Combination Strategies in Treatment-Resistant Depression

  • Francisco López-Muñoz
  • Cecilio Álamo
  • Pilar García-García


Treatment-resistant depression (TRD) is a serious public health problem: high prevalence (40–50 % of outpatient depression patients fail to respond satisfactorily to treatment with antidepressants in monotherapy, with the correct dose, regime and duration); social significance (high medical cost); individual suffering it causes (poor prognosis, chronicity, increased risk of suicide). The combination strategy is an option being used more and more frequently at the clinical level, and tends to be effective in 50–60 % of cases, though this varies according to the drug employed. This review analyze the state of the evidence on this therapeutic strategy, focusing on the family of antidepressants known as selective noradrenaline reuptake inhibitors (NARIs), particularly reboxetine, one of the antidepressants most widely used in combination therapy for TRD in recent years. The results obtained in combination strategies with reboxetine–especially in conjunction with SSRIs–suggest that it is a potentially useful tool.


Major Depressive Disorder Remission Rate Combination Strategy Lithium Salt Depression Patient 
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  1. 1.
    Álamo C, López-Muñoz F, Rubio G, et al. Combined treatment with reboxetine in depressed patients with no response to venlafaxine: a six-week follow-up study. Acta Neuropsychiatr. 2007;19:291–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Álamo C, López-Muñoz F, Armada MJ. Agomelatina: un nuevo enfoque farmacológico en el tratamiento de la depresión con traducción clínica. Psiquiatr Biol. 2008;15:125–39.CrossRefGoogle Scholar
  3. 3.
    Amsterdam JD, Hornig-Rohan M. Treatment algorithms in treatment-resistant depression. Clin N Am. 1996;19:371–86.Google Scholar
  4. 4.
    Avenoso A, Facciolà G, Scordo MG, Spina E. No effect of the new antidepressant reboxetine on CYP2D6 activity in healthy volunteers. Ther Drug Monit. 1999;21:577–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Balestri M, Calati R, Souery D, et al. Socio-demographic and clinical predictors of treatment resistant depression: a prospective European multicenter study. J Affect Disord. 2016;189:224–32.CrossRefPubMedGoogle Scholar
  6. 6.
    Bares M, Novak T, Kopecek M, et al. Is combined treatment more effective than switching to monotherapy in patients with resistant depression? A retrospective study. Neuroendocrinol Lett. 2009;30:723–8.PubMedGoogle Scholar
  7. 7.
    Bauer M, Forsthoff A, Baethge C, et al. Lithium augmentation therapy in refractory depression – update 2002. Eur Arch Psychiatr Clin Neurosci. 2003;253:132–9.CrossRefGoogle Scholar
  8. 8.
    Berzewski H, Van Moffaert M, Gagiano CA. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacol. 1997;7:S37–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Bhatara VS, Magnus R, Lynn P, Preskorn S. Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms. Ann Pharmacother. 1998;32:889–91.CrossRefGoogle Scholar
  10. 10.
    Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major depression in a National Community Sample: the National Comorbidity Survey. Am J Psychiatry. 1994;151:979–86.CrossRefPubMedGoogle Scholar
  11. 11.
    Blier P, Szabo S. Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry. 2005;66:S30–40.Google Scholar
  12. 12.
    Blier P, Galzin AM, Langer SZ. Interactions between serotonin uptake inhibitors and alpha-2 adrenergic heteroreceptors in the rat hypothalamus. J Pharmacol Exp Ther. 1990;254:2364–440.Google Scholar
  13. 13.
    Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA. 2008;299:901–13.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Brosen K. Reboxetine: pharmacokinetics in humans. Abstract Booklet Simposium. Sardegna, 1–3 May 1998.Google Scholar
  15. 15.
    Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60:45–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51:183–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Carpenter LL, Milosavljevic N, Schecter JM, et al. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66:1234–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Carvalho AF, Cavalcante JL, Castelo MS, Lima MC. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther. 2007;32:415–28.CrossRefPubMedGoogle Scholar
  20. 20.
    Ciraulo D, Shader R. Fluoxetine drug-drug interactions: I Antidepressants and antipsychotics. J Clin Psychopharmacol. 1990;10:48–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Cowen PJ, Anderson IM. New approaches to treating resistant depression. Adv Psychiatr Treat. 2015;21:315–23.Google Scholar
  22. 22.
    Cuenca E, Alamo C, López-Muñoz F, Coullaut-Jáuregui J. Perfil farmacodinámico y farmacocinético de un nuevo antidepresivo: reboxetine. Psiquiatr Biol. 1999;6:86–90.Google Scholar
  23. 23.
    Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95:81–97.CrossRefPubMedGoogle Scholar
  24. 24.
    Danjou P, Hackett D. Safety and tolerance profile of venlafaxine. Int Clin Psychopharmacol. 1995;10 Suppl 2:15–20.CrossRefPubMedGoogle Scholar
  25. 25.
    De Boer TH, Maura G, Raiteri M, et al. Neurochemical and autonomic pharmacological profiles of the 6 aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropharmacology. 1988;27:399–408.CrossRefPubMedGoogle Scholar
  26. 26.
    De la Gándara J, Agüera L, Ferre F, et al. Eficacia y seguridad de la asociación de antidepresivos. Actas Esp Psiquiatr. 2002;30:75–84.Google Scholar
  27. 27.
    De la Gándara J, Rojo JE, Agüera L, De Pedro JM. Neuropharmacological basis of combining antidepressants. Acta Psychiatr Scand. 2005;112:11–3.CrossRefGoogle Scholar
  28. 28.
    De Montigny C, Silverstone PH, Debonnel G, et al. Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial. J Clin Psychopharmacol. 1999;19:401–6.CrossRefPubMedGoogle Scholar
  29. 29.
    DeBattista C, Solvason HB, Poirier J, et al. A prospective trial of bupropion SR augmentation of partial and nonresponders to serotonin antidepressants. J Clin Psychopharmacol. 2003;23 Suppl 1:27–30.CrossRefPubMedGoogle Scholar
  30. 30.
    Devarajan S, Dursun SM. Citalopram plus reboxetine in treatment-resistant depression. Can J Psychiatr. 2000;45:489–90.Google Scholar
  31. 31.
    Dewilde KE, Levitch CF, Murrough JW, et al. The promise of ketamine for treatment-resistant depression: current evidence and future directions. Ann N Y Acad Sci. 2015;1345:47–58.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Entsuah AR, Huang H, Thase ME. Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitor, or placebo. J Clin Psychiatry. 2001;62:869–77.CrossRefPubMedGoogle Scholar
  33. 33.
    ESEMeD/MHEDEA 2000. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand. 2004;420:21–7.CrossRefGoogle Scholar
  34. 34.
    Fagiolini A, Kupfer DJ. Is treatment-resistant depression a unique subtype of depression? Biol Psychiatr. 2003;53:640–8.CrossRefGoogle Scholar
  35. 35.
    Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatr. 2003;53:649–59.CrossRefGoogle Scholar
  36. 36.
    Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin N Am. 1996;19:179–200.CrossRefGoogle Scholar
  37. 37.
    Fava M, Rosenbaum JF, McGrath PJ, et al. Lithium and tricyclic augmentation of fluoxetina treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry. 1994;151:1372–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Fava M, Rish AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D Report. Am J Psychiatry. 2006;163:1161–72.CrossRefPubMedGoogle Scholar
  39. 39.
    Ferreri M, Lavergne F, Berlin I, et al. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand. 2001;103:66–72.CrossRefPubMedGoogle Scholar
  40. 40.
    Fleishaker JC. Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clin Pharmacokinet. 2000;39:413–27.CrossRefPubMedGoogle Scholar
  41. 41.
    Fleishaker JC, Herman BD, Pearson LK, et al. Evaluation of the potential pharmacokinetic/pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest. 1999;18:141–50.CrossRefGoogle Scholar
  42. 42.
    Fonagy P, Rost F, Carlyle JA, et al. Pragmatic randomized controlled trial of long-term psychoanalytic psychotherapy for treatment-resistant depression: the Tavistock Adult Depression Study (TADS). World Psychiatry. 2015;14:312–21.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Frampton JE, Plosker GL. Duloxetine. A review of its use in the treatment of major depressive disorder. CNS Drugs. 2007;21:581–609.CrossRefPubMedGoogle Scholar
  44. 44.
    Fredman SJ, Fava M, Kienke AS, et al. Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: a survey of current “next-step” practices. J Clin Psychiatr. 2000;61:403–8.CrossRefGoogle Scholar
  45. 45.
    George M, Rush A, Marangell L, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58:364–73.CrossRefPubMedGoogle Scholar
  46. 46.
    Girolamo G. Diferencias transculturales en la depresión. Focus Depression. 1993;3(2):28–40.Google Scholar
  47. 47.
    Gómez-Gómez JM, Teixido-Perramón C. Combined treatment with venlafaxine and tricyclic antidepressants in depressed patients who had partial response to clomipramine or imipramine: initial findings. J Clin Psychiatry. 2000;61:285–9.PubMedGoogle Scholar
  48. 48.
    Gonul AS, Akdeniz F, Donat O, Vahip S. Selective serotonin reuptake inhibitors combined with venlafaxine in depressed patients who had partial response to venlafaxine: four cases. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:889–91.CrossRefPubMedGoogle Scholar
  49. 49.
    Gorman JM, Sullivan MG. Noradrenergic approaches to antidepressant therapy. J Clin Psychiatry. 2000;61 Suppl 1:13–6.PubMedGoogle Scholar
  50. 50.
    Gotto J, Rapaport MH. Treatment options in treatment-resistant depression. Prim Psychiatr. 2005;12:42–50.Google Scholar
  51. 51.
    Greenberg PE, Corey-Lisley PK, Birnbaum HG, et al. Economic implications of treatment-resistant depression among employees. Pharmacoeconomics. 2004;9:83–91.Google Scholar
  52. 52.
    Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465–75.CrossRefPubMedGoogle Scholar
  53. 53.
    Hannan N, Hamzah Z, Omoniyi-Akinpeloye H, Meagher D. Venlafaxine-mirtazapine combination in the treatment of persistent depressive illness. J Psychopharmacol. 2007;21:161–4.CrossRefPubMedGoogle Scholar
  54. 54.
    Harkin A, Kelly JP, McNamara M, et al. Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression. Eur J Pharmacol. 1999;364:123–32.CrossRefPubMedGoogle Scholar
  55. 55.
    Hawley CJ, Sivakumaran T, Ochocki M, Bevan J. Coadministration therapy with reboxetine and serotonin specific reuptake inhibitors in twenty-four patients with major depression. 13th Congress of European College of Neuropsychopharmacology. Munich, September 2000, pp. 9–13.Google Scholar
  56. 56.
    Healy D. Reboxetine, fluoxetine and social functioning as an outcome measure in antidepressant trials: implications. Prim Care Psychiatr. 1998;4:81–9.Google Scholar
  57. 57.
    Hirschfeld RM, Montgomery SA, Aguglia E, et al. Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry. 2002;63:826–37.CrossRefPubMedGoogle Scholar
  58. 58.
    Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs. 1995;49:280–94.CrossRefPubMedGoogle Scholar
  59. 59.
    Horst WD, Preskorn SH. The pharmacology and mode of action of venlafaxine. Rev Contemp Pharmacother. 1998;9:293–302.Google Scholar
  60. 60.
    Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17:111–26.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Joffe RT. Substitution therapy in patients with major depression. CNS Drugs. 1999;11:175–80.CrossRefGoogle Scholar
  62. 62.
    Katona C, Bercoff E, Chiu E, et al. Reboxetine versus imipramine in the treatment of elderly patents with depressive disorders: a double-blind randomised trial. J Affect Disord. 1999;55:203–13.CrossRefPubMedGoogle Scholar
  63. 63.
    Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry. 2005;66:S5–12.CrossRefGoogle Scholar
  64. 64.
    Kennedy SH, Giacobbe P. Treatment resistant depression – advances in somatic therapies. Ann Clin Psychiaty. 2007;19:279–87.CrossRefGoogle Scholar
  65. 65.
    Kennedy SH, McCann SM, Masellis M, et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry. 2002;63:181–6.CrossRefPubMedGoogle Scholar
  66. 66.
    Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet. 2000;355:911–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.CrossRefPubMedGoogle Scholar
  68. 68.
    Kiss B, Horvath A, Nemethy Z, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010;333:328–40.CrossRefPubMedGoogle Scholar
  69. 69.
    Kuhn UD, Kirsch M, Merkel U, et al. Reboxetine and cytochrome P450-comparison with paroxetine treatment in humans. Int Clin Pharmacol Ther. 2007;45:36–46.CrossRefGoogle Scholar
  70. 70.
    Kupfer DJ, Frank E, Perel JM, et al. 5-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1992;49:769–73.CrossRefPubMedGoogle Scholar
  71. 71.
    Kuyken W, Hayes R, Barrett B, et al. Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial. Lancet. 2015;386(9988):63–73.CrossRefPubMedGoogle Scholar
  72. 72.
    Lam RW, Wan DD, Cohen NL, Kennedy SH. Combining antidepressants for treatment-resistant depression: a review. J Clin Psychiatry. 2002;63:685–93.CrossRefPubMedGoogle Scholar
  73. 73.
    Lepine JP, Gastpar M, Mendlewicz J, Tylee A. Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol. 1997;12:19–29.CrossRefPubMedGoogle Scholar
  74. 74.
    López-Muñoz F, Álamo C. Depression at the frontier of the new century. Front Neurosci. 2009;3:226–9.Google Scholar
  75. 75.
    López-Muñoz F, Álamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des. 2009;15:1563–86.CrossRefPubMedGoogle Scholar
  76. 76.
    López-Muñoz F, Rubio G, Alamo C, et al. Reboxetine addition in patients with mirtazapine-resistant depression: a case series. Clin Neuropharmacol. 2006;29:192–6.CrossRefPubMedGoogle Scholar
  77. 77.
    López-Muñoz F, Álamo C, Rubio G, et al. Reboxetine combination in treatment-resistant depression to selective serotonin-reuptake inhibitors. Pharmacopsychiatry. 2007;40:14–9.CrossRefPubMedGoogle Scholar
  78. 78.
    López-Muñoz F, Álamo C, García-García P. Combination strategies in treatment-resistant depression: a focus on selective noradrenaline-reuptake inhibitors. Curr Topics Pharmacol. 2009;13(2):25–50.Google Scholar
  79. 79.
    López-Muñoz F, Álamo C. Contribution of pharmacology to development of monoaminergic hypotheses of depression. In: López-Muñoz F, Álamo C, editors. Neurobiology of depression. Boca Raton: CRC Press Taylor & Francis Group; 2012. p. 119–41.Google Scholar
  80. 80.
    Lucca A, Serretti A, Smeraldi E. Effect of reboxetine augmentation in SRRI resistant patients. Hum Psychopharmacol Clin Exp. 2000;15:143–5.CrossRefGoogle Scholar
  81. 81.
    Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin dopamine activity modulator. J Pharmacol Exp Ther. 2014;350:589–604.CrossRefPubMedGoogle Scholar
  82. 82.
    Malhi GS, Parker GB, Crawford J, et al. Treatment-resistant depression: resistant to definition? Acta Psychiatr Scand. 2005;112:302–9.CrossRefPubMedGoogle Scholar
  83. 83.
    Malhi GS, Ng F, Berk M. Dual-dual action? Combining venlafaxine and mirtazapine in the treatment of depression. Aust NZ J Psychiatry. 2008;42:346–9.CrossRefGoogle Scholar
  84. 84.
    Martín-Águeda B, López-Muñoz F, Rubio G, et al. Management of depression in primary care: a survey of general practitioners in Spain. Gen Hosp Psychiatr. 2005;27:305–12.CrossRefGoogle Scholar
  85. 85.
    McEwen BS, Chattarji S, Diamond DM, et al. The neurobiological properties of Tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry. 2010;15:237–49.CrossRefPubMedGoogle Scholar
  86. 86.
    McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163:1531–41.CrossRefPubMedGoogle Scholar
  87. 87.
    McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1–7.CrossRefPubMedGoogle Scholar
  88. 88.
    Messer T, Schmauss M, Lambert-Baumann J. Efficacy and tolerability of reboxetine in depressive patients treated in routine clinical practice. CNS Drugs. 2005;19:43–54.CrossRefPubMedGoogle Scholar
  89. 89.
    Mongeau R, Blier P, de Montigny C. The serotoninergic and noradrenergic system of the hippocampus: their interactions and the effects of antidepressant treatments. Brain Res Rev. 1997;23:145–95.CrossRefPubMedGoogle Scholar
  90. 90.
    Montgomery SA. Reboxetine: additional benefits to the depressed patients. J Psychopharmakother. 1997;4:S9–15.Google Scholar
  91. 91.
    Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr Serv. 2014;65:977–87.CrossRefPubMedGoogle Scholar
  92. 92.
    Nelson JC. Synergistic benefits of serotonin and noradrenaline reuptake inhibition. Depress Anxiety. 1998;7 Suppl 1:5–6.CrossRefPubMedGoogle Scholar
  93. 93.
    Nelson JC, Mazure CM, Jatlow PI, et al. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatr. 2004;55:296–300.CrossRefGoogle Scholar
  94. 94.
    Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68 Suppl 8:17–25.PubMedGoogle Scholar
  95. 95.
    Nierenberg AA, Amsterdam JD. Resistant depression: definition and treatment approaches. J Clin Psychiatry. 1990;51:S39–47.Google Scholar
  96. 96.
    Nierenberg AA, DeCecco L. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:5–9.PubMedGoogle Scholar
  97. 97.
    Nierenberg AA, Feighner JP, Rudolph R, et al. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol. 1994;14:419–23.CrossRefPubMedGoogle Scholar
  98. 98.
    Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519–30.CrossRefPubMedGoogle Scholar
  99. 99.
    Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin N Am. 2007;30:13–29.CrossRefGoogle Scholar
  100. 100.
    O’Reardon JP, Brunswick DJ, Amsterdam JD. Treatment-resistant depression in the age of serotonin: evolving strategies. Curr Opin Psychiatry. 2000;13:93–8.CrossRefGoogle Scholar
  101. 101.
    O’Reardon J, Solvason H, Janicak P, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–16.CrossRefPubMedGoogle Scholar
  102. 102.
    Otsuka and Lundbeck submit New Drug Application for brexpiprazole for the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression, Press release 14 July 2014.
  103. 103.
    Pagnin D, de Queiroz V, Pini S, et al. Efficacy of ECT: a meta-analytic review. J ECT. 2004;20:13–20.CrossRefPubMedGoogle Scholar
  104. 104.
    Papakostas GI, Worthington JJ, Iosifescu DV, et al. The combination of duloxetine and bupropion for treatment-resistant major depressive disorder. Depress Anxiety. 2006;23:178–81.CrossRefPubMedGoogle Scholar
  105. 105.
    Parker G. ‘New’ and ‘old’ antidepressants: all equal in the eyes of the lore? Br J Psychiatry. 2001;179:95–6.CrossRefPubMedGoogle Scholar
  106. 106.
    Parker GB, Malhi GS, Crawford JG, Thase ME. Identifying ‘paradigm failures’ contributing to treatment-resistant depression. J Affect Disord. 2005;87:185–91.CrossRefPubMedGoogle Scholar
  107. 107.
    Paykel ES. Epidemiology of refractory depression. In: Nolen WA, Zohar J, Rosse SP, editors. Refractory depression: current strategies and future directions. New York: Wiley; 1994. p. 3–18.Google Scholar
  108. 108.
    Pellizzoni C, Poggesi I, Jorgensen NP, et al. Pharmacokinetics of reboxetine in healthy volunteers: single vs repeated oral doses and lack of enzymatic alterations. Biopharm Drug Dispos. 1996;17:623–33.CrossRefPubMedGoogle Scholar
  109. 109.
    Puigdemont D, Portella MJ, Pérez-Egea R, et al. A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatr Neurosci. 2015;40:224–31.CrossRefGoogle Scholar
  110. 110.
    Qureshi NA, Al-Bedah AM. Mood disorders and complementary and alternative medicine: a literature review. Neuropsychiatr Dis Treat. 2013;9:639–58.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Rapaport M, Wilcox C, Heiser J, Londborg P. Reboxetine augmentation or fluoxetine for patients with major depressive disorder: an 8-week open-label study. Eur Neuropsypharmacol. 2002;12:S205.CrossRefGoogle Scholar
  112. 112.
    Ravindran LN, Eisfeld BS, Kennedy SH. Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function. J Clin Psychopharmacol. 2008;28:107–8.CrossRefPubMedGoogle Scholar
  113. 113.
    Rojo JE, Ros S, Agüera L, et al. Combined antidepressant: clinical experience. Acta Psychiatr Scand. 2005;112:25–31.CrossRefGoogle Scholar
  114. 114.
    Ros S, Agüera L, De la Gándara J, et al. Potentiation strategies for treatment-resistant depression. Acta Psychiatr Scand. 2005;112:14–24.CrossRefGoogle Scholar
  115. 115.
    Rubio G, San L, López-Muñoz F, et al. Tratamiento de combinación con reboxetina en pacientes con depresión mayor no respondedores o con respuesta parcial a inhibidores selectivos de la recaptación de serotonina. Actas Esp Psiquiatr. 2003;31:315–24.PubMedGoogle Scholar
  116. 116.
    Rubio G, San L, López-Muñoz F, Alamo C. Reboxetine adjunct for partial or nonresponders to antidepressant treatment. J Affect Disord. 2004;81:67–72.CrossRefPubMedGoogle Scholar
  117. 117.
    Rush AJ, Trivedi M, Fava M. Depression. IV: STAR*D treatment trial for depression. Am J Psychiatry. 2003;160:237.CrossRefPubMedGoogle Scholar
  118. 118.
    Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials. 2004;25:119–42.CrossRefPubMedGoogle Scholar
  119. 119.
    Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31:1841–53.CrossRefPubMedGoogle Scholar
  120. 120.
    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.CrossRefPubMedGoogle Scholar
  121. 121.
    Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. New Eng J Med. 2006;354:1231–42.CrossRefPubMedGoogle Scholar
  122. 122.
    Sáiz-Ruiz J, Ibañez A, Díaz-Marsá M, et al. Eficacia de la venlafaxina en pacientes depresivos resistentes o que no toleran inhibidores selectivos de la recaptación de serotonina. Psiquiatr Biol. 1999;6:106–12.Google Scholar
  123. 123.
    Sargant W. Combining the antidepressant drugs. Lancet. 1963;2:1062.CrossRefGoogle Scholar
  124. 124.
    Schatzberg AF, Cole JO, Cohen BM, et al. Survey of depressed patients who have failed to respond to treatment. In: Davis JM, Maas JW, editors. The affective disorders. Washington, DC: American Psychiatric Press; 1983. p. 73–85.Google Scholar
  125. 125.
    Schule C, Baghai T, Schmidbauer S, et al. Reboxetine acutely stimulates cortisol, ACTH, growth hormone and prolactin secretion in healthy male subjects. Psychoneuroendocrinology. 2004;29:185–200.CrossRefPubMedGoogle Scholar
  126. 126.
    Seguí J, López-Muñoz F, Alamo C, et al. Effects of adjunctive reboxetine in patients with duloxetine-resistant depression: a 12-week prospective study. J Psychopharmacol. 2010;24:1201–7.CrossRefPubMedGoogle Scholar
  127. 127.
    Serretti A, Lucca A, Cusin C, Smeraldi E. Associazione di reboxetine nella depressione resistente a SSRI effect of reboxetine augmentation in SSRI resistant patients. Giornale Ital Psicopatol. 2001;7:9–14.Google Scholar
  128. 128.
    Sheng CX, Chen ZQ, Cui HJ, et al. Is the Chinese medicinal formula Guipi Decoction effective as an adjunctive treatment for depression? A meta-analysis of randomized controlled trials. Chin J Integr Med 2015, Epub 2015 Oct 10.Google Scholar
  129. 129.
    Simon GE, Von Korff M, Barlow W. Health care costs of primary care patients with recognized depression. Arch Gen Psychiatry. 1995;52:850–6.CrossRefPubMedGoogle Scholar
  130. 130.
    Sokolov STH, Joffe RT. Practical guidelines for combination drug therapy of treatment-resistant depression. CNS Drugs. 1995;4:341–50.CrossRefGoogle Scholar
  131. 131.
    Souery D, Amsterdam J, De Montigny C, et al. Treatment-resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9:83–91.CrossRefPubMedGoogle Scholar
  132. 132.
    Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin Psychiatry. 2006;67:16–22.CrossRefPubMedGoogle Scholar
  133. 133.
    Souery D, Serretti A, Calati R, et al. Switching antidepressant class does not improve response or remission in treatment-resistant depression. J Clin Psychopharmacol. 2011;31:512–6.CrossRefPubMedGoogle Scholar
  134. 134.
    Souetre E. Economic evaluation in mental disorders. Community versus Institutional care. Pharmacoeconomics. 1994;3:330–6.Google Scholar
  135. 135.
    Stanley B. An integration of ethical and clinical considerations in the use of placebos. Psychopharmacol Bull. 1988;24:180–220.Google Scholar
  136. 136.
    Sühs KW, Correll C, Eberlein CK, et al. Combination of agomelatine and bupropion for treatment-resistant depression: results from a chart review study including a matched control group. Brain Behav. 2015;5(4):1–6.CrossRefGoogle Scholar
  137. 137.
    Szabo ST, Blier P. Effects of the selective norepinephrine reuptake inhibitors reboxetine on norepinephrine and serotonin transmission in the rat hippocampus. Neuropsychopharmacology. 2001;25:845–57.CrossRefPubMedGoogle Scholar
  138. 138.
    Thase ME, Schwartz TL. Choosing medications for treatment-resistant depression based on mechanism of action. J Clin Psychiatry. 2015;76:720–7.CrossRefPubMedGoogle Scholar
  139. 139.
    Thase M, Friedman E, Biggs M, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:739–52.CrossRefPubMedGoogle Scholar
  140. 140.
    Thomas SJ, Shin M, McInnis MG, Bostwick JR. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: Strategies for the management of treatment-resistant depression. Pharmacotherapy. 2015;35:433–49.CrossRefPubMedGoogle Scholar
  141. 141.
    Trevino K, McClintock SM, Fischer NM, et al. Defining treatment-resistant depression: a comprehensive review of the literature. Ann Clin Psychiatry. 2014;26:222–32.PubMedGoogle Scholar
  142. 142.
    Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-bases care in STAR* D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.CrossRefPubMedGoogle Scholar
  143. 143.
    Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRI for depression. New Eng J Med. 2006;354:1243–52.CrossRefPubMedGoogle Scholar
  144. 144.
    Trivedi RB, Nieuwsma JA, Williams JW. Examination of the utility of psychotherapy for patients with treatment resistant depression: a systematic review. J Gen Int Med. 2011;26:643–50.CrossRefGoogle Scholar
  145. 145.
    Tse WS, Bond AJ. Noradrenaline might enhance assertive human social behaviours: an investigation in a flatmate relationship. Pharmacopsychiatry. 2006;39:175–9.CrossRefPubMedGoogle Scholar
  146. 146.
    Tundo A, de Filippis R, Proietti L. Pharmacologic approaches to treatment resistant depression: evidences and personal experience. World J Psychiatry. 2015;5:330–41.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Üstün TB, Ayuso-Mateos JL, Chatteerji S, Mathers C. Global burden of depressive disorders in the year 2000. Br J Psychiatry. 2004;184:386–92.CrossRefPubMedGoogle Scholar
  148. 148.
    Versiani M, Moreno R, Ramakers-van Moorsel CJ, Schutte AJ, Comparative Efficacy Antidepressants Study Group. Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients. CNS Drugs. 2005;19:137–46.CrossRefPubMedGoogle Scholar
  149. 149.
    Weilburg JB, Rosenbaum JF, Meltzer-Brody S, et al. Tricyclic augmentation of fluoxetine. Ann Clin Psychiaty. 1991;3:209–13.CrossRefGoogle Scholar
  150. 150.
    Wijeratne C, Sachdev P. Treatment-resistant depression: critique of current approaches. Aust N Z J Psychiatry. 2008;42:752–62.CrossRefGoogle Scholar
  151. 151.
    Wong EH, Sonders MS, Amara SG, et al. Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry. 2000;47:818–29.CrossRefPubMedGoogle Scholar
  152. 152.
    World Health Organization. Mental and neurological disorders. Fact sheet N° 265; 2001. Available at:
  153. 153.
    Zhou X, Rivadean AV, Qin B, et al. Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis. J Clin Psychiatry. 2015;76:e487–98.CrossRefPubMedGoogle Scholar
  154. 154.
    Zisook S, Rush AJ, Haight BR, et al. Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry. 2006;59:203–10.CrossRefPubMedGoogle Scholar

Copyright information

© Springer India 2016

Authors and Affiliations

  • Francisco López-Muñoz
    • 1
    • 2
    • 3
  • Cecilio Álamo
    • 4
  • Pilar García-García
    • 4
  1. 1.Faculty of Health SciencesCamilo José Cela UniversityMadridSpain
  2. 2.Neuropsychopharmacology UnitHospital 12 de Octubre Research Institute (i+12)MadridSpain
  3. 3.Portucalense Institute of Neuropsychology and Cognitive and Behavioural NeurosciencesPortucalense UniversityPortoPortugal
  4. 4.Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health SciencesUniversity of AlcaláMadridSpain

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