Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

  • Chiara Fabbri
  • Alessandro SerrettiEmail author
Genetic Disorders (W Berrettini, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetic Disorders


The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are SLC6A4, HTR2A, BDNF, GNB3, FKBP5, ABCB1, and cytochrome P450 genes (CYP2D6 and CYP2C19). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of SLC6A4, HTR2A, ABCB1, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.


Pharmacogenetics Major depressive disorder Antidepressant Gene Polymorphism Pathway 


Compliance with Ethics Guidelines

Conflict of Interest

Chiara Fabbri declares no conflict of interest.

Alessandro Serretti is or has been a consultant/speaker for Abbott, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Pfizer, Sanofi, and Servier.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382:1575–86.PubMedGoogle Scholar
  2. 2.
    U.S. Burden of Disease Collaborators. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310:591–608.Google Scholar
  3. 3.
    Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009;66:848–56.PubMedGoogle Scholar
  4. 4.
    Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.PubMedGoogle Scholar
  5. 5.
    O’Reilly RL, Bogue L, Singh SM. Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry. 1994;36:467–71.PubMedGoogle Scholar
  6. 6.
    Pare CM, Rees L, Sainsbury MJ. Differentiation of two genetically specific types of depression by the response to anti-depressants. Lancet. 1962;2:1340–3.PubMedGoogle Scholar
  7. 7.
    Franchini L, Serretti A, Gasperini M, Smeraldi E. Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res. 1998;32:255–9.PubMedGoogle Scholar
  8. 8.
    Tansey KE, Guipponi M, Hu X, et al. Contribution of common genetic variants to antidepressant response. Biol Psychiatry. 2013;73:679–82.PubMedGoogle Scholar
  9. 9.•
    Fabbri C, Di Girolamo G, Serretti A. Pharmacogenetics of antidepressant drugs: an update after almost 20 years of research. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:487–520. A recent and comprehensive review of antidepressant pharmacogenetics.PubMedGoogle Scholar
  10. 10.
    Garriock HA, Kraft JB, Shyn SI, et al. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry. 2010;67:133–8.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Ising M, Lucae S, Binder EB, et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry. 2009;66:966–75.PubMedGoogle Scholar
  12. 12.
    Uher R, Perroud N, Ng MY, et al. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am J Psychiatry. 2010;167:555–64.PubMedGoogle Scholar
  13. 13.
    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.PubMedGoogle Scholar
  14. 14.
    Gudayol-Ferre E, Herrera-Guzman I, Camarena B, et al. Prediction of remission of depression with clinical variables, neuropsychological performance, and serotonergic/dopaminergic gene polymorphisms. Hum Psychopharmacol. 2012;27:577–86.PubMedGoogle Scholar
  15. 15.
    Bousman CA, Sarris J, Won ES, et al. Escitalopram efficacy in depression: a cross-ethnicity examination of the serotonin transporter promoter polymorphism. J Clin Psychopharmacol. 2014;34:645–8.PubMedGoogle Scholar
  16. 16.
    Staeker J, Leucht S, Laika B, Steimer W. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomark. 2014;18:20–31.Google Scholar
  17. 17.•
    Fabbri C, Marsano A, Albani D, et al. PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway. Pharmacogenomics J. 2014;14:463–72. Pharmacogenetic study across different samples that used pathway analysis to identify the molecular mechanisms behind the association of a gene with antidepressant response.PubMedGoogle Scholar
  18. 18.
    Noordam R, Direk N, Sitlani CM, et al. Identifying genetic loci associated with antidepressant drug response with drug-gene interaction models in a population-based study. J Psychiatr Res. 2015.Google Scholar
  19. 19.••
    Niitsu T, Fabbri C, Bentini F, Serretti A. Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;45:183–94. The most recent meta-analysis that investigated all the top candidate genes outlined by antidepressant pharmacogenetic studies.PubMedGoogle Scholar
  20. 20.
    Tiwari AK, Zai CC, Sajeev G, Arenovich T, Muller DJ, Kennedy JL. Analysis of 34 candidate genes in bupropion and placebo remission. Int J Neuropsychopharmacol. 2013;16:771–81.PubMedGoogle Scholar
  21. 21.
    Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ. Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet. 2003;123B:19–22.PubMedGoogle Scholar
  22. 22.
    Yoshida K, Higuchi H, Kamata M, et al. The G196A polymorphism of the brain-derived neurotrophic factor gene and the antidepressant effect of milnacipran and fluvoxamine. J Psychopharmacol. 2007;21:650–6.PubMedGoogle Scholar
  23. 23.
    Zou YF, Wang Y, Liu P, et al. Association of BDNF Val66Met polymorphism with both baseline HRQOL scores and improvement in HRQOL scores in Chinese major depressive patients treated with fluoxetine. Hum Psychopharmacol. 2010;25:145–52.PubMedGoogle Scholar
  24. 24.
    Choi MJ, Kang RH, Lim SW, Oh KS, Lee MS. Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res. 2006;1118:176–82.PubMedGoogle Scholar
  25. 25.
    Alexopoulos GS, Glatt CE, Hoptman MJ, et al. BDNF Val66met polymorphism, white matter abnormalities and remission of geriatric depression. J Affect Disord. 2010.Google Scholar
  26. 26.
    Taylor WD, McQuoid DR, Ashley-Koch A, et al. BDNF Val66Met genotype and 6-month remission rates in late-life depression. Pharmacogenomics J. 2010.Google Scholar
  27. 27.
    Kocabas NA, Antonijevic I, Faghel C, et al. Brain-derived neurotrophic factor gene polymorphisms: influence on treatment response phenotypes of major depressive disorder. Int Clin Psychopharmacol. 2011;26:1–10.PubMedGoogle Scholar
  28. 28.
    El-Hage W, Vourc’h P, Gaillard P, et al. The BDNF Val(66)Met polymorphism is associated with escitalopram response in depressed patients. Psychopharmacology (Berl). 2015;232:575–81.Google Scholar
  29. 29.
    Zill P, Baghai TC, Zwanzger P, et al. Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment. Neuroreport. 2000;11:1893–7.PubMedGoogle Scholar
  30. 30.
    Serretti A, Lorenzi C, Cusin C, et al. SSRIs antidepressant activity is influenced by Gbeta3 variants. Eur Neuropsychopharmacol. 2003;13:117–22.PubMedGoogle Scholar
  31. 31.
    Lee HJ, Cha JH, Ham BJ, et al. Association between a G-protein beta3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenomics J. 2004;4:29–33.PubMedGoogle Scholar
  32. 32.
    Keers R, Bonvicini C, Scassellati C, et al. Variation in GNB3 predicts response and adverse reactions to antidepressants. J Psychopharmacol. 2010.Google Scholar
  33. 33.
    Hu Q, Zhang SY, Liu F, et al. Influence of GNB3 C825T polymorphism on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. J Affect Disord. 2014;172C:103–9.PubMedGoogle Scholar
  34. 34.
    Lekman M, Laje G, Charney D, et al. The FKBP5-gene in depression and treatment response—an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort. Biol Psychiatry. 2008;63:1103–10.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Binder EB, Salyakina D, Lichtner P, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004;36:1319–25.PubMedGoogle Scholar
  36. 36.
    Kirchheiner J, Lorch R, Lebedeva E, et al. Genetic variants in FKBP5 affecting response to antidepressant drug treatment. Pharmacogenomics. 2008;9:841–6.PubMedGoogle Scholar
  37. 37.
    Ellsworth KA, Moon I, Eckloff BW, et al. FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder. Pharmacogenet Genomics. 2013;23:156–66.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Zou YF, Wang F, Feng XL, et al. Meta-analysis of FKBP5 gene polymorphisms association with treatment response in patients with mood disorders. Neurosci Lett. 2010;484:56–61.PubMedGoogle Scholar
  39. 39.
    Kato M, Fukuda T, Serretti A, et al. ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:398–404.PubMedGoogle Scholar
  40. 40.
    Nikisch G, Eap CB, Baumann P. Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. Pharmacol Res. 2008;58:344–7.PubMedGoogle Scholar
  41. 41.
    Uhr M, Tontsch A, Namendorf C, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron. 2008;57:203–9.PubMedGoogle Scholar
  42. 42.
    Sarginson JE, Lazzeroni LC, Ryan HS, Ershoff BD, Schatzberg AF, Murphy Jr GM. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression. Pharmacogenet Genomics. 2010;20:467–75.PubMedGoogle Scholar
  43. 43.
    Peters EJ, Slager SL, Kraft JB, et al. Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample. PLoS One. 2008;3, e1872.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Tsai MH, Lin KM, Hsiao MC, et al. Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response. Pharmacogenomics. 2010;11:537–46.PubMedGoogle Scholar
  45. 45.
    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;59:803–7.PubMedGoogle Scholar
  46. 46.
    Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants—a pilot study. Clin Pharmacol Ther. 2004;75:386–93.PubMedGoogle Scholar
  47. 47.
    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;88:354–9.PubMedGoogle Scholar
  48. 48.
    Muller DJ, Kekin I, Kao AC, Brandl EJ. Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. Int Rev Psychiatry. 2013;25:554–71.PubMedGoogle Scholar
  49. 49.
    Yin OQ, Wing YK, Cheung Y, et al. Phenotype-genotype relationship and clinical effects of citalopram in Chinese patients. J Clin Psychopharmacol. 2006;26:367–72.PubMedGoogle Scholar
  50. 50.
    Mrazek DA, Biernacka JM, O’Kane DJ, et al. CYP2C19 variation and citalopram response. Pharmacogenet Genomics. 2011;21:1–9.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Nutt D, Demyttenaere K, Janka Z, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. 2007;21:461–71.PubMedGoogle Scholar
  52. 52.
    Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009;117 Suppl 1:S26–43.PubMedGoogle Scholar
  53. 53.
    Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin trasporter gene expression. J Neurochem. 1996;66:2621–4.PubMedGoogle Scholar
  54. 54.
    Serretti A, Calati R, Mandelli L, De Ronchi D. Serotonin transporter gene variants and behavior: a comprehensive review. Curr Drug Targets. 2006;7:1659–69.PubMedGoogle Scholar
  55. 55.
    McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78:804–14.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Peters EJ, Slager SL, Jenkins GD, et al. Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response. Pharmacogenet Genomics. 2009;19:1–10.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Uher R, Huezo-Diaz P, Perroud N, et al. Genetic predictors of response to antidepressants in the GENDEP project. Pharmacogenomics J. 2009;9:225–33.PubMedGoogle Scholar
  58. 58.
    Kishi T, Yoshimura R, Kitajima T, et al. HTR2A is associated with SSRI response in major depressive disorder in a Japanese cohort. Neuromol Med. 2009.Google Scholar
  59. 59.
    Perlis RH, Fijal B, Adams DH, Sutton VK, Trivedi MH, Houston JP. Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder. Biol Psychiatry. 2009;65:785–91.PubMedGoogle Scholar
  60. 60.
    Horstmann S, Lucae S, Menke A, et al. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010;35:727–40.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Lucae S, Ising M, Horstmann S, et al. HTR2A gene variation is involved in antidepressant treatment response. Eur Neuropsychopharmacol. 2010;20:65–8.PubMedGoogle Scholar
  62. 62.
    Illi A, Setala-Soikkeli E, Viikki M, et al. 5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression. Neuroreport. 2009;20:1125–8.PubMedGoogle Scholar
  63. 63.
    Stein DJ, Daniels WM, Savitz J, Harvey BH. Brain-derived neurotrophic factor: the neurotrophin hypothesis of psychopathology. CNS Spectr. 2008;13:945–9.PubMedGoogle Scholar
  64. 64.
    Cattaneo A, Gennarelli M, Uher R, et al. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology. 2013;38:377–85.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Bath KG, Jing DQ, Dincheva I, et al. BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology. 2012;37:1297–304.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–69.PubMedGoogle Scholar
  67. 67.
    Govindarajan A, Rao BS, Nair D, et al. Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci U S A. 2006;103:13208–13.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Petryshen TL, Sabeti PC, Aldinger KA, et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry. 2010;15:810–5.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Ruiz-Velasco V, Ikeda SR. A splice variant of the G protein beta 3-subunit implicated in disease states does not modulate ion channels. Physiol Genomics. 2003;13:85–95.PubMedGoogle Scholar
  70. 70.
    Klenke S, Kussmann M, Siffert W. The GNB3 C825T polymorphism as a pharmacogenetic marker in the treatment of hypertension, obesity, and depression. Pharmacogenet Genomics. 2011;21:594–606.PubMedGoogle Scholar
  71. 71.
    Hong CJ, Chen TJ, Yu YW, Tsai SJ. Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J. 2006;6:27–33.PubMedGoogle Scholar
  72. 72.
    Kato M, Wakeno M, Okugawa G, et al. Antidepressant response and intolerance to SSRI is not influenced by G-protein beta3 subunit gene C825T polymorphism in Japanese major depressive patients. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1041–4.PubMedGoogle Scholar
  73. 73.
    Kang RH, Hahn SW, Choi MJ, Lee MS. Relationship between G-protein beta-3 subunit C825T polymorphism and mirtazapine responses in Korean patients with major depression. Neuropsychobiology. 2007;56:1–5.PubMedGoogle Scholar
  74. 74.
    Pei H, Li L, Fridley BL, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009;16:259–66.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Beaulieu JM, Gainetdinov RR, Caron MG. Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol. 2009;49:327–47.PubMedGoogle Scholar
  76. 76.
    Dwivedi Y, Rizavi HS, Zhang H, Roberts RC, Conley RR, Pandey GN. Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subjects. Biol Psychiatry. 2010;67:1017–25.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 2012;35:47–56.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology. 2000;141:4107–13.PubMedGoogle Scholar
  79. 79.
    Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34 Suppl 1:S186–95.PubMedGoogle Scholar
  80. 80.
    Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J Clin Endocrinol Metab. 2003;88:277–84.PubMedGoogle Scholar
  81. 81.
    Guidotti G, Calabrese F, Anacker C, Racagni G, Pariante CM, Riva MA. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology. 2013;38:616–27.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Papiol S, Arias B, Gasto C, Gutierrez B, Catalan R, Fananas L. Genetic variability at HPA axis in major depression and clinical response to antidepressant treatment. J Affect Disord. 2007;104:83–90.PubMedGoogle Scholar
  83. 83.
    Sarginson JE, Lazzeroni LC, Ryan HS, Schatzberg AF, Murphy Jr GM. FKBP5 polymorphisms and antidepressant response in geriatric depression. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:554–60.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Tsai SJ, Hong CJ, Chen TJ, Yu YW. Lack of supporting evidence for a genetic association of the FKBP5 polymorphism and response to antidepressant treatment. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:1097–8.PubMedGoogle Scholar
  85. 85.
    Zobel A, Schuhmacher A, Jessen F, et al. DNA sequence variants of the FKBP5 gene are associated with unipolar depression. Int J Neuropsychopharmacol. 2010;13:649–60.PubMedGoogle Scholar
  86. 86.
    Eichelbaum M, Fromm MF, Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit. 2004;26:180–5.PubMedGoogle Scholar
  87. 87.
    Dong C, Wong ML, Licinio J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry. 2009;14:1105–18.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Huang X, Yu T, Li X, et al. ABCB6, ABCB1 and ABCG1 genetic polymorphisms and antidepressant response of SSRIs in Chinese depressive patients. Pharmacogenomics. 2013;14:1723–30.PubMedGoogle Scholar
  89. 89.
    Gex-Fabry M, Eap CB, Oneda B, et al. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit. 2008;30:474–82.PubMedGoogle Scholar
  90. 90.
    Mihaljevic Peles A, Bozina N, Sagud M, Rojnic Kuzman M, Lovric M. MDR1 gene polymorphism: therapeutic response to paroxetine among patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1439–44.PubMedGoogle Scholar
  91. 91.
    Perlis RH, Fijal B, Dharia S, Heinloth AN, Houston JP. Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biol Psychiatry. 2010;67:1110–3.PubMedGoogle Scholar
  92. 92.
    Laika B, Leucht S, Steimer W. ABCB1 (P-glycoprotein/MDR1) gene G2677T/a sequence variation (polymorphism): lack of association with side effects and therapeutic response in depressed inpatients treated with amitriptyline. Clin Chem. 2006;52:893–5.PubMedGoogle Scholar
  93. 93.
    Porcelli S, Fabbri C, Spina E, Serretti A, De Ronchi D. Genetic polymorphisms of cytochrome P450 enzymes and antidepressant metabolism. Expert Opin Drug Metab Toxicol. 2011;7:1101–15.PubMedGoogle Scholar
  94. 94.
    Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther. 2006;31:493–502.PubMedGoogle Scholar
  95. 95.
    Nichols AI, Lobello K, Guico-Pabia CJ, Paul J, Preskorn SH. Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status. J Clin Psychopharmacol. 2009;29:383–6.PubMedGoogle Scholar
  96. 96.
    van der Weide J, van Baalen-Benedek EH, Kootstra-Ros JE. Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype. Ther Drug Monit. 2005;27:478–83.PubMedGoogle Scholar
  97. 97.
    Whyte EM, Romkes M, Mulsant BH, et al. CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly. Int J Geriatr Psychiatry. 2006;21:542–9.PubMedGoogle Scholar
  98. 98.
    Eap CB, Lessard E, Baumann P, et al. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics. 2003;13:39–47.PubMedGoogle Scholar
  99. 99.
    Fukuda T, Nishida Y, Zhou Q, Yamamoto I, Kondo S, Azuma J. The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Eur J Clin Pharmacol. 2000;56:175–80.PubMedGoogle Scholar
  100. 100.
    Fukuda T, Yamamoto I, Nishida Y, et al. Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers. Br J Clin Pharmacol. 1999;47:450–3.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteux G. Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit. 2003;25:738–42.PubMedGoogle Scholar
  102. 102.
    LLerena A, Dorado P, Berecz R, Gonzalez AP, Penas LEM. Effect of CYP2D6 and CYP2C9 genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions. Eur J Clin Pharmacol. 2004;59:869–73.PubMedGoogle Scholar
  103. 103.
    Eap CB, Bondolfi G, Zullino D, et al. Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers. J Clin Psychopharmacol. 2001;21:330–4.PubMedGoogle Scholar
  104. 104.
    Scordo MG, Spina E, Dahl ML, Gatti G, Perucca E. Influence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fluoxetine and norfluoxetine. Basic Clin Pharmacol Toxicol. 2005;97:296–301.PubMedGoogle Scholar
  105. 105.
    Sawamura K, Suzuki Y, Someya T. Effects of dosage and CYP2D6-mutated allele on plasma concentration of paroxetine. Eur J Clin Pharmacol. 2004;60:553–7.PubMedGoogle Scholar
  106. 106.
    Ueda M, Hirokane G, Morita S, et al. The impact of CYP2D6 genotypes on the plasma concentration of paroxetine in Japanese psychiatric patients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:486–91.PubMedGoogle Scholar
  107. 107.
    Dalen P, Dahl ML, Bernal Ruiz ML, Nordin J, Bertilsson L. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther. 1998;63:444–52.PubMedGoogle Scholar
  108. 108.
    Kvist EE, Al-Shurbaji A, Dahl ML, Nordin C, Alvan G, Stahle L. Quantitative pharmacogenetics of nortriptyline: a novel approach. Clin Pharmacokinet. 2001;40:869–77.PubMedGoogle Scholar
  109. 109.
    Morita S, Shimoda K, Someya T, Yoshimura Y, Kamijima K, Kato N. Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients: impact of CYP2D6 genotype on the hydroxylation of nortriptyline. J Clin Psychopharmacol. 2000;20:141–9.PubMedGoogle Scholar
  110. 110.
    Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequence-based CYP2D6 genotyping in the Korean population. Ther Drug Monit. 2006;28:382–7.PubMedGoogle Scholar
  111. 111.
    Fudio S, Borobia AM, Pinana E, et al. Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram. Eur J Pharmacol. 2010;626:200–4.PubMedGoogle Scholar
  112. 112.
    Yu BN, Chen GL, He N, et al. Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19. Drug Metab Dispos. 2003;31:1255–9.PubMedGoogle Scholar
  113. 113.
    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;11:359–67.PubMedGoogle Scholar
  114. 114.
    Rudberg I, Hendset M, Uthus LH, Molden E, Refsum H. Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Ther Drug Monit. 2006;28:102–5.PubMedGoogle Scholar
  115. 115.
    Jin Y, Pollock BG, Frank E, et al. Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. J Clin Pharmacol. 2010;50:62–72.PubMedCentralPubMedGoogle Scholar
  116. 116.
    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. 2008;83:322–7.PubMedGoogle Scholar
  117. 117.
    Hodgson K, Tansey K, Dernovsek MZ, et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. 2014;28:133–41.PubMedGoogle Scholar
  118. 118.
    Steimer W, Zopf K, von Amelunxen S, et al. Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem. 2004;50:1623–33.PubMedGoogle Scholar
  119. 119.
    Shimoda K, Someya T, Yokono A, et al. The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients. J Clin Psychopharmacol. 2002;22:371–8.PubMedGoogle Scholar
  120. 120.
    Kirchheiner J, Brosen K, Dahl ML, et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand. 2001;104:173–92.PubMedGoogle Scholar
  121. 121.
    Jin L, Zuo XY, Su WY, et al. Pathway-based analysis tools for complex diseases: a review. Genomics Proteomics Bioinformatics. 2014;12:210–20.PubMedCentralPubMedGoogle Scholar
  122. 122.•
    Hunter AM, Leuchter AF, Power RA, et al. A genome-wide association study of a sustained pattern of antidepressant response. J Psychiatr Res. 2013;47:1157–65. A re-analyses of STAR*D data that included a genome-wide pathway analysis.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Fabbri C, Crisafulli C, Gurwitz D, et al. Neuronal cell adhesion genes and antidepressant response in three independent samples. Pharmacogenomics J. 2015 [Accepted for publication].Google Scholar
  124. 124.
    Janssen DG, Caniato RN, Verster JC, Baune BT. A psychoneuroimmunological review on cytokines involved in antidepressant treatment response. Hum Psychopharmacol. 2010;25:201–15.PubMedGoogle Scholar
  125. 125.
    Maes M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:664–75.PubMedGoogle Scholar
  126. 126.
    Zhu H, Bogdanov MB, Boyle SH, et al. Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder—possible role for methoxyindole pathway. PLoS One. 2013;8, e68283.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Cutler JA, Rush AJ, McMahon FJ, Laje G. Common genetic variation in the indoleamine-2,3-dioxygenase genes and antidepressant treatment outcome in major depressive disorder. J Psychopharmacol. 2012;26:360–7.PubMedGoogle Scholar
  128. 128.
    Scott GN, DuHadaway J, Pigott E, et al. The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J Immunol. 2009;182:7509–17.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Maes M, Stevens WJ, DeClerck LS, et al. A significantly increased number and percentage of B cells in depressed subjects: results of flow cytometric measurements. J Affect Disord. 1992;24:127–34.PubMedGoogle Scholar
  130. 130.
    Hernandez ME, Martinez-Fong D, Perez-Tapia M, Estrada-Garcia I, Estrada-Parra S, Pavon L. Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder. Eur Neuropsychopharmacol. 2010;20:88–95.PubMedGoogle Scholar
  131. 131.
    Edgar VA, Cremaschi GA, Sterin-Borda L, Genaro AM. Altered expression of autonomic neurotransmitter receptors and proliferative responses in lymphocytes from a chronic mild stress model of depression: effects of fluoxetine. Brain Behav Immun. 2002;16:333–50.PubMedGoogle Scholar
  132. 132.
    Banasr M, Duman RS. Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets. 2007;6:311–20.PubMedGoogle Scholar
  133. 133.
    Duman RS. Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: stress and depression. Dialogues Clin Neurosci. 2009;11:239–55.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Ganea K, Menke A, Schmidt MV, et al. Convergent animal and human evidence suggests the activin/inhibin pathway to be involved in antidepressant response. Transl Psychiatry. 2012;2, e177.PubMedCentralPubMedGoogle Scholar
  135. 135.
    Murphy Jr GM, Sarginson JE, Ryan HS, O’Hara R, Schatzberg AF, Lazzeroni LC. BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenet Genomics. 2013;23:301–13.PubMedGoogle Scholar
  136. 136.
    Hussaini SM, Choi CI, Cho CH, Kim HJ, Jun H, Jang MH. Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior. Neurosci Biobehav Rev. 2014;47:369–83.PubMedGoogle Scholar
  137. 137.
    Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.PubMedCentralPubMedGoogle Scholar
  138. 138.
    Verhaagen J, Oestreicher AB, Grillo M, Khew-Goodall YS, Gispen WH, Margolis FL. Neuroplasticity in the olfactory system: differential effects of central and peripheral lesions of the primary olfactory pathway on the expression of B-50/GAP43 and the olfactory marker protein. J Neurosci Res. 1990;26:31–44.PubMedGoogle Scholar
  139. 139.
    Duric V, Banasr M, Stockmeier CA, et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol. 2013;16:69–82.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Morris RG. Long-term potentiation and memory. Philos Trans R Soc Lond B Biol Sci. 2003;358:643–7.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33:88–109.PubMedGoogle Scholar
  142. 142.
    Cooke JD, Cavender HM, Lima HK, Grover LM. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus. Psychopharmacology (Berl). 2014;231:4429–41.Google Scholar
  143. 143.
    Tanti A, Belzung C. Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific? Neuroscience. 2013;252:234–52.PubMedGoogle Scholar
  144. 144.
    Okamoto H, Voleti B, Banasr M, et al. Wnt2 expression and signaling is increased by different classes of antidepressant treatments. Biol Psychiatry. 2010;68:521–7.PubMedCentralPubMedGoogle Scholar
  145. 145.
    Leu B, Koch E, Schmidt JT. GAP43 phosphorylation is critical for growth and branching of retinotectal arbors in zebrafish. Dev Neurobiol. 2010;70:897–911.PubMedGoogle Scholar
  146. 146.
    Bronicki LM, Jasmin BJ. Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction. RNA. 2013;19:1019–37.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Pechnick RN, Zonis S, Wawrowsky K, et al. Antidepressants stimulate hippocampal neurogenesis by inhibiting p21 expression in the subgranular zone of the hipppocampus. PLoS One. 2011;6, e27290.PubMedCentralPubMedGoogle Scholar
  148. 148.
    Epp JR, Beasley CL, Galea LA. Increased hippocampal neurogenesis and p21 expression in depression: dependent on antidepressants, sex, age, and antipsychotic exposure. Neuropsychopharmacology. 2013;38:2297–306.PubMedCentralPubMedGoogle Scholar
  149. 149.
    Pedram A, Razandi M, Deschenes RJ, Levin ER. DHHC-7 and −21 are palmitoylacyltransferases for sex steroid receptors. Mol Biol Cell. 2012;23:188–99.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Ooishi Y, Kawato S, Hojo Y, et al. Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J Steroid Biochem Mol Biol. 2012;131:37–51.PubMedGoogle Scholar
  151. 151.
    Parker G, Brotchie H. Gender differences in depression. Int Rev Psychiatry. 2010;22:429–36.PubMedGoogle Scholar
  152. 152.
    Tamasi V, Petschner P, Adori C, et al. Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also glutatmatergic- and insulin-mediated neuronal processes. PLoS One. 2014;9, e113662.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Jin M, Wang XM, Tu Y, et al. The negative cell cycle regulator, Tob (transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory. Neuroscience. 2005;131:647–59.PubMedGoogle Scholar
  154. 154.
    Liu X, Bates R, Yin DM, et al. Specific regulation of NRG1 isoform expression by neuronal activity. J Neurosci. 2011;31:8491–501.PubMedCentralPubMedGoogle Scholar
  155. 155.
    Gerstein H, O’Riordan K, Osting S, Schwarz M, Burger C. Rescue of synaptic plasticity and spatial learning deficits in the hippocampus of Homer1 knockout mice by recombinant adeno-associated viral gene delivery of Homer1c. Neurobiol Learn Mem. 2012;97:17–29.PubMedCentralPubMedGoogle Scholar
  156. 156.
    Serretti A, Olgiati P, Bajo E, Bigelli M, De Ronchi D. A model to incorporate genetic testing (5-HTTLPR) in pharmacological treatment of major depressive disorders. World J Biol Psychiatry. 2011;12:501–15.PubMedGoogle Scholar
  157. 157.••
    Winner J, Allen JD, Altar CA, Spahic-Mihajlovic A. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry. 2013;3:e242. The first study demonstrating that genotyping can impact on health resource utilization in anxiety and depressive disorders treated with antidepressants.PubMedCentralPubMedGoogle Scholar
  158. 158.••
    Breitenstein B, Scheuer S, Pfister H, et al. The clinical application of ABCB1 genotyping in antidepressant treatment: a pilot study. CNS Spectr. 2014;19:165–75. The first study demonstrating that a treatment algorithm based on ABCB1 genotyping is able to improve antidepressant treatment outcome in major depression.PubMedGoogle Scholar
  159. 159.
    Laje G, McMahon FJ. Genome-wide association studies of antidepressant outcome: a brief review. Prog Neuropsychopharmacol Biol Psychiatry. 2010.Google Scholar
  160. 160.
    Shen X, Carlborg O. Beware of risk for increased false positive rates in genome-wide association studies for phenotypic variability. Front Genet. 2013;4:93.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.PubMedGoogle Scholar
  162. 162.
    Fabbri C, Minarini A, Niitsu T, Serretti A. Understanding the pharmacogenetics of selective serotonin reuptake inhibitors. Expert Opin Drug Metab Toxicol. 2014;10:1093–118.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Biomedical and Neuromotor SciencesUniversity of BolognaBolognaItaly

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