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Unipolar treatment resistant depression in adults: Epidemiology, risk factors, assessment, and prognosis

Michael Thase, MD
K Ryan Connolly, MD, MS
Section Editor
Peter P Roy-Byrne, MD
Deputy Editor
David Solomon, MD


Many patients presenting with unipolar major depression (major depressive disorder) do not recover after their initial treatment. As an example, one prospective observational study found that among 3671 outpatients who were treated with citalopram, remission occurred in 37 percent [1]. In addition, patients who fail their initial treatment often do not respond to subsequent trials, and frequently experience a course of illness marked by chronic depression, impaired psychosocial functioning, and poor overall general health [2].

This topic reviews the epidemiology, risk factors, assessment, identification, and prognosis of treatment resistant depression. The treatment of resistant depression and highly resistant (refractory) depression are each discussed separately, as are the initial treatment of depression and the clinical features and diagnosis of depression.

(See "Unipolar depression in adults: Treatment of resistant depression".)

(See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)

(See "Unipolar major depression in adults: Choosing initial treatment".)  


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Literature review current through: Sep 2016. | This topic last updated: Dec 30, 2015.
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  1. 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.
  2. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289:3095.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  4. Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry 2005; 66 Suppl 8:5.
  5. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs 2009; 23:627.
  6. Berlim MT, Turecki G. What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials. Eur Neuropsychopharmacol 2007; 17:696.
  7. Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry 2006; 163:1864.
  8. National Institute for Health & Clinical Excellence. The Treatment and Management of Depression in Adults (updated edition). National Clinical Practice Guideline 90, 2010. http://www.nice.org.uk/ (Accessed on December 09, 2012).
  9. Keitner GI, Garlow SJ, Ryan CE, et al. A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression. J Psychiatr Res 2009; 43:205.
  10. Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry 2001; 62 Suppl 16:10.
  11. Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin Psychiatry 2006; 67 Suppl 6:16.
  12. 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.
  13. Barbee JG, Thompson TR, Jamhour NJ, et al. A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. J Clin Psychiatry 2011; 72:1405.
  14. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999; 60:142.
  15. Quitkin FM, Petkova E, McGrath PJ, et al. When should a trial of fluoxetine for major depression be declared failed? Am J Psychiatry 2003; 160:734.
  16. Hamilton M. Hamilton Rating Scale for Depression (HAM-D). In: Handbook of Psychiatric Measures, Second Edition, Rush Jr AJ, First MB, Blacker D. (Eds), American Psychiatric Publishing, Inc, Washington, DC 2008. p.508.
  17. Montgomery SA, Asberg M. Montgomery-Asberg Depression Rating Scale (MADRS). In: Handbook of Psychiatric Measures, Second Edition, Rush Jr AJ, First MB, Blacker D. (Eds), American Psychiatric Publishing, Inc, Washington, DC 2008. p.514.
  18. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28.
  19. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996; 19:179.
  20. Keitner GI, Ryan CE, Miller IW, et al. 12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression). Am J Psychiatry 1991; 148:345.
  21. Iosifescu DV, Nierenberg AA, Alpert JE, et al. The impact of medical comorbidity on acute treatment in major depressive disorder. Am J Psychiatry 2003; 160:2122.
  22. Iosifescu DV, Clementi-Craven N, Fraguas R, et al. Cardiovascular risk factors may moderate pharmacological treatment effects in major depressive disorder. Psychosom Med 2005; 67:703.
  23. Howland RH. Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. J Clin Psychiatry 1993; 54:47.
  24. Vieta E, Colom F. Therapeutic options in treatment-resistant depression. Ann Med 2011; 43:512.
  25. Carter GC, Cantrell RA, Haynes VS, et al. Comprehensive review of factors implicated in the heterogeneity of response in depression. Depress Anxiety 2012; 29:340.
  26. Gaynes BN. Identifying difficult-to-treat depression: differential diagnosis, subtypes, and comorbidities. J Clin Psychiatry 2009; 70 Suppl 6:10.
  27. Patten SB, Barbui C. Drug-induced depression: a systematic review to inform clinical practice. Psychother Psychosom 2004; 73:207.
  28. Souery D, Oswald P, Massat I, et al. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry 2007; 68:1062.
  29. 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.
  30. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53:649.
  31. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343.
  32. De Almeida Fleck MP, Simon G, Herrman H, et al. Major depression and its correlates in primary care settings in six countries. 9-month follow-up study. Br J Psychiatry 2005; 186:41.
  33. Amital D, Fostick L, Silberman A, et al. Serious life events among resistant and non-resistant MDD patients. J Affect Disord 2008; 110:260.
  34. Denton WH, Carmody TJ, Rush AJ, et al. Dyadic discord at baseline is associated with lack of remission in the acute treatment of chronic depression. Psychol Med 2010; 40:415.
  35. Tunnard C, Rane LJ, Wooderson SC, et al. The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression. J Affect Disord 2014; 152-154:122.
  36. Dudek D, Rybakowski JK, Siwek M, et al. Risk factors of treatment resistance in major depression: association with bipolarity. J Affect Disord 2010; 126:268.
  37. Cohen A, Houck PR, Szanto K, et al. Social inequalities in response to antidepressant treatment in older adults. Arch Gen Psychiatry 2006; 63:50.
  38. Jakubovski E, Bloch MH. Prognostic subgroups for citalopram response in the STAR*D trial. J Clin Psychiatry 2014; 75:738.
  39. Dudek D, Siwek M, Borowiecka-Kluza J. [The analysis of bipolar spectrum features in drug resistant unipolar depression patients as compared to depressive patients who responded to standard antidepressant treatment. A pilot study]. Psychiatr Pol 2008; 42:283.
  40. Perlis RH, Uher R, Ostacher M, et al. Association between bipolar spectrum features and treatment outcomes in outpatients with major depressive disorder. Arch Gen Psychiatry 2011; 68:351.
  41. Drozda K, Müller DJ, Bishop JR. Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy 2014; 34:166.
  42. 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.
  43. Rochat B, Baumann P, Audus KL. Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium. Brain Res 1999; 831:229.
  44. Uhr M, Steckler T, Yassouridis A, Holsboer F. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22:380.
  45. Parsey RV, Hastings RS, Oquendo MA, et al. Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 2006; 163:48.
  46. Lin JY, Jiang MY, Kan ZM, Chu Y. Influence of 5-HTR2A genetic polymorphisms on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. J Affect Disord 2014; 168:430.
  47. 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.
  48. Zhang C, Li Z, Wu Z, et al. A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacology (Berl) 2014; 231:685.
  49. Anttila S, Huuhka K, Huuhka M, et al. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm (Vienna) 2007; 114:1065.
  50. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 2007; 12:247.
  51. Lewis G, Mulligan J, Wiles N, et al. Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial. Br J Psychiatry 2011; 198:464.
  52. McGuffin P, Alsabban S, Uher R. The truth about genetic variation in the serotonin transporter gene and response to stress and medication. Br J Psychiatry 2011; 198:424.
  53. 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.
  54. Li CT, Su TP, Wang SJ, et al. Prefrontal glucose metabolism in medication-resistant major depression. Br J Psychiatry 2015; 206:316.
  55. McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry 2014; 76:527.
  56. Lui S, Wu Q, Qiu L, et al. Resting-state functional connectivity in treatment-resistant depression. Am J Psychiatry 2011; 168:642.
  57. Peng HJ, Zheng HR, Ning YP, et al. Abnormalities of cortical-limbic-cerebellar white matter networks may contribute to treatment-resistant depression: a diffusion tensor imaging study. BMC Psychiatry 2013; 13:72.
  58. Serra-Blasco M, Portella MJ, Gómez-Ansón B, et al. Effects of illness duration and treatment resistance on grey matter abnormalities in major depression. Br J Psychiatry 2013; 202:434.
  59. de Diego-Adeliño J, Pires P, Gómez-Ansón B, et al. Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression. Psychol Med 2014; 44:1171.
  60. Trangle M, Dieperink B, Gabert T, et al. Institute for Clinical Systems Improvement. Major Depression in Adults in Primary Care. Updated May 2012. http://www.icsi.org/depression_5/depression__major__in_adults_in_primary_care_3.html (Accessed on December 12, 2012).
  61. Correa R, Akiskal H, Gilmer W, et al. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord 2010; 127:10.
  62. Schlaak JF, Trippler M, Hoyo-Becerra C, et al. Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy. PLoS One 2012; 7:e38668.
  63. Harrison-Woolrych M, Ashton J. Psychiatric adverse events associated with varenicline: an intensive postmarketing prospective cohort study in New Zealand. Drug Saf 2011; 34:763.
  64. Fardet L, Petersen I, Nazareth I. Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. Am J Psychiatry 2012; 169:491.
  65. Desseilles M, Witte J, Chang TE, et al. Assessing the adequacy of past antidepressant trials: a clinician's guide to the antidepressant treatment response questionnaire. J Clin Psychiatry 2011; 72:1152.
  66. Posternak MA, Zimmerman M. How accurate are patients in reporting their antidepressant treatment history? J Affect Disord 2003; 75:115.
  67. Simon GE, Rutter CM, Stewart C, et al. Response to past depression treatments is not accurately recalled: comparison of structured recall and patient health questionnaire scores in medical records. J Clin Psychiatry 2012; 73:1503.
  68. Chandler GM, Iosifescu DV, Pollack MH, et al. RESEARCH: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neurosci Ther 2010; 16:322.
  69. Oquendo MA, Baca-Garcia E, Kartachov A, et al. A computer algorithm for calculating the adequacy of antidepressant treatment in unipolar and bipolar depression. J Clin Psychiatry 2003; 64:825.
  70. Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58 Suppl 13:23.
  71. Petersen T, Papakostas GI, Posternak MA, et al. Empirical testing of two models for staging antidepressant treatment resistance. J Clin Psychopharmacol 2005; 25:336.
  72. Fekadu A, Wooderson S, Donaldson C, et al. A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J Clin Psychiatry 2009; 70:177.
  73. Souery D, Amsterdam J, de Montigny C, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol 1999; 9:83.
  74. Hetrick SE, Parker AG, Hickie IB, et al. Early identification and intervention in depressive disorders: towards a clinical staging model. Psychother Psychosom 2008; 77:263.
  75. Fekadu A, Rane LJ, Wooderson SC, et al. Prediction of longer-term outcome of treatment-resistant depression in tertiary care. Br J Psychiatry 2012; 201:369.
  76. Ruhé HG, van Rooijen G, Spijker J, et al. Staging methods for treatment resistant depression. A systematic review. J Affect Disord 2012; 137:35.
  77. Adli M, Bauer M, Rush AJ. Algorithms and collaborative-care systems for depression: are they effective and why? A systematic review. Biol Psychiatry 2006; 59:1029.
  78. Quitkin FM, McGrath PJ, Stewart JW, et al. Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients. J Clin Psychiatry 2005; 66:670.
  79. Rush AJ, Thase ME, Dubé S. Research issues in the study of difficult-to-treat depression. Biol Psychiatry 2003; 53:743.
  80. 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.
  81. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008; 165:342.
  82. Greenlee A, Karp JF, Dew MA, et al. Anxiety impairs depression remission in partial responders during extended treatment in late-life. Depress Anxiety 2010; 27:451.
  83. Rush AJ, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry 2008; 65:870.
  84. Perlis RH, Alpert J, Nierenberg AA, et al. Clinical and sociodemographic predictors of response to augmentation, or dose increase among depressed outpatients resistant to fluoxetine 20 mg/day. Acta Psychiatr Scand 2003; 108:432.