doi:10.1016/j.jpsychires.2013.05.002

    Article  PubMed Central  PubMed  Google Scholar 

  24. Ising M, Lucae S, Binder EB, Bettecken T, Uhr M, Ripke S, Kohli MA, Hennings JM, Horstmann S, Kloiber S, Menke A, Bondy B, Rupprecht R, Domschke K, Baune BT, Arolt V, Rush AJ, Holsboer F, Muller-Myhsok B (2009) A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry 66(9):966–975

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Kato M, Serretti A (2010) Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 15(5):473–500

    Article  CAS  PubMed  Google Scholar 

  26. Kawaguchi DM, Glatt SJ (2014) GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis. Pharmacogenomics 15(11):1451–1459. doi:10.2217/pgs.14.96

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Murphy GM Jr, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF (2004) Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 61(11):1163–1169

    Article  CAS  PubMed  Google Scholar 

  28. Niitsu T, Fabbri C, Bentini F, Serretti A (2013) Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 45:183–194. doi:10.1016/j.pnpbp.2013.05.011

    Article  CAS  PubMed  Google Scholar 

  29. Peters EJ, Slager SL, Jenkins GD, Reinalda MS, Garriock HA, Shyn SI, Kraft JB, McGrath PJ, Hamilton SP (2009) Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response. Pharmacogenet Genomics 19(1):1–10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Porcelli S, Drago A, Fabbri C, Gibiino S, Calati R, Serretti A (2011) Pharmacogenetics of antidepressant response. J Psychiatry Neurosci 36(2):87–113

    Article  PubMed Central  PubMed  Google Scholar 

  31. Porcelli S, Drago A, Fabbri C, Serretti A (2011) Mechanisms of antidepressant action: an integrated dopaminergic perspective. Prog Neuropsychopharmacol Biol Psychiatry 35(7):1532–1543

    Article  CAS  PubMed  Google Scholar 

  32. Porcelli S, Fabbri C, Serretti A (2012) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol 22(4):239–258

    Article  CAS  PubMed  Google Scholar 

  33. Porcelli S, Fabbri C, Spina E, Serretti A, De Ronchi D (2011) Genetic polymorphisms of cytochrome P450 enzymes and antidepressant metabolism. Expert Opin Drug Metab Toxicol 7(9):1101–1115

    Article  CAS  PubMed  Google Scholar 

  34. Rosenhagen MC, Uhr M (2010) Single nucleotide polymorphism in the drug transporter gene ABCB1 in treatment-resistant depression: clinical practice. J Clin Psychopharmacol 30(2):209–211

    Article  PubMed  Google Scholar 

  35. Savitz J, Lucki I, Drevets WC (2009) 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol 88(1):17–31. doi:10.1016/j.pneurobio.2009.01.009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Schatzberg AF, DeBattista C, Lazzeroni LC, Etkin A, Murphy GM Jr, Williams LM (2015) ABCB1 genetic effects on antidepressant outcomes: a report from the iSPOT-D trial. Am J Psychiatry. doi:10.1176/appi.ajp.2015.14050680

    Google Scholar 

  37. Secher A, Bukh J, Bock C, Koefoed P, Rasmussen HB, Werge T, Kessing LV, Mellerup E (2009) Antidepressive-drug-induced bodyweight gain is associated with polymorphisms in genes coding for COMT and TPH1. Int Clin Psychopharmacol 24(4):199–203. doi:10.1097/YIC.0b013e32832d6be2

    Article  PubMed  Google Scholar 

  38. Serretti A, Chiesa A, Calati R, Massat I, Linotte S, Kasper S, Lecrubier Y, Antonijevic I, Forray C, Snyder L, Bollen J, Zohar J, De Ronchi D, Souery D, Mendlewicz J (2011) A preliminary investigation of the influence of CREB1 gene on treatment resistance in major depression. J Affect Disord 128(1–2):56–63. doi:10.1016/j.jad.2010.06.025

    Article  CAS  PubMed  Google Scholar 

  39. Sotnikov S, Wittmann A, Bunck M, Bauer S, Deussing J, Schmidt M, Touma C, Landgraf R, Czibere L (2014) Blunted HPA axis reactivity reveals glucocorticoid system dysbalance in a mouse model of high anxiety-related behavior. Psychoneuroendocrinology 48:41–51. doi:10.1016/j.psyneuen.2014.06.006

    Article  CAS  PubMed  Google Scholar 

  40. Tansey KE, Guipponi M, Hu X, Domenici E, Lewis G, Malafosse A, Wendland JR, Lewis CM, McGuffin P, Uher R (2013) Contribution of common genetic variants to antidepressant response. Biol Psychiatry 73(7):679–682. doi:10.1016/j.biopsych.2012.10.030

    Article  CAS  PubMed  Google Scholar 

  41. Tansey KE, Guipponi M, Perroud N, Bondolfi G, Domenici E, Evans D, Hall SK, Hauser J, Henigsberg N, Hu X, Jerman B, Maier W, Mors O, O’Donovan M, Peters TJ, Placentino A, Rietschel M, Souery D, Aitchison KJ, Craig I, Farmer A, Wendland JR, Malafosse A, Holmans P, Lewis G, Lewis CM, Stensbol TB, Kapur S, McGuffin P, Uher R (2012) Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis. PLoS Med 9(10):e1001326. doi:10.1371/journal.pmed.1001326

    Article  PubMed Central  PubMed  Google Scholar 

  42. Udina M, Moreno-Espana J, Navines R, Gimenez D, Langohr K, Gratacos M, Capuron L, de la Torre R, Sola R, Martin-Santos R (2013) Serotonin and interleukin-6: the role of genetic polymorphisms in IFN-induced neuropsychiatric symptoms. Psychoneuroendocrinology 38(9):1803–1813. doi:10.1016/j.psyneuen.2013.03.007

    Article  CAS  PubMed  Google Scholar 

  43. Uher R, Perroud N, Ng MY, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Zagar T, Czerski PM, Jerman B, Larsen ER, Schulze TG, Zobel A, Cohen-Woods S, Pirlo K, Butler AW, Muglia P, Barnes MR, Lathrop M, Farmer A, Breen G, Aitchison KJ, Craig I, Lewis CM, McGuffin P (2010) Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am J Psychiatry 167(5):555–564. doi:10.1176/appi.ajp.2009.09070932

    Article  PubMed  Google Scholar 

  44. Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, Dose T, Ebinger M, Rosenhagen M, Kohli M, Kloiber S, Salyakina D, Bettecken T, Specht M, Putz B, Binder EB, Muller-Myhsok B, Holsboer F (2008) Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 57(2):203–209

    Article  CAS  PubMed  Google Scholar 

  45. Veenit V, Riccio O, Sandi C (2014) CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors. J Psychiatr Res 53:1–7. doi:10.1016/j.jpsychires.2014.02.015

    Article  PubMed  Google Scholar 

  46. Watson JM, Dawson LA (2007) Characterization of the potent 5-HT(1A/B) receptor antagonist and serotonin reuptake inhibitor SB-649915: preclinical evidence for hastened onset of antidepressant/anxiolytic efficacy. CNS Drug Rev 13(2):206–223. doi:10.1111/j.1527-3458.2007.00012.x

    Article  CAS  PubMed  Google Scholar 

  47. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678

    Article  Google Scholar 

  48. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382(9904):1575–1586. doi:10.1016/S0140-6736(13)61611-6

    Article  PubMed  Google Scholar 

  49. Winner J, Allen JD, Altar CA, Spahic-Mihajlovic A (2013) Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry 3:e242. doi:10.1038/tp.2013.2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Zakharyan R, Petrek M, Arakelyan A, Mrazek F, Atshemyan S, Boyajyan A (2012) Interleukin-6 promoter polymorphism and plasma levels in patients with schizophrenia. Tissue Antigens 80(2):136–142. doi:10.1111/j.1399-0039.2012.01886.x

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Viale Carlo Pepoli 5, Bologna, 40123, Italy

    Chiara Fabbri MD & Alessandro Serretti MD, PhD

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Correspondence to Alessandro Serretti MD, PhD .

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  1. Department of Adult Psychiatry, Poznan University of Medical Scienc, Poznan, Poland

    Janusz K. Rybakowski

  2. Department of Biomedical and Neuromotor, University of Bologna, Bologna, Italy

    Alessandro Serretti

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Fabbri, C., Serretti, A. (2016). Pharmacogenetics of the Efficacy and Side Effects of Antidepressant Drugs. In: Rybakowski, J., Serretti, A. (eds) Genetic Influences on Response to Drug Treatment for Major Psychiatric Disorders. Adis, Cham. https://doi.org/10.1007/978-3-319-27040-1_3

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