Precision Psychiatry: Personalized Clinical Approach to Depression

  • Giampaolo Perna
  • Raffaele Balletta
  • Charles B. NemeroffEmail author


Major depressive disorder (MDD) is a common and debilitating illness, often causing disability and premature death, with a significant rate of non-response to current therapies. Precision medicine is based on the assumption that every person is relatively unique and proposes to tailor the health care of each individual by integrating information about clinical features, genetic and epigenetic factors, and other biomarkers and environmental influences. The “personalized medicine” approach in MDD as in all of medicine is the ultimate goal to identify predictors that can be used in clinical practice and can guide psychiatrists in improving treatment outcomes and reducing side effects.


Major depressive disorder Personalized medicine Biomarkers Endophenotypes Antidepressants 



The authors thank Alessandra Alciati, MD, for her help in the preparation of the chapter.

Financial Disclosures

Dr. Nemeroff discloses Research/Grants: National Institutes of Health (NIH), Stanley Medical Research Institute; Consulting (last 3 years): Xhale, Takeda, Taisho Pharmaceutical Inc., Prismic Pharmaceuticals, Bracket (Clintara), Total Pain Solutions (TPS), Gerson Lehrman Group (GLG) Healthcare & Biomedical Council, Fortress Biotech, Sunovion Pharmaceuticals Inc., Sumitomo Dainippon Pharma, Janssen Research & Development LLC, Magstim, Inc.; Stockholder: Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Bracket Intermediate Holding Corp., Network Life Sciences Inc., Antares;

Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF) (formerly named National Alliance for Research on Schizophrenia and Depression [NARSAD]), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Bracket (Clintara), RiverMend Health LLC, Laureate Institute for Brain Research, Inc.; Board of Directors:

AFSP, Gratitude America, ADAA; Income sources or equity of $10,000 or more:

American Psychiatric Publishing, Xhale, Bracket (Clintara), CME Outfitters, Takeda; Patents:

Method and devices for transdermal delivery of lithium (US 6,375,990B1); Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2); Speakers Bureau: None.

All other authors report no financial relationships with commercial interests.


  1. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, Mohebbi-Rasa S, Raznahan M, Kamalipour A. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety. 2009;26:607–11.PubMedCrossRefGoogle Scholar
  2. Alhajji L, Nemeroff CB. Personalized Medicine and Mood Disorders. Psychiatr Clin North Am. 2015;38(3):395–403.PubMedCrossRefGoogle Scholar
  3. Altar CA, Carhart J, Allen JD, Hall-Flavin D, Winner J, Dechairo B. Clinical utility of combinatorial pharmacogenomics-guided antidepressant therapy: evidence from three clinical studies. Mol Neuropsychiatry. 2015;1(3):145–55.PubMedPubMedCentralCrossRefGoogle Scholar
  4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Publishing; 2013.CrossRefGoogle Scholar
  5. American Psychiatric Association (APA) (2010) Practice guideline for the treatment of patients with major depressive disorder. Accessed May 2017.
  6. Aratò M, Bankl CM, Bissette G, Nemeroff CB. Elevated CSF CRF in suicide victims. Biol Psychiatry. 1989;25(3):355–9.PubMedCrossRefGoogle Scholar
  7. Arnow BA, Blasey C, Williams LM, Palmer DM, Rekshan W, Schatzberg AF, Etkin A, Kulkarni J, Luther JF, Rush AJ. Depression subtypes in predicting antidepressant response: a report from the iSPOT-D trial. Am J Psychiatry. 2015;172(8):743–50.PubMedCrossRefGoogle Scholar
  8. Arns M, Etkin A, Hegerl U, Williams LM, DeBattista C, Palmer DM, Fitzgerald PB, Harris A, deBeuss R, Gordon E. Frontal and rostral anterior cingulate (rACC) theta EEG in depression: implications for treatment outcome? Eur Neuropsychopharmacol. 2015;25(8):1190–200.PubMedCrossRefGoogle Scholar
  9. Arns M, Bruder G, Hegerl U, Spooner C, Palmer DM, Etkin A, Fallahpour K, Gatt JM, Hirshberg L, Gordon E. EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study. Clin Neurophysiol. 2016;127(1):509–19.PubMedCrossRefGoogle Scholar
  10. Aubry JM, Gervasoni N, Osiek C, Perret G, Rossier MF, Bertschy G, Bondolfi G. The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressed outpatients. J Psychiatr Res. 2007;41:290–4.PubMedCrossRefGoogle Scholar
  11. Baldwin DS, Papakostas GI. Symptoms of fatigue and sleepiness in major depressive disorder. J Clin Psychiatry. 2006;67(Suppl 6):9–15.Google Scholar
  12. Başterzi AD, Yazici K, Aslan E, Delialioğlu N, Taşdelen B, Tot Acar S, Yazici A. Effects of fluoxetine and venlafaxine on serum brain derived neurotrophic factor levels in depressed patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33(2):281–5.CrossRefGoogle Scholar
  13. Belzeaux R, Bergon A, Jeanjean V, Loriod B, Formisano-Tréziny C, Verrier L, Loundou A, Baumstarck-Barrau K, Boyer L, Gall V, Gabert J, Nguyen C, Azorin JM, Naudin J, Ibrahim EC. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl Psychiatry. 2012;13(2):e185.CrossRefGoogle Scholar
  14. Berg JM, Kennedy JC, Dunlop BW, Ramirez CL, Stewart LM, Nemeroff CB, Mayberg HS, Craighead WE. The structure of personality disorders within a depressed sample: implications for personalizing treatment. Pers Med Psychiatr. 2017;1–2:59–64.PubMedCentralGoogle Scholar
  15. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Künzel 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, Köhnlein O, Dabitz H, Brückl T, Müller N, Pfister H, Lieb R, Mueller JC, Lõhmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004;36(12):1319–25.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Binder EB, Kunzel HE, Nickel T, Kern N, Pfennig A, Majer M, Uhr M, Ising M, Holsboer F. HPA axis regulation at in-patient admission is associated with antidepressant therapy outcome in male but not in female depressed patients. Psychoneuroendocrinology. 2009;34:99–109.PubMedCrossRefGoogle Scholar
  17. Binder EB, Owens MJ, Liu W, Deveau TC, Rush AJ, Trivedi MH, Fava M, Bradley B, Ressler KJ, Nemeroff CB. Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response. Arch Gen Psychiatry. 2010;67(4):369–79.PubMedCrossRefGoogle Scholar
  18. Biomarker Definition Working Group. Biomarkers and surrogate endpoints: preferred definition and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.CrossRefGoogle Scholar
  19. Bousman CA, Hopwood M. Commercial pharmacogenetic-based decision-support tools in psychiatry. Lancet Psychiatry. 2016;3(6):585–90.PubMedCrossRefGoogle Scholar
  20. Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W, Gillespie CF, Berg T, Evces M, Newport DJ, Stowe ZN, Heim CM, Nemeroff CB, Schwartz A, Cubells JF, Ressler KJ. Influence of child abuse on adult depression: moderation of corticotropin-releasing hormone receptor gene. JAMA Psychiatry. 2008;65(2):190–200.Google Scholar
  21. Brent D, Melhem N, Ferrell R, Emslie G, Wagner KD, Ryan N, Vitiello B, Birmaher B, Mayes T, Zelazny J, Onorato M, Devlin B, Clarke G, DeBar L, Keller M. Association of FKBP5 polymorphisms with suicidal events in the treatment of resistant depression in adolescents (TORDIA) study. Am J Psychiatry. 2010;167(2):190–7.PubMedCrossRefGoogle Scholar
  22. Bruder GE, Sedoruk JP, Stewart JW, McGrath PJ, Quitkin FM, Tenke CE. Electroencephalographic alpha measures predict therapeutic response to a selective serotonin reuptake inhibitor antidepressant: pre- and post-treatment findings. Biol Psychiatry. 2008;63:1171–7.PubMedCrossRefGoogle Scholar
  23. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by polymorphism in the 5-HTT gene. Science. 2003;301(5631):386–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Coelho R, Viola TW, Walss-Bass C, Brietzke E, Grassi-Oliveira R. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand. 2014;129(3):180–92.PubMedCrossRefGoogle Scholar
  25. Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, De Ronchi D, Serretti A. Pharmacogenetics of antidepressants. Front Pharmacol. 2011;2:6.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Deuschle M, Hamann B, Meichel C, Krumm B, Lederbogen F, Kniest A, Colla M, Heuser I. Antidepressive treatment with amitriptyline and paroxetine: effects on saliva cortisol concentrations. J Clin Psychopharmacol. 2003;23(2):201–5.PubMedCrossRefGoogle Scholar
  27. Dichter GS, Gibbs D, Smoski MJ. A systematic review of relations between resting state functional-MRI and treatment response in major depressive disorder. J Affect Disord. 2014;172:8–17.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Domschke K, Tidow N, Schwarte K, Deckert J, Lesch KP, Arolt V, Zwanzger P, Baune BT. Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response. Int J Neuropsychopharmacol. 2014;17(8):1167–76.PubMedCrossRefGoogle Scholar
  29. Dunlop BW, Rajendra JK, Craighead WE, Kelley ME, McGrath CL, Choi KS, Kinkead B, Nemeroff CB, Mayberg HS. Functional connectivity of the subcallosal cingulate cortex and differential outcomes to treatment with cognitive-behavioral therapy or antidepressant medication for major depressive disorder. Am J Psychiatry. 2017;174(6):533–45.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Eller T, Vasar V, Shlik J, Maron E. Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32(2):445–50.CrossRefGoogle Scholar
  31. Fabbri C, Hosak L, Mössner R, Giegling I, Mandelli L, Bellivier F, Claes S, Collier DA, Corrales A, Delisi LE, Gallo C, Gill M, Kennedy JL, Leboyer M, Lisoway A, Maier W, Marquez M, Massat I, Mors O, Muglia P, Nöthen MM, O’Donovan MC, Ospina-Duque J, Propping P, Shi Y, St Clair D, Thibaut F, Cichon S, Mendlewicz J, Rujescu D, Serretti A. Consensus paper of the WFSBP Task Force on Genetics: eenetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response. World J Biol Psychiatry. 2017;18(1):5–28.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Gao J, Pan Z, Jiao Z, Li F, Zhao G, Wei Q, Pan F, Evangelou E. TPH2 gene polymorphisms and major depression - a metaanalysis. PLoS One. 2012;7(5):e367271.Google Scholar
  33. García-González J, Tansey KE, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Žagar T, Czerski PM, Jerman B, Buttenschøn HN, Schulze TG, Zobel A, Farmer A, Aitchison KJ, Craig I, McGuffin P, Giupponi M, Perroud N, Bondolfi G, Evans D, O’Donovan M, Peters TJ, Wendland JR, Lewis G, Kapur S, Perlis R, Arolt V, Domschke K, Breen G, Curtis C, Sang-Hyuk L, Kan C, Newhouse S, Patel H, Baune BT, Uher R, Lewis CM, Fabbri C, Major Depressive Disorder Working Group of the Psychiatric Genomic Consortium. Pharmacogenetics of antidepressant response: a polygenic approach. Prog Neuro-Psychopharmacol Biol Psychiatry. 2017;75:128–34.CrossRefGoogle Scholar
  34. GENDEP Investigators, MARS Investigators, STAR*D Investigators. Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetics studies. Am J Psychiatry. 2013;170(2):207–21.CrossRefGoogle Scholar
  35. Gizatullin R, Zaboli G, Jonsson EG, Asberg M, Leopardi R. Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression. Biol Psychiatry. 2006;59(4):295–300.PubMedCrossRefGoogle Scholar
  36. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–45.PubMedCrossRefGoogle Scholar
  37. Greden F, Gardner R, King D, Grunhaus L, Carroll J, Kronfol Z. Dexamethasone suppression test in antidepressant treatment of melancholia. Arch Gen Psychiatry. 1983;40:493–500.PubMedCrossRefGoogle Scholar
  38. Green E, Goldstein-Piekarski AN, Schatzberg AF, Rush AJ, Ma J, Williams L. Personalizing antidepressant choice by sex, body mass index, and symptom profile: an iSPOT-D report. Pers Med Psychiatr. 2017;1–2:65–73.Google Scholar
  39. Hecht H, van Calker D, Berger M, von Zerssen D. Personality in patients with affective disorders and their relatives. J Affect Disord. 1998;5(1):33–43.PubMedCrossRefGoogle Scholar
  40. Hobara T, Uchida S, Otsuki K, Matsubara T, Funato H, Matsuo K, Suetsugi M, Watanabe Y. Altered gene expression of histone deacetylases in mood disorder patients. J Psychiatr Res. 2010;44(5):263–70.PubMedCrossRefGoogle Scholar
  41. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71(2):171–86.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Iga J, Ueno S, Yamauchi K, Numata S, Kinouchi S, Tayoshi-Shibuya S, Song H, Ohmori T. Altered HDAC5 and CREB mRNA expressions in the peripheral leukocytes of major depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(3):628–32.CrossRefGoogle Scholar
  43. Jablensky A. The conflict of the nosologists: views on schizophrenia and manic-depressive illness in the early part of the 20th century. Schizophr Res. 1999;39:95–100.PubMedCrossRefGoogle Scholar
  44. Jakubovski E, Bloch MH. Prognostic subgroups for citalopram response in the STAR*D trial. J Clin Psychiatry. 2014;75(7):738–47.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Januar V, Ancelin ML, Ritchie K, Saffery R, Ryan J. BDNF promoter methylation and genetic variation in late-life depression. Transl Psychiatry. 2015;5:e619.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Jha MK, Minhajuddin A, Gadad BS, Greer T, Grannemann B, Soyombo A, Mayes TL, Rush AJ, Trivedi MH. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017;78:105–13.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Juckel G, Pogarell O, Augustin H, Mulert C, Müller-Siecheneder F, Frodl T, Mavrogiorgou P, Hegerl U. Differential prediction of first clinical response to sertonergic and noadrenergic antidepressants using the loudness dependence of auditory evoked potentials in patients with major depressive disorder. J Clin Psychiatry. 2007;68:1206–12.PubMedCrossRefGoogle Scholar
  48. Kang HJ, Kim JM, Stewart R, Kim SY, Bae KY, Kim SW, Shin IS, Shin MG, Yoon JS. Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;44:23–8.CrossRefGoogle Scholar
  49. Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2010;15(5):473–500.PubMedCrossRefGoogle Scholar
  50. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342(20):1462–70.PubMedCrossRefGoogle Scholar
  51. Khodayari-Rostamabad A, Reilly JP, Hasey GM, de Bruin H, Maccrimmon DJ. A machine learning approach using EEG data to predict response to SSRI treatment for major depressive disorder. Clin Neurophysiol. 2013;124(10):1975–85.PubMedCrossRefGoogle Scholar
  52. Knott VJ, Telner JI, Lapierre YD, Browne M, Horn ER. Quantitative EEG in the prediction of antidepressant response to imipramine. J Affect Disord. 1996;39:175–84.PubMedCrossRefGoogle Scholar
  53. Knott V, Mahoney C, Kennedy S, Evans K. Pre-treatment EEG and its relationship to depression severity and paroxetine treatment outcome. Pharmacopsychiatry. 2000;22:201–5.CrossRefGoogle Scholar
  54. Koo PC, Thome J, Berger C, Foley P, Hoeppner J. Current source density analysis of resting state EEG in depression: a review. J Neural Transm. 2017;124(1):109–18.PubMedCrossRefGoogle Scholar
  55. Korte SM, Prins J, Krajnc AM, Hendriksen H, Oosting RS, Westphal KG, Korte-Bouws GAH, Olivier B. The many different faces of major depression: it is time for personalized medicine. Eur J Pharmacol. 2015;753:88–104.PubMedCrossRefGoogle Scholar
  56. Kunugi H, Hori H, Ogawa S. Biochemical markers subtyping major depressive disorder. Psychiatry Clin Neurosci. 2015;69(10):597–608.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Labermaier C, Masana M, Müller MB. Biomarkers predicting antidepressant treatment response: how can we advance the field? Dis Markers. 2013;35(1):23–31.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Lamers F, de Jonge P, Nolen WA, Smith JH, Zitman FG, Beekman AT, Penninx BW. Identifying depressive subtypes in a large cohort study: results from the Netherlands study of depression and anxiety (NESDA). J Clin Psychiatry. 2010;71(12):1582–9.PubMedCrossRefGoogle Scholar
  59. Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW. Evidence for a differential role of HPA axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013;18(6):692–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lee BH, Park YM, Lee SH, Shim M. Prediction of long-term treatment response to selective serotonin reuptake inhibitors (SSRIs) using scalp and source loudness dependence of auditory evoked potentials (LDAEP) analysis in patients with major depressive disorder. Int J Mol. 2015;16(3):6251–65.CrossRefGoogle Scholar
  61. Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJM, Lipsky R, Wisniewski SR, Manji H, McMahon FJ, Paddock S. The FKBP5-gene in depression and treatment response - an action study in the sequenced treatment alternatives to relieve depression (STAR*D) cohort. Biol Psychiatry. 2008;63(12):1103–10.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, Greenwald S. Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in major depressive disorder: results of the BRITE-MD study. Psychiatry Res. 2009;169:124–31.PubMedCrossRefGoogle Scholar
  63. Lewis CC, Simons AD, Nguyen LJ, Murakami JL, Reid MW, Silva SG, et al. Impact of childhood trauma on treatment outcome in the treatment for adolescents with depression study (TADS). J Am Acad Child Adolesc Psychiatry. 2010;49(2):132–40.PubMedGoogle Scholar
  64. Licinio J, Dong C, Wong ML. Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry. 2009;66(5):488–97.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Lisoway AJ, Zai CC, Tiwari AK, Kennedy JL. DNA methylation and clinical response to antidepressant medication in major depressive disorder: a review and recommendations. Neurosci Lett. 2017. Jan [Epub ahead of print].Google Scholar
  66. Liu Z, Zhu F, Wang G, Xiao Z, Wang H, Tang J, Wang X, Qiu D, Liu W, Cao Z, Li W. Association of corticotropin releasing hormone receptor 1 gene SNP and haplotype with major depression. Neurosci Lett. 2006;404(3):358–62.PubMedCrossRefGoogle Scholar
  67. Mamdani F, Berlim MT, Beaulieu MM, Labbe A, Merette C, Turecki G. Gene expression biomarkers of response to citalopram treatment in major depressive disorder. Transl Psychiatry. 2011;21(1):e13.CrossRefGoogle Scholar
  68. McCabe C, Cowen PJ, Harmer CJ. Neural representation of reward in recovered depresses patients. Psychopharmachology. 2009;205(4):667–77.CrossRefGoogle Scholar
  69. McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, Mayberg HS. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70(8):521–9.CrossRefGoogle Scholar
  70. McMakin DL, Olino TM, Porta G, Dietz LJ, Emslie G, Clarke G, Wagner KD, Asarnow JR, Ryan ND, Birmaher B, Shamseddeen W, Mayes T, Kennard B, Spirito A, Keller M, Lynch FL, Dickerson JF, Brent DA. Anhedonia predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-resistant depression. J Am Acad Child Adolesc Psychiatry. 2012;51(4):404–11.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Mikoteit T, Beck J, Eckert A, Hemmeter U, Brand S, Bischof R, Holsboer-Trachsler E, Delini-Stula A. High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression. Psychopharmacology. 2014;231(15):2955–65.PubMedCrossRefGoogle Scholar
  72. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Mocling RJT, Nap TS, Westerink AM, Assies J, Vaz FM, Koeter MWJ, Ruhe HG, Schene AH. Biological profiling of prospective antidepressant response in major depressive disorder: association with (neuro)inflammation, fatty acid metabolism and amygdala reactivity. Psychoneuroendocrinology. 2017;79:84–92.CrossRefGoogle Scholar
  74. Moylan S, Maes M, Wray NR, Berk M. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2013;18(5):595–606.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Mumtaz W, Xia L, Mohd Yasin MA, Azhar Ali SS, Malik AS. A wavelet-based technique to predict treatment outcome for major depressive disorder. PLoS One. 2017;12(2):e0171409.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Myers AJ, Nemeroff CB. New vistas in the management of treatment-refractory psychiatric disorders: genomics and personalized medicine. Focus. 2010;8(4):525–35.CrossRefGoogle Scholar
  77. Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry. 2012;169(2):141–51.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Nase S, Köhler S, Jennebach J, Eckert A, Schweinfurth N, Gallinat J, Lang UE, Kühn S. Role of serum brain derived neurotrophic factor and central N-acetylaspartate for clinical response under antidepressive pharmacotherapy. Neurosignals. 2016;24(1):1–14.PubMedCrossRefGoogle Scholar
  79. Nemeroff CB. Paradise lost: the neurobiological and clinical consequences of child abuse and neglect. Neuron. 2016;89(5):892–909.PubMedCrossRefGoogle Scholar
  80. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson J, Eklund K, Kilts CD, Loosen PT, Vale W. Elevated concentration of CSF corticotropin releasing factor-like immunoreactivity in depressed patients. Science. 1984;226(4680):1342–4.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Nemeroff CB, Heim CM, Thase ME, Klein DN, Shatzberg AF, Ninan PT, McCollough JP, Weiss PM, Dunner DL, Rothbaum BO, Kornstein S, Keitner G, Keller MB. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depressive disorder and childhood trauma. Proc Natl Acad Sci U S A. 2003;100(24):14293–6.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebocontrolled study. Hum Psychopharmacol. 2008;23:87–94.PubMedCrossRefGoogle Scholar
  83. Neto FL, Borges G, Torres-Sanchez S, Mico JA, Berrocoso E. Neurotrophins role in depression neurobiology: a review of basic and clinical evidence. Curr Neuropharmacol. 2011;9(4):530–52.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Nikisch G, Mathé AA, Czernik A, Thiele J, Bohner J, Eap CB, Agren H, Baumann P. Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response. Psychopharmacology. 2005;181(4):751–60.PubMedCrossRefGoogle Scholar
  85. Norman RE, Byambaa M, De R, Butchart A, Scott J, Vos T. The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis. PLoS Med. 2012;9(11):e1001349.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Okada S, Morinobu S, Fuchikami M, Segawa M, Yokomaku K, Kataoka T, Okamoto Y, Yamawaki S, Inoue T, Kusumi I, Koyama T, Tsuchiyama K, Terao T, Kokubo Y, Mimura M. The potential of SLC6A4 gene methylation analysis for the diagnosis and treatment of major depression. J Psychiatr Res. 2014;53(43):47–53.PubMedCrossRefGoogle Scholar
  87. Ozomaro U, Wahlestedt C, Nemeroff CB. Personalized medicine in psychiatry: problems and promises. BMC Med. 2013;11:132.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Papiol S, Arias B, Gastò 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(1–3):83–90.PubMedCrossRefGoogle Scholar
  89. Parekh A, Smeeth D, Milner Y, Thure S. The role of lipid biomarkers in major depression. Healthcare. 2017;5(1):E5.PubMedCrossRefGoogle Scholar
  90. Perna G, Nemeroff CB. Personalized medicine in psychiatry: back to the future. Pers Med Psychiatr. 2017;1–2:1.Google Scholar
  91. Pettai K, Milani L, Tammiste A, Võsa U, Kolde R, Eller T, Nutt D, Metspalu A, Maron E. Whole-genome expression analysis reveals genes associated with treatment response to escitalopram in major depression. Eur Neuropsychopharmacol. 2016;26(9):1475–83.PubMedCrossRefGoogle Scholar
  92. Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacol Rev. 2011;36:183–206.CrossRefGoogle Scholar
  93. Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter ML. BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis. J Affect Disord. 2015;174:432–40.PubMedCrossRefGoogle Scholar
  94. Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2012;22(4):239–58.CrossRefGoogle Scholar
  95. Powell TR, Smith RG, Hackinger S, Schalkwyk LC, Uher R, McGuffin P, Mill PJ, Tansey KE. DNA methylation in interleukin-11 predicts clinical response to antidepressants in GENDEP. Transl Psychiatry. 2013;3:e300.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Prendes-Alvarez S, Nemeroff CB. Personalized medicine: prediction of disease vulnerability in mood disorders. Neurosci Lett. 2016. Oct [Epub ahead of print].Google Scholar
  97. Quilty LC, Marshe V, Lobo DS, Harkness KL, Müller DJ, Bagby RM. Childhood abuse history in depression predicts better response to antidepressants with higher serotonin transporter affinity: a pilot investigation. Neuropsychobiology. 2017;74(2):78–83.CrossRefGoogle Scholar
  98. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31–41.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Rao U, Chen LA, Bidesi AS, Shad MU, Thomas MA, Hammen CL. Hippocampal changes associated with early-life adversity and vulnerability to depression. Biol Psychiatry. 2010;67(4):357–64.PubMedCrossRefGoogle Scholar
  100. Roy A, Hodgkinson CA, DeLuca V, Goldman D, Enoch MA. Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior. J Psychiatry Res. 2012;46(1):72–9.CrossRefGoogle Scholar
  101. Rudolf S, Greggersen W, Kahl KG, Hüppe M, Schweiger U. Elevated IL-6 levels in patients with atypical depression but not in patients with typical depression. Psychiatry Res. 2014;217(1–2):34–8.PubMedCrossRefGoogle Scholar
  102. Sabunciyan S, Aryee MJ, Irizarry RA, Rongione M, Webster MJ, Kaufman WE, Murakami P, Lessard A, Yolken RH, Feinberg AP, Potash JB, GenRED Consortium. Genome-wide DNA methylation scan in major depressive disorder. PLoS ONE. 2012;7(4):e34451.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Schmaal L, Veltman DJ, Van Erp TGM, Samann PG, Frodl T, Jahanshad N, Loehrer E, Tiemeier H, Hofman A, Niessen WJ, Vernooij MW, Ikram MA, Wittfeld K, Grabe HJ, Block A, Hegenscheid K, Völzke H, Hoehn D, Czisch M, Lagopoulos J, Hatton SN, Hickie IB, Goya-Maldonado R, Krämer B, Gruber O, Couvy-Duchesne B, Rentería ME, Strike LT, Mills NT, de Zubicaray GI, McMahon KL, Medland SE, Martin NG, Gillespie NA, Wright MJ, Hall GB, MacQueen GM, Frey EM, Carballedo A, van Velzen LS, van Tol MJ, van der Wee NJ, Veer IM, Walter H, Schnell K, Schramm E, Normann C, Schoepf D, Konrad C, Zurowski B, Nickson T, McIntosh AM, Papmeyer M, Whalley HC, Sussmann JE, Godlewska BR, Cowen PJ, Fischer FH, Rose M, Penninx BW, Thompson PM, Hibar DP. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA major depressive disorder working group. Mol Psychiatry. 2016;21(6):806–12.PubMedCrossRefGoogle Scholar
  104. Schmidt FM, Schroder T, Kirkby KC, Sander C, Suslow T, Holdt LM, Teupser D, Hegerl U, Himmerich H. Pro- and anti-inflammatory cutokines, but not CRP, are inversely correlated with severity and symptoms of major depression. Psychiatry Res. 2016;239:85–91.PubMedCrossRefGoogle Scholar
  105. Sharpley CF, Palanisamy SK, Glyde NS, Dillingham PW, Agnew LL. An update on the interaction between the serotonin transporter promoter variant (5-HTTLPR), stress and depression, plus an exploration of non-confirming findings. Behav Brain Res. 2014;273:89–105.PubMedCrossRefGoogle Scholar
  106. Sheline YI, Price JL, Yan Z, Mintun MA. Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci U S A. 2010;107(24):11020–5.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS. Can’t shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biol Psychiatry. 2002;51(9):693–1007.PubMedCrossRefGoogle Scholar
  108. Sotelo JL, Nemeroff CB. Depression as a systemic disease. Pers Med Psychiatr. 2017;1–2:11–25.Google Scholar
  109. Stenz L, Zewdie S, Laforge-Escarra T, Prados J, La Harpe R, Dayer A, Paoloni-Giacobino A, Perroud N, Aubry JM. BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues. Neurosci Res. 2015;91:1–7.PubMedCrossRefGoogle Scholar
  110. Stewart JW, Quitkin FM, McGrath PJ, Klein DF. Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions. J Affect Disord. 2005;86(2–3):161–7.PubMedCrossRefGoogle Scholar
  111. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: a meta-analysis. Eur Neuropsychopharmacol. 2015;25:1532–43.PubMedCrossRefGoogle Scholar
  112. Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(3):261–8.PubMedCrossRefGoogle Scholar
  113. Tadić A, Müller-Engling L, Schlicht KF, Kotsiari A, Dreimüller N, Kleimann A, Bleich S, Lieb K, Frieling H. Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Mol Psychiatry. 2014;19(3):281–3.PubMedCrossRefGoogle Scholar
  114. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M. STAR*D Study Team: evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D; implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40.PubMedCrossRefGoogle Scholar
  115. Uher R, Dernovsek MZ, Mors O, Hauser J, Souery D, Zobel A, Maier W, Henigsberg N, Kalember P, Rietschel M, Placentino A, Mendlewicz J, Aitchison KJ, McGuffin P, Farmer A. Melancholic, atypical, and anxious depression subtypes and outcome of treatment with escitalopram and nortriptyline. J Affect Disord. 2011;132:112–20.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer A, McGuffin P. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171(12):1278–86.PubMedCrossRefGoogle Scholar
  117. Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150(3):736–44.PubMedCrossRefGoogle Scholar
  118. Van Heesch F, Prins J, Konsman JP, Korte-Bouws GA, Westphal KG, Rybka J, Olivier B, Kraneveld AD, Korte SM. Lipopolysaccharide increases degradation of central monoamines: an in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice. Eur J Pharmacol. 2014;725:55–63.PubMedCrossRefGoogle Scholar
  119. Vreeburg SA, Hoogendijk WJ, van Pelt J, Derijk RH, Verhagen JC, van Dyck R, Smit JH, Zitman FG, Penninx BW. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry. 2009;66(6):617–26.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Wardenaar KJ, Giltay EJ, van Veen T, Zitman FG, Penninx BW. Symptom dimensions as predictors of the two-year course of depressive and anxiety disorders. J Affect Disord. 2012;136(3):1198–203.PubMedCrossRefGoogle Scholar
  121. Wichers M, Myin-Germeys I, Jacobs N, Peeters F, Kenis G, Derom C, Vlietinck R, Delespaul P, Van Os J. Genetic risk of depression and stress-induced negative affect in daily life. Br J Psychiatry. 2007;191:218–23.PubMedCrossRefGoogle Scholar
  122. Williams LM, Debattista C, Duchemin AM, Schatzberg AF, Nemeroff CB. Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression. Transl Psychiatry. 2016;6:e799.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P, Karp B, McCutcheon JE, Geracioti TD Jr, DeBellis MD, Rice KC, Goldstein DS, Veldhuis JD, Chrousos GP, Oldfield EH, McCann SM, Gold PW. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to Hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci U S A. 2000;97:325–30.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Yang JJ, Wang N, Yang C, Shi JY, HY Y, Hashimoto K. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry. 2015;77(3):e19–20.PubMedCrossRefGoogle Scholar
  125. Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwarz DA, Krishnan KRR, Caron MG. Loss-of-function mutation in tryptophan hydroxilase-2 identified in unipolar depression. Neuron. 2005;45:11–6.PubMedCrossRefGoogle Scholar
  126. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M. SNP and haplotype analysis of a novel tryptophan hydrolase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry. 2004;9:1030–6.PubMedCrossRefGoogle Scholar
  127. Zimmermann P, Brückl T, Nocon A, Pfister H, Binder EB, Uhr M, Lieb R, Moffitt TE, Caspi A, Holsboer F, Ising M. Interaction of FKBP5 gene variants and life events in predicting depression onset: results from a 10-years prospective community study. Am J Psychiatry. 2011;168(10):1107–16.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Zou YF, Ye DQ, Feng XL, Su H, Pan FM, Liao FF. Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder. Eur Neuropsychopharmacol. 2010;20(8):535–44.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Giampaolo Perna
    • 1
    • 2
    • 3
  • Raffaele Balletta
    • 1
    • 4
  • Charles B. Nemeroff
    • 2
    Email author
  1. 1.Department of Clinical NeurosciencesHermanas Hospitalarias, Villa San Benedetto Menni Hospital, FoRiPsi, Albese con CassanoComoItaly
  2. 2.Department of Psychiatry and Behavioral SciencesLeonard Miller School of Medicine, Miami UniversityMiamiUSA
  3. 3.Research Institute of Mental Health and Neuroscience and Department of Psychiatry and NeuropsychologyFaculty of Health, Medicine and Life Sciences, University of MaastrichtMaastrichtThe Netherlands
  4. 4.Villa Elisa HospitalCasamarcianoNaplesItaly

Personalised recommendations