Factors associated with pharmaco resistance in major depressive disorder

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Published Feb 15, 2026
https://doi.org/10.62438/tunismed.v103i12.6274
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Vol. 103 No. 12 (2025): Tunis Med Dec 2025

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Sirine Ben Othman
Psychiatry Department, Tahar Maamouri Hospital, Nabeul. Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Haifa Mami
Psychiatry Department, Tahar Maamouri Hospital, Nabeul. Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Mohamed Wassim Krir
Psychiatry Department, Tahar Maamouri Hospital, Nabeul. Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Ons Ghorbel
Psychiatry Department, Tahar Maamouri Hospital, Nabeul. Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Wafa Abdelghaffar
Psychiatry and Addiction Medicine Department, Jebel Oust. Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Abdelaziz Oumaya
Psychiatry Department, Tunis Main Military Hospital, Tunis Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia

Abstract

Background: Depressivedisorderis a commonpsychiatricdisorderthatrepresents a major public healthproblem. The failure of pharmacologicaltreatmentremainsfrequent, resulting in significantsocio-professionaldisability and high economiccosts.  The objective of ourworkwas to specify the rates of resistance and remissionunderantidepressants and to determine the factorsassociatedwithdrugresistance in thisdisorder.


Methods: It was a prospective, longitudinal, analyticalstudyconducted in the psychiatrydepartment of the Military Hospital of Tunis in patients consulting for a depressivedisorder. The participants were put on antidepressantswith a regularevaluation of the response to the treatmentthrough the Hamilton depressionscale. The absence of responseaftertwo successive antidepressantswasconsidered as resistance to antidepressanttreatment.


 Results: Our studyincluded 80 patients, of whom 13 wereexcluded and 67 completed the study. The meanage of the final samplewas 42.2 yearswith a slight male majority of 56.7%.


The resistance rate was 28.4%. There was a significant association of the resistantcharacter of the depressionwith the followingfactors: severity of the depressiveepisode (p<0.001), duration of the depressivesymptomatology (p=0.026), belonging to a militaryfamily (p=0.009), presence of a non-addictive psychiatriccomorbidity (p=0.005), particularly an anxietydisorder (p=0.003) and the presence of a post-traumatic stress disorder (p=0.007).


Conclusion: This studyunderlines the importance of early and adequate management of resistantdepression, whichremainsfrequent. There are manypredictivefactorsthat must bedetected at an early stage in order to adapttherapeuticstrategies.

Keywords:

Depressive disorder, Drug resistance, Antidepressants, Prospective study

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References

  1. Lucas N, Hubain P, Loas G, Jurysta F. Treatment resistant depression: actuality and perspectives in 2017. Rev Med Brux. 2017;38(1):16-25.
  2. Trevino K, Mcclintock S, Fischer N, Vora A, Husain M. Defining treatment-resistant
  3. depression: a comprehensive review of the literature. Ann Clin Psychiatry. 2014;26(3):222-32.
  4. Demyttenaere K, Van Duppen Z. The impact of (the concept of) treatmentresistant
  5. depression: an opinion review. Int J Neuropsychopharmacol. 2019;22(2):85-92.
  6. Zhdanava M, Kuvadia H, Joshi K, Daly E, Pilon D, Rossi C, et al. Economic burden
  7. of treatment-resistant depression in privately insured U.S. patients with physical
  8. conditions. J Manag Care Spec Pharm. 2020;26(8):996-1007.
  9. Souery D, Oswald P, Massat I, Bailer U, Bollen J, Demyttenaere K, et al. Clinical
  10. factors associated with treatment resistance in major depressive disorder. J Clin Psychiatry. 2007;68(7):1062-70.
  11. Balestri M, Calati R, Souery D, Kautzky A, Kasper S, Montgomery S, et al. Sociodemographic and clinical predictors of treatment resistant depression: a
  12. prospectiveeuropean multicenter study. J Affect Disord. 2016;189:224-32.
  13. Worboys M. The hamilton rating scale for depression: the making of a « gold
  14. standard » and the unmaking of a chronic illness, 1960-1980. Chronic Illn. 2013;9(3):202-19.
  15. Alhadi AN, Alarabi MA, Alshomrani AT, Shuqdar RM, Alsuwaidan MT, McIntyre RS. Arabic translation, validation and cultural adaptation of the 7-item hamilton
  16. depression rating scale in two community samples. Sultan QaboosUniv Med J. 2018;18(2):167-72.
  17. Judd LL, Paulus MJ, Schettler PJ, Akiskal HS, Endicott J, Leon AC, et al. Does
  18. incomplete recovery from first lifetime major depressive episode herald a chronic
  19. course of illness? Am J Psychiatry. 2000;157(9):1501-4.
  20. Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K. Severity
  21. classification on the hamilton depression rating scale. J Affect Disord. 2013;150(2):384-8.
  22. Dold M, Kasper S. Evidence-based pharmacotherapy of treatment-resistant
  23. unipolardepression. Int J Psychiatry Clin Pract. 2017;21(1):13-23.
  24. Saguem BN, Mtiraoui A, Nakhli J, Mannaï J, Ben Salah N, El Kissi Y, et al. Affective temperaments and their relationships with life events in bipolar patients and siblings: a controlled study. J Ment Health. 2021;30(1):36-42.
  25. Chan AY, Horne R, Hankins M, Chisari C. The medication adherence report scale: a measurement tool for eliciting patients’ reports of nonadherence. Br J Clin Pharmacol. 2020;86(7):1281-8.
  26. Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of
  27. antidepressant therapies in adults. J Pharm Pract. 2013;26(4):389-96.
  28. Charpeaud T, Moliere F, Bubrovszky M, Haesebaert F, Allaïli N, Bation R, et al.
  29. Dépression résistante : les stratégies de changement et d’association de
  30. médicamentsantidépresseurs. Presse Med. 2016;45(3):329-37.
  31. Souery D, Serretti A, Calati R, Oswald P, Massat I, Konstantinidis A, et al. Switching antidepressant class does not improve response or remission in treatment-resistant depression. J ClinPsychopharmacol. 2011;31(4):512-6.
  32. Pandarakalam JP. Challenges of treatment-resistant depression. PsychiatrDanub. 2018;30(3):273-84.
  33. Gauthier C, Abdel Ahad P, Gaillard R. Switching and stopping antidepressants. Encephale. 2018;44(4):379-86.
  34. Gadzhanova S, Roughead EE, Pont LG. Antidepressant switching patterns in the
  35. elderly. IntPsychogeriatr. 2018;30(9):1365-74.
  36. Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, et al.
  37. Background and rationale for the sequenced treatment alternatives to relieve
  38. depression (STAR*D) study. PsychiatrClin North Am. 2003;26(2):457-94.
  39. 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(11):696-707.
  40. Souery D, Papakostas GI, Trivedi MH. Treatment-resistantdepression. J Clin Psychiatry. 2006;67Suppl 6:16-22.
  41. Petersen T, Papakostas GI, Posternak MA, Kant A, Guyker WM, Iosifescu DV, et al. Empirical testing of two models for staging antidepressant treatment resistance. J ClinPsychopharmacol. 2005;25(4):336-41.
  42. Ruhé HG, Van Rooijen G, Spijker J, Peeters FL, Schene AH. Staging methods for
  43. treatment resistant depression. A systematic review. J Affect Disord. 2012;137(1):35-45.
  44. Kautzky A, Dold M, Bartova L, Spies M, Kranz GS, Souery D, et al. Clinical factors predicting treatment resistant depression: affirmative results from the european multicenter study. ActaPsychiatr Scand. 2019;139(1):78-88.
  45. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, et al.
  46. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and
  47. design. Control Clin Trials. 2004;25(1):119-42.
  48. Souery D, Pitchot W. Definitions and predictors of treatment-resistant depression. In: Kasper S, Montgomery S, dir. Treatment-resistant depression. Oxford: John Wiley & Sons; 2013. p. 1‑20.
  49. Nemeroff CB. Prevalence and Management of Treatment-Resistant Depression. J
  50. Clin Psychiatry. 2007;68Suppl 8:17-25.
  51. Bschor T, Baethge C. No evidence for switching the antidepressant: systematic
  52. review and meta-analysis of RCTs of a common therapeutic strategy. Acta Psychiatr Scand. 2010;121(3):174-9.
  53. Ruhé H. Dose-escalation in the picture : pharmacological and imaging studies in
  54. depression [En ligne]. University of Amsterdam [cité le 28/01/2022] ; [302 pages].
  55. Disponible à l’URL : https://www.semanticscholar.org/paper/Dose-escalation-inthe-
  56. picture-%3A-pharmacological-in-
  57. Ruh%C3%A9/db8af2e35edb1452d818326ca4a53b6a9fe82155
  58. Döme P, Kunovszki P, Takács P, Fehér L, Balázs T, Dede K, et al. Clinical
  59. characteristics of treatment-resistant depression in adults in hungary: real-world
  60. evidence from a 7-year-long retrospective data analysis. PLoS One. 2021;16(1):e0245510.
  61. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant
  62. depression. PsychiatrClin North Am. 1996;19(2):179-200.
  63. Bergfeld IO, Mantione M, Figee M, Schuurman PR, Lok A, Denys D. Treatmentresistant depression and suicidality. J Affect Disord. 2018;235:362-7.
  64. Thomas L, Kessler D, Campbell J, Morrison J, Peters TJ, Williams C, et al.
  65. Prevalence of treatment-resistant depression in primary care: cross-sectional data. Br J GenPract. 2013;63(617):852-8.
  66. Said M. Incidence de la dépression résistante chez une cohorte de patients lors
  67. d’un premier épiosde dépressif majeur [Thèse]. Médecine: Tunis; 2016. 85p.
  68. Sinyor M, Schaffer A, Levitt A. The sequenced treatment alternatives to relieve
  69. depression (STAR*D) trial: a review. Can J Psychiatry. 2010;55(3):126-35.
  70. MacQueen G, Santaguida P, Keshavarz H, Jaworska N, Levine M, Beyene J, et al. Systematic review of clinical practice guidelines for failed antidepressant treatment response in major depressive disorder, dysthymia, and subthreshold depression in adults. Can J Psychiatry. 2017;62(1):11-23.
  71. Dudek D, Rybakowski JK, Siwek M, Pawłowski T, Lojko D, Roczeń R, et al. Risk
  72. factors of treatment resistance in major depression: association with bipolarity. J
  73. Affect Disord. 2010;126(1):268‑71.
  74. Gronemann FH, Jorgensen MB, Nordentoft M, Andersen PK, Osler M. Sociodemographic and clinical risk factors of treatment-resistant depression: a danish population-based cohort study. J Affect Disord. 2020;261:221-9.
  75. Legg TJ, Kerr M. Depression&military: service members&spouses [En ligne].
  76. Healthline [cité le 10/05/2021] ; [environ 41 écrans]. Disponible à l’URL :
  77. https://www.healthline.com/health/depression/military-service
  78. Zàaba, N. F., et al. (2025). Neuroinflammation and nociception in intervertebral disc herniation. Pain Medicine, 26(2), 123-134.
  79. Sisignano, M., et al. (2022). Drug repurposing to targetneuroinflammation and pain. Frontiers in Pharmacology, 13, 789.
  80. Bennabi D, Aouizerate B, El Hage W, Doumy O, Moliere F, Courtet P, et al. Risk
  81. factors for treatment resistance in unipolar depression: a systematic review. J Affect Disord. 2015;171:137-41.
  82. Rush AJ, Wisniewski SR, Warden D, Luther JF, Davis LL, Fava M, et al. Selecting
  83. among second-step antidepressant medication monotherapies: predictive value of
  84. clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65(8):870-80.
  85. Bagby RM, Ryder AG, Cristi C. Psychosocial and clinical predictors of response to
  86. pharmacotherapy for depression. J Psychiatry Neurosci. 2002;27(4):250-7.
  87. Worthington J, Fava M, Agustin C, Alpert J, Nierenberg AA, Pava JA, et al.
  88. Consumption of alcohol, nicotine, and caffeine among depressed outpatients:
  89. relationship with response to treatment. Psychosomatics. 1996;37(6):518-22.
  90. Brenner P, Brandt L, Li G, Di Bernardo A, Bodén R, Reutfors J. Substance use
  91. disorders and risk for treatment resistant depression: a population‐based, nested
  92. case‐control study. Addiction. 2020;115(4):768-77.
  93. Young M. Treatment-resistant depression: the importance of identifying and
  94. treating co-occurring personality disorders. PsychiatrClin North Am. 2018;41(2):249-61.
  95. Joyce PR, Mulder RT, Cloninger CR. Temperament predicts clomipramine and
  96. desipramine response in major depression. J Affect Disord. 1994;30(1):35‑46.