Skip to main content
SpringerLink
Log in

Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023

  • REVIEW
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature.

Recent Findings

Recent evidence suggests some forms of psychotherapy can be effective as adjunctive treatments for TRD, but not as monotherapies alone. Little recent evidence supports the use of adjunctive non-antidepressant pharmacotherapies such as buprenorphine and antipsychotics for the treatment of TRD; side effects and increased medication discontinuation rates may outweigh the benefits of these adjunctive pharmacotherapies. Finally, a wealth of recent evidence supports the use of interventional approaches such as electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation for TRD.

Summary

Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Trevino K, McClintock SM, McDonald Fischer N, Vora A, Husain MM. Defining treatment-resistant depression: a comprehensive review of the literature. Ann Clin Psychiatry. 2014;26(3):222–32.

    PubMed  Google Scholar 

  2. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37(2):134–45. https://doi.org/10.1002/da.22968.

    Article  PubMed  Google Scholar 

  3. •• McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394–412. https://doi.org/10.1002/WPS.21120. This recent work is an excellent overview of international efforts to define and manage TRD.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhdanava M, Pilon D, Ghelerter I, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82(2). https://doi.org/10.4088/JCP.20m13699.

  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. https://doi.org/10.1016/j.jad.2015.09.033.

    Article  PubMed  Google Scholar 

  6. Gronemann FH, Jorgensen MB, Nordentoft M, Andersen PK, Osler M. Socio-demographic and clinical risk factors of treatment-resistant depression: a Danish population-based cohort study. J Affect Disord. 2020;261:221–9. https://doi.org/10.1016/j.jad.2019.10.005.

    Article  PubMed  Google Scholar 

  7. De Carlo V, Calati R, Serretti A. Socio-demographic and clinical predictors of non-response/non-remission in treatment resistant depressed patients: a systematic review. Psychiatry Res. 2016;240:421–30. https://doi.org/10.1016/j.psychres.2016.04.034.

    Article  PubMed  Google Scholar 

  8. Dunner DL, Rush AJ, Russell JM, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry. 2006;67(5):688–95. https://doi.org/10.4088/jcp.v67n0501.

    Article  PubMed  Google Scholar 

  9. Hantouche E, Angst J, Azorin JM. Explained factors of suicide attempts in major depression. J Affect Disord. 2010;127(1–3):305–8. https://doi.org/10.1016/j.jad.2010.04.032.

    Article  PubMed  Google Scholar 

  10. Bernal M, Haro JM, Bernert S, et al. Risk factors for suicidality in Europe: results from the ESEMED study. J Affect Disord. 2007;101(1–3):27–34. https://doi.org/10.1016/j.jad.2006.09.018.

    Article  CAS  PubMed  Google Scholar 

  11. Nelsen MR, Dunner DL. Clinical and differential diagnostic aspects of treatment-resistant depression. J Psychiatr Res. 1995;29(1):43–50. https://doi.org/10.1016/0022-3956(94)00042-P.

    Article  CAS  PubMed  Google Scholar 

  12. Gibson TB, Jing Y, Smith Carls G, et al. Cost burden of treatment resistance in patients with depression. Am J Manag Care. 2010;16(5):370–7.

    PubMed  Google Scholar 

  13. Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002;63(11):963–71. https://doi.org/10.4088/jcp.v63n1102.

    Article  PubMed  Google Scholar 

  14. Ivanova JI, Birnbaum HG, Kidolezi Y, Subramanian G, Khan SA, Stensland MD. Direct and indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive disorder. Curr Med Res Opin. 2010;26(10):2475–84. https://doi.org/10.1185/03007995.2010.517716.

    Article  PubMed  Google Scholar 

  15. Olchanski N, McInnis Myers M, Halseth M, et al. The economic burden of treatment-resistant depression. Clin Ther. 2013;35(4):512–22. https://doi.org/10.1016/j.clinthera.2012.09.001.

    Article  PubMed  Google Scholar 

  16. Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resistant/refractory major depression: an overview. Ann Med. 2008;40(2):149–59. https://doi.org/10.1080/07853890701769728.

    Article  PubMed  Google Scholar 

  17. McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023; 22(3): 394–412. https://pubmed.ncbi.nlm.nih.gov/37713549/

  18. Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(Suppl 13):23–9.

    PubMed  Google Scholar 

  19. Zhou X, Keitner GI, Qin B, et al. Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. Int J Neuropsychopharmacol. 2015;18(11):pyv060. https://doi.org/10.1093/ijnp/pyv060.

    Article  CAS  PubMed  Google Scholar 

  20. Inoue K. Cognitive-behavioral therapy for treatment-resistant depression. Seishin Shinkeigaku Zasshi. 2010;112(11):1097–104.

    PubMed  Google Scholar 

  21. Nakagawa A, Mitsuda D, Sado M, et al. Effectiveness of supplementary cognitive-behavioral therapy for pharmacotherapy-resistant depression: a randomized controlled trial. J Clin Psychiatry. 2017;78(8):1126–35. https://doi.org/10.4088/JCP.15m10511.

    Article  PubMed  Google Scholar 

  22. Dougherty DD, Rauch SL. Somatic therapies for treatment- resistant depression: new neurotherapeutic interventions. Psychiatr Clin North Am. 2007;30(1):31–7. https://doi.org/10.1016/j.psc.2006.12.006.

    Article  PubMed  Google Scholar 

  23. Kennedy SH, Giacobbe P. Treatment resistant depression— advances in somatic therapies. Ann Clin Psychiatry. 2007;19(4):279–87. https://doi.org/10.1080/10401230701675222.

    Article  PubMed  Google Scholar 

  24. Al-harbi. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. Published online May 2012:369. https://doi.org/10.2147/PPA.S29716.

  25. Wilkinson ST, Rosenheck RA. Electroconvulsive therapy at a Veterans Health Administration medical center. J ECT. 2017;33(4):249–52. https://doi.org/10.1097/YCT.0000000000000400.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sobule R, Ithman M. Ketamine: studies show benefit. Mo Med. 2023;120(1):29–30.

    PubMed  PubMed Central  Google Scholar 

  27. •• Ijaz S, Davies P, Williams CJ, Kessler D, Lewis G, Wiles N. Psychological therapies for treatment‐resistant depression in adults. Cochrane Database Syst Rev. 2018;(5). https://doi.org/10.1002/14651858.CD010558.PUB2. This systematic review and meta-analysis found the addition of psychotherapy to “treatment as usual” for TRD produced a significant improvement in depression scores at six months.

  28. Van Bronswijk S, Moopen N, Beijers L, Ruhe HG, Peeters F. Effectiveness of psychotherapy for treatment-resistant depression: a meta-analysis and meta-regression. Psychol Med. 2019;49(3):366–79. https://doi.org/10.1017/S003329171800199X.

    Article  PubMed  Google Scholar 

  29. Foroughi A, Sadeghi K, Parvizifard A, et al. The effectiveness of mindfulness-based cognitive therapy for reducing rumination and improving mindfulness and self-compassion in patients with treatment-resistant depression. Trends Psychiatry Psychother. 2020;42(2):138–46. https://doi.org/10.1590/2237-6089-2019-0016.

    Article  PubMed  Google Scholar 

  30. • Li JM, Zhang Y, Su WJ, et al. Cognitive behavioral therapy for treatment-resistant depression: a systematic review and meta-analysis. Psychiatry Res. 2018;268:243–50. https://doi.org/10.1016/J.PSYCHRES.2018.07.020. This paper is the only recent type-specific meta-analysis of a psychotherapeutic approach for treating TRD.

    Article  PubMed  Google Scholar 

  31. Dinoff A, Lynch ST, Sekhri N, Klepacz L. A meta-analysis of the potential antidepressant effects of buprenorphine versus placebo as an adjunctive pharmacotherapy for treatment-resistant depression. J Affect Disord. 2020;271:91–9. https://doi.org/10.1016/J.JAD.2020.03.089.

    Article  CAS  PubMed  Google Scholar 

  32. Gobbi G, Ghabrash MF, Nuñez N, et al. Antidepressant combination versus antidepressants plus second-generation antipsychotic augmentation in treatment-resistant unipolar depression. Int Clin Psychopharmacol. 2018;33(1):34–43. https://doi.org/10.1097/YIC.0000000000000196.

    Article  PubMed  Google Scholar 

  33. Davies P, Ijaz S, Williams CJ, Kessler D, Lewis G, Wiles N. Pharmacological interventions for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2019;(12). https://doi.org/10.1002/14651858.CD010557.PUB2/MEDIA/CDSR/CD010557/IMAGE_N/NCD010557-CMP-008-08.PNG.

  34. Su L, Jia Y, Liang S, Shi S, Mellor D, Xu Y. Multicenter randomized controlled trial of bifrontal, bitemporal, and right unilateral electroconvulsive therapy in major depressive disorder. Psychiatry Clin Neurosci. 2019;73(10):636–41. https://doi.org/10.1111/PCN.12907.

    Article  PubMed  Google Scholar 

  35. Kronsell A, Nordenskjöld A, Bell M, Amin R, Mittendorfer-Rutz E, Background MT. The effect of anaesthetic dose on response and remission in electroconvulsive therapy for major depressive disorder: nationwide register-based cohort study. BJPsych Open. 2021;7(2):e71. https://doi.org/10.1192/BJO.2021.31.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Rönnqvist I, Nilsson FK, Nordenskjöld A. Electroconvulsive therapy and the risk of suicide in hospitalized patients with major depressive disorder. JAMA Netw Open. 2021;4(7):e2116589. https://doi.org/10.1001/JAMANETWORKOPEN.2021.16589.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Carspecken CW, Borisovskaya A, Lan ST, et al. Ketamine anesthesia does not improve depression scores in electroconvulsive therapy: a randomized clinical trial. J Neurosurg Anesthesiol. 2018;30(4):305–13. https://doi.org/10.1097/ANA.0000000000000511.

    Article  PubMed  Google Scholar 

  38. Gamble JJ, Bi H, Bowen R, et al. Ketamine-based anesthesia improves electroconvulsive therapy outcomes: a randomized-controlled study. Can J Anaesth. 2018;65(6):636–46. https://doi.org/10.1007/S12630-018-1088-0.

    Article  PubMed  Google Scholar 

  39. • Cai H, Du R, Song J, et al. Suicidal ideation and electroconvulsive therapy: outcomes in adolescents with major depressive disorder. J ECT. Published online 9900. https://journals.lww.com/ectjournal/Fulltext/9900/Suicidal_Ideation_and_Electroconvulsive_Therapy_.65.aspx. This paper is a clinical trial monitoring both the effects of ECT as an adjunct to pharmacotherapy for TRD, as well as potential long-term cognitive adverse events of this treatment.

  40. Hein M, Mungo A, Loas G. Nonremission after electroconvulsive therapy in individuals with major depression: role of borderline personality disorder. J ECT. 2022;38(4):238–43. https://doi.org/10.1097/YCT.0000000000000857.

    Article  PubMed  Google Scholar 

  41. Lee JH, Kung S, Rasmussen KG, Palmer BA. Effectiveness of electroconvulsive therapy in patients with major depressive disorder and comorbid borderline personality disorder. J ECT. 2019;35(1):44. https://doi.org/10.1097/YCT.0000000000000533.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lisanby SH, McClintock SM, Alexopoulos G, et al. Neurocognitive effects of combined electroconvulsive therapy (ECT) and venlafaxine in geriatric depression: phase 1 of the PRIDE study. Am J Geriatr Psychiatry. 2020;28(3):304. https://doi.org/10.1016/J.JAGP.2019.10.003.

    Article  PubMed  Google Scholar 

  43. •• Lisanby SH, McClintock SM, McCall WV, et al. Longitudinal neurocognitive effects of combined electroconvulsive therapy (ECT) and pharmacotherapy in major depressive disorder in older adults: phase 2 of the PRIDE study. Am J Geriatr Psychiatry. 2022;30(1):15–28. https://doi.org/10.1016/J.JAGP.2021.04.006. This pair of studies (references 42 and 43) is an excellent medium-term assessment of both the efficacy of both ECT for TRD, as well as potential adverse effects on cognition.

    Article  PubMed  Google Scholar 

  44. Wilkinson ST, Sint K, Forester BP, Rhee TG. Effects of electroconvulsive therapy on functional outcomes among medicare patients with comorbid depression and dementia: a nationwide 1-year follow-up study. J Clin Psychiatry. 2023;84(2). https://doi.org/10.4088/JCP.22M14583.

  45. • Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315–25. https://doi.org/10.1056/NEJMOA2302399. This recent study established the non-inferiority of ketamine to ET for treatment of TRD.

    Article  CAS  PubMed  Google Scholar 

  46. Wilkinson ST, Rhee TG, Joormann J, et al. Cognitive behavioral therapy to sustain the antidepressant effects of ketamine in treatment-resistant depression: a randomized clinical trial. Psychother Psychosom. 2021;90(5):318–27. https://doi.org/10.1159/000517074.

    Article  PubMed  Google Scholar 

  47. Zydb T, Hart M. Efficacy of oral ketamine combined with psychotherapy for treatment resistant depression. Eur J Med Health Sci. 2021;3(4):106–8. https://doi.org/10.24018/EJMED.2021.3.4.979.

    Article  Google Scholar 

  48. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–48. https://doi.org/10.1001/JAMAPSYCHIATRY.2017.3739.

    Article  PubMed  Google Scholar 

  49. • Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893–903. https://doi.org/10.1001/JAMAPSYCHIATRY.2019.1189. This study established the efficacy of esketamine as an adjunctive therapy to antidepressants for treating those with TRD.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):10773. https://doi.org/10.4088/JCP.19M12891.

    Article  Google Scholar 

  51. Takahashi N, Yamada A, Shiraishi A, Shimizu H, Goto R, Tominaga Y. Efficacy and safety of fixed doses of intranasal esketamine as an add-on therapy to oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study. BMC Psychiatry. 2021;21(1):1–13. https://doi.org/10.1186/S12888-021-03538-Y/TABLES/4.

    Article  Google Scholar 

  52. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression—TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121–41. https://doi.org/10.1016/J.JAGP.2019.10.008.

    Article  PubMed  Google Scholar 

  53. Chen MH, Li CT, Lin WC, et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: a randomized, double-blind control study. Psychiatry Res. 2018;269:207–11. https://doi.org/10.1016/J.PSYCHRES.2018.08.078.

    Article  CAS  PubMed  Google Scholar 

  54. Chen MH, Li CT, Lin WC, et al. Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion. J Affect Disord. 2018;241:1–7. https://doi.org/10.1016/J.JAD.2018.07.033.

    Article  CAS  PubMed  Google Scholar 

  55. • Chen MH, Lin WC, Wu HJ, et al. Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the adjunctive ketamine study of Taiwanese patients with treatment-resistant depression. CNS Spectr. 2021;26(4):362–7. https://doi.org/10.1017/S1092852920001194. This study clarified effective dosing for ketamine infusion in those with TRD.

    Article  PubMed  Google Scholar 

  56. Liu W, Zhou Y, Zheng W, et al. Repeated intravenous infusions of ketamine: neurocognition in patients with anxious and nonanxious treatment-resistant depression. J Affect Disord. 2019;259:1–6. https://doi.org/10.1016/J.JAD.2019.08.012.

    Article  CAS  PubMed  Google Scholar 

  57. Smith-Apeldoorn SY, Veraart JKE, Ruhé HG, et al. Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study. BJPsych Open. 2022;8(1): e4. https://doi.org/10.1192/BJO.2021.1059.

    Article  Google Scholar 

  58. Correia-Melo FS, Leal GC, Vieira F, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527–34. https://doi.org/10.1016/J.JAD.2019.11.086.

    Article  CAS  PubMed  Google Scholar 

  59. Singh B, Kung S, Pazdernik V, et al. Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression: an observational study. J Clin Psychiatry. 2023;84(2):45331. https://doi.org/10.4088/JCP.22M14548.

    Article  Google Scholar 

  60. Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment in a clinical setting. JAMA Psychiatry. 2022;79(7):736–8. https://doi.org/10.1001/JAMAPSYCHIATRY.2022.1074.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Jones RR, Freeman MP, Kornstein SG, et al. Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials. Arch Womens Ment Health. 2022;25(2):313–26. https://doi.org/10.1007/S00737-021-01185-6/TABLES/6.

    Article  PubMed  PubMed Central  Google Scholar 

  62. • Cullen KR, Amatya P, Roback MG, et al. Intravenous ketamine for adolescents with treatment-resistant depression: an open-label study. J Child Adolesc Psychopharmacol. 2018;28(7):437–44. https://doi.org/10.1089/CAP.2018.0030/ASSET/IMAGES/LARGE/FIGURE3.JPEG. This open-label study demonstrated ketamine’s efficacy and tolerability in adolescents with TRD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Griffiths C, O’Neill-Kerr A, Millward T, da Silva K. Repetitive transcranial magnetic stimulation (rTMS) for depression: outcomes in a United Kingdom (UK) clinical practice. 2019;23(2):122-7. https://doi.org/10.1080/13651501.2018.1562077.

  64. Akpinar K, Kalkan Oğuzhanoğlu N, Toker Uğurlu T. Efficacy of transcranial magnetic stimulation in treatment-resistant depression. https://doi.org/10.55730/1300-0144.5441.

  65. Ozcan S, Gica S, Gulec H. Suicidal behavior in treatment resistant major depressive disorder patients treated with transmagnetic stimulation (TMS) and its relationship with cognitive functions. Psychiatry Res. 2020;286:112873. https://doi.org/10.1016/J.PSYCHRES.2020.112873.

    Article  PubMed  Google Scholar 

  66. Croarkin PE, Elmaadawi AZ, Aaronson ST, et al. Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial. Neuropsychopharmacology. 2020;46(2):462–9. https://doi.org/10.1038/s41386-020-00829-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Adu MK, Shalaby R, Eboreime E, et al. Apparent lack of benefit of combining repetitive transcranial magnetic stimulation with internet-delivered cognitive behavior therapy for the treatment of resistant depression: patient-centered randomized controlled pilot trial. Brain Sciences. 2023;13(2):293. https://doi.org/10.3390/BRAINSCI13020293.

    Article  PubMed  PubMed Central  Google Scholar 

  68. • Rothärmel M, Quesada P, Husson T, et al. The priming effect of repetitive transcranial magnetic stimulation on clinical response to electroconvulsive therapy in treatment-resistant depression: a randomized, double-blind, sham-controlled study. Psychol Med. 2023;53(5):2060–71. https://doi.org/10.1017/S0033291721003810. This study is perhaps the only recent peer-reviewed study describing a primer effect of one TRD treatment on the efficacy of another TRD treatment.

    Article  PubMed  Google Scholar 

  69. Fava M, Freeman MP, Flynn M, et al. Double-blind, proof-of-concept (POC) trial of low-field magnetic stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD). Brain Stimul. 2018;11(1):75–84. https://doi.org/10.1016/J.BRS.2017.09.010.

    Article  PubMed  Google Scholar 

  70. Mehta S, Downar J, Mulsant BH, et al. Effect of high frequency versus theta-burst repetitive transcranial magnetic stimulation on suicidality in patients with treatment-resistant depression. Acta Psychiatr Scand. 2022;145(5):529–38. https://doi.org/10.1111/ACPS.13412.

    Article  PubMed  PubMed Central  Google Scholar 

  71. •• Blumberger DM, Mulsant BH, Thorpe KE, et al. Effectiveness of standard sequential bilateral repetitive transcranial magnetic stimulation vs bilateral theta burst stimulation in older adults with depression: the FOUR-D randomized noninferiority clinical trial. JAMA Psychiatry. 2022;79(11):1065–73. https://doi.org/10.1001/JAMAPSYCHIATRY.2022.2862. This study found that a form of TMS lasting just 4 minutes was non-inferior to standard rTMS (average duration, 47.5 minutes) in improving symptoms for those with TRD.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Clinical investigation of medicinal products in the treatment of depression - scientific guideline | European Medicines Agency. Accessed 7 Oct 2023. https://www.ema.europa.eu/en/clinical-investigation-medicinal-products-treatment-depression-scientific-guideline.

  73. Major Depressive Disorder: Developing Drugs for Treatment | FDA. Accessed 7 Oct 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/major-depressive-disorder-developing-drugs-treatment.

Download references

Author information

Authors and Affiliations

  1. Yale University School of Medicine, New Haven, CT, USA

    John L. Havlik

  2. The University of Chicago, Chicago, IL, USA

    Syed Wahid

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    John H. Krystal & Taeho Greg Rhee

  4. Department of Public Health Sciences, University of Connecticut, Farmington, CT, USA

    Taeho Greg Rhee

  5. Brain and Cognition Discovery Foundation, Toronto, Canada

    Kayla M. Teopiz & Roger S. McIntyre

  6. Department of Psychiatry, University of Toronto, Toronto, Canada

    Roger S. McIntyre

  7. Department of Pharmacology, University of Toronto, Toronto, Canada

    Roger S. McIntyre

Authors
  1. John L. Havlik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Syed Wahid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kayla M. Teopiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roger S. McIntyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John H. Krystal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taeho Greg Rhee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TGR and JLH conceptualized the study. JLH, SW, and TGR wrote the manuscript text. JLH and SW prepared tables. KT, RSM, and JHK reviewed and edited the manuscript.

Corresponding author

Correspondence to Taeho Greg Rhee.

Ethics declarations

Conflict of Interest

  1. 1.

    Havlik reported none.

  2. 2.

    Wahid reported none.

  3. 3.

    Teopiz has received fees from Braxia Scientific Corp.

  4. 4.

    McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

  5. 5.

    Krystal has served as a consultant for: Aptinyx, Inc.; Biogen, Idec, MA; Bionomics, Limited (Australia); Boehringer Ingelheim International; Clearmind Medicine, Inc.; Cybin IRL (Ireland Limited Company); Enveric Biosciences; Epiodyne, Inc.; EpiVario, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Otsuka America Pharmaceutical, Inc.; Perception Neuroscience, Inc.; Praxis Precision Medicines, Inc.; Spring Care, Inc.; Sunovion Pharmaceuticals, Inc. Dr. Krystal has served as a scientific advisory board member for: Biohaven Pharmaceuticals; BioXcel Therapeutics, Inc. (Clinical Advisory Board); Cerevel Therapeutics, LLC; Delix Therapeutics, Inc.; Eisai, Inc.; EpiVario, Inc.; Freedom Biosciences, Inc.; Jazz Pharmaceuticals, Inc.; Neumora Therapeutics, Inc.; Neurocrine Biosciences, Inc.; Novartis Pharmaceuticals Corporation; Praxis Precision Medicines, Inc.; PsychoGenics, Inc.; Tempero Bio, Inc.; Terran Biosciences, Inc. In the past 3 years, Dr. Krystal has the following patents: John Krystal, Godfrey Pearlson, Stephanie O’Malley, Marc Potenza, Fabrizio Gasparini, Baltazar Gomez-Mancilla, Vincent Malaterre. Mavoglurant in treating gambling and gaming disorders. U.S. Provisional Patent Application No. 63/125,181filed on December 14, 2020 by Yale University Office of Cooperative Research OCR 8065 US00. In addition, Dr. Krystal has stock options from: Biohaven Pharmaceuticals Medical Sciences; Clearmind Medicine, Inc.; EpiVario, Inc.; Neumora Therapeutics, Inc.; Tempero Bio, Inc.; Terran Biosciences, Inc.

  6. 6.

    Rhee was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. Dr. Rhee has also been funded by the NIA (#R21AG070666; R21AG078972; R01AG080647), National Institute of Mental Health (#R21MH117438; R01MH131528), National Institute on Drug Abuse (#R21DA057540) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). Dr. Rhee is currently a co-editor-in-chief of Mental Health Science and has received honorarium payments annually from the publisher, John Wiley & Sons, Inc.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Havlik, J.L., Wahid, S., Teopiz, K.M. et al. Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023. Curr Psychiatry Rep 26, 176–213 (2024). https://doi.org/10.1007/s11920-024-01494-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-024-01494-4

Keywords

Search

Navigation