Genomic Studies of Treatment Resistance in Major Depressive Disorder

  • Roy H. PerlisEmail author


Treatment-resistant depression describes the subset of individuals with major depressive disorder who do not reach symptomatic remission despite multiple adequate treatment trials. While treatment resistance has a substantial impact on functioning, quality of life, and healthcare costs, little is known about the underlying neurobiology. While at least some treatment-resistant depression (TRD) risk is likely to be heritable, based primarily on evidence from antidepressant pharmacogenomics, studies to date have failed to reliably identify rare or common genetic variation associated with this phenotype. Challenges in the study of TRD include misclassification arising from medication intolerance or inadequate treatment trials, the heterogeneity of the concept itself, and most notably the absence of well-characterized cohorts with DNA available for study. New strategies to identify large cohorts from biobanks or disease registries and efforts to meta-analyze multiple cohorts may facilitate the identification of risk variants. In addition, further studies to understand the potential utility of pharmacogenomic testing among individuals with TRD or to stratify risk for TRD are needed.


Major Depressive Disorder Poor Metabolizers Treatment Resistance Antidepressant Response Extreme Phenotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Alexanderson B, Evans DA, Sjoqvist F (1969) Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 4(5686):764–768PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Anonymous (2014) Table of pharmacogenomic biomarkers in drug labeling, [online]. Available:
  3. 3.
    Anttila S, Viikki M, Huuhka K, Huuhka M, Huhtala H, Rontu R et al (2009) TPH2 polymorphisms may modify clinical picture in treatment-resistant depression. Neurosci Lett 464(1):43–46Google Scholar
  4. 4.
    Calati R, Crisafulli C, Balestri M, Serretti A, Spina E, Calabrò M et al (2013) Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 44:271–278Google Scholar
  5. 5.
    Cantrell CR, Eaddy MT, Shah MB, Regan TS, Sokol MC (2006) Methods for evaluating patient adherence to antidepressant therapy: a real-world comparison of adherence and economic outcomes. Med Care 44(4):300–303Google Scholar
  6. 6.
    Congiu C, Minelli A, Bonvicini C, Bortolomasi M, Sartori R, Maj C et al (2015) The role of the potassium channel gene KCNK2 in major depressive disorder. Psychiatry Res 225(3):489–492Google Scholar
  7. 7.
    Crowley JJ, Brodkin ES, Blendy JA, Berrettini WH, Lucki I (2006) Pharmacogenomic evaluation of the antidepressant citalopram in the mouse tail suspension test. Neuropsychopharmacology 31(11):2433–2442Google Scholar
  8. 8.
    Dannlowski U, Domschke K, Birosova E, Lawford B, Young R, Voisey J et al (2013) Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression. Int J Neuropsychopharmacol 16(7):1443–1459Google Scholar
  9. 9.
    Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA et al (2003) Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 26(2):457–494, xGoogle Scholar
  10. 10.
    Fountoulakis KN, Moller HJ (2011) Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. Int J Neuropsychopharmacol 14(3):405–412Google Scholar
  11. 11.
    Franchini L, Serretti A, Gasperini M, Smeraldi E (1998) Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res 32(5):255–259Google Scholar
  12. 12.
    Gabriela Nielsen M, Congiu C, Bortolomasi M, Bonvicini C, Bignotti S, Abate M et al (2015) MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder. J Affect Disord 183:179–186Google Scholar
  13. 13.
    Gibson TB, Jing Y, Smith Carls G, Kim E, Bagalman JE, Burton WN et al (2010) Cost burden of treatment resistance in patients with depression. Am J Manag Care 16(5):370–377Google Scholar
  14. 14.
    Háber A, Rideg O, Osváth P, Fekete S, Szücs F, Fittler A et al (2013) Patients with difficult-to-treat depression do not exhibit an increased frequency of CYP2D6 allele duplication. Pharmacopsychiatry 46(4):156–160Google Scholar
  15. 15.
    Heimann H (1974) Therapy-resistant depressions: symptoms and syndromes. Contributions to symptomatology and syndromes. Pharmakopsychiatr Neuropsychopharmakol 7(3):139–144Google Scholar
  16. 16.
    Herbild L, Bech M, Gyrd-Hansen D (2009) Estimating the Danish populations’ preferences for pharmacogenetic testing using a discrete choice experiment. The case of treating depression. Value Health 12(4):560–567Google Scholar
  17. 17.
    Houston JP, Lau K, Aris V, Liu W, Fijal BA, Heinloth AN, Perlis RH (2012) Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis. J Clin Psychiatry 73(6):878–885Google Scholar
  18. 18.
    Huuhka K, Kampman O, Anttila S, Huuhka M, Rontu R, Mattila KM et al (2008) RGS4 polymorphism and response to electroconvulsive therapy in major depressive disorder. Neurosci Lett 437(1):25–28Google Scholar
  19. 19.
    Huuhka M, Anttila S, Leinonen E, Huuhka K, Rontu R, Mattila KM et al (2005) The apolipoprotein E polymorphism is not associated with response to electroconvulsive therapy in major depressive disorder. J ECT 21(1):7–11Google Scholar
  20. 20.
    Keers R, Bonvicini C, Scassellati C, Uher R, Placentino A, Giovannini C et al (2011) Variation in GNB3 predicts response and adverse reactions to antidepressants. J Psychopharmacol 25(7):867–874Google Scholar
  21. 21.
    Li Z, Zhang Y, Wang Z, Chen J, Fan J, Guan Y et al (2013) The role of BDNF, NTRK2 gene and their interaction in development of treatment-resistant depression: data from multicenter, prospective, longitudinal clinic practice. J Psychiatr Res 47(1):8–14Google Scholar
  22. 22.
    Mendlewicz J, Crisafulli C, Calati R, Kocabas NA, Massat I, Linotte S et al (2012) Influence of COX-2 and OXTR polymorphisms on treatment outcome in treatment resistant depression. Neurosci Lett 516(1):85–88Google Scholar
  23. 23.
    O’Reilly RL, Bogue L, Singh SM (1994) Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry 36(7):467–471Google Scholar
  24. 24.
    Oquendo MA, Baca-Garcia E, Kartachov A, Khait V, Campbell CE, Richards M et al (2003) A computer algorithm for calculating the adequacy of antidepressant treatment in unipolar and bipolar depression. J Clin Psychiatry 64(7):825–833Google Scholar
  25. 25.
    Pare CM, Rees L, Sainsbury MJ (1962) Differentiation of two genetically specific types of depression by the response to anti-depressants. Lancet 2(7270):1340–1343Google Scholar
  26. 26.
    Perlis R (2014) Pharmacogenomic testing and personalized treatment of depression. Clin Chem 60(1):53–59Google Scholar
  27. 27.
    Perlis RH (2013) A clinical risk stratification tool for predicting treatment resistance in major depressive disorder. Biol Psychiatry 74(1):7–14Google Scholar
  28. 28.
    Perlis RH, Iosifescu DV, Castro V, Murphy S, Gainer V, Minnier J et al (2012) Using electronic medical records to enable large-scale studies in psychiatry: treatment resistant depression as a model. Psychol Med 42(1):41–50Google Scholar
  29. 29.
    Perlis RH, Moorjani P, Fagerness J, Purcell S, Trivedi MH, Fava M et al (2008) Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study. Neuropsychopharmacology 33(12):2810–2819Google Scholar
  30. 30.
    Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–9Google Scholar
  31. 31.
    Rush A, Trivedi M, Wisniewski S, Nierenberg A, Stewart J, Warden D et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163(11):1905–1917Google Scholar
  32. 32.
    Serretti A, Chiesa A, Calati R, Massat I, Linotte S, Kasper S et al (2011) A preliminary investigation of the influence of CREB1 gene on treatment resistance in major depression. J Affect Disord 128(1–2):56–63Google Scholar
  33. 33.
    Stein MB, Cantrell CR, Sokol MC, Eaddy MT, Shah MB (2006) Antidepressant adherence and medical resource use among managed care patients with anxiety disorders. Psychiatr Serv 57(5):673–680Google Scholar
  34. 34.
    Stewart JA, Kampman O, Huuhka M, Anttila S, Huuhka K, Lehtimäki T et al (2009) ACE polymorphism and response to electroconvulsive therapy in major depression. Neurosci Lett 458(3):122–125Google Scholar
  35. 35.
    Tansey KE, Guipponi M, Hu X, Domenici E, Lewis G, Malafosse A et al (2013) Contribution of common genetic variants to antidepressant response. Biol Psychiatry 73(7):679–682Google Scholar
  36. 36.
    Tansey KE, Rucker JJ, Kavanagh DH, Guipponi M, Perroud N, Bondolfi G et al (2014) Copy number variants and therapeutic response to antidepressant medication in major depressive disorder. Pharmacogenomics J 14(4):395–399Google Scholar
  37. 37.
    Thase ME, Rush AJ (1997) When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 59(Suppl(13)):23–29Google Scholar
  38. 38.
    Viikki M, Anttila S, Kampman O, Illi A, Huuhka M, Setälä-Soikkeli E et al (2010) Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression. Neurosci Lett 477(3):105–108Google Scholar
  39. 39.
    Viikki M, Huuhka K, Leinonen E, Illi A, Setälä-Soikkeli E, Huuhka M et al (2011) Interaction between two HTR2A polymorphisms and gender is associated with treatment response in MDD. Neurosci Lett 501(1):20–24Google Scholar
  40. 40.
    Viikki M, Jarventausta K, Leinonen E, Huuhka K, Mononen N, Lehtimäki T, Kampman O (2013) BDNF polymorphism rs11030101 is associated with the efficacy of electroconvulsive therapy in treatment-resistant depression. Psychiatr Genet 23(3):134–136Google Scholar
  41. 41.
    Viikki M, Kampman O, Illi A, Setälä-Soikkeli E, Anttila S, Huuhka M et al (2010) TPH1 218A/C polymorphism is associated with major depressive disorder and its treatment response. Neurosci Lett 468(1):80–84Google Scholar
  42. 42.
    Warden D, Trivedi MH, Carmody T, Toups M, Zisook S, Lesser I et al (2014) Adherence to antidepressant combinations and monotherapy for major depressive disorder: a CO-MED report of measurement-based care. J Psychiatr Pract 20(2):118–132Google Scholar
  43. 43.
    Zarate C, Duman RS, Liu G, Sartori S, Quiroz J, Murck H (2013) New paradigms for treatment-resistant depression. Ann N Y Acad Sci 1292:21–31Google Scholar
  44. 44.
    Zhang C, Li Z, Wu Z, Chen J, Wang Z, Peng D et al (2014) A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacology (Berl) 231(4):685–693Google Scholar
  45. 45.
    Zhang L, Evans DS, Raheja UK, Stephens SH, Stiller JW, Reeves GM et al (2015) Chronotype and seasonality: morningness is associated with lower seasonal mood and behavior changes in the Old Order Amish. J Affect Disord 174:209–214Google Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Psychiatry and the Center for Human Genetic ResearchCenter for Experimental Drugs and Diagnostics, Massachusetts General HospitalBostonUSA

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