MODERN STRATEGIES FOR THE TREATMENT OF TREATMENT-RESISTANT DEPRESSION – A LITERATURE REVIEW
Abstract
Treatment-resistant depression (TRD) remains a major therapeutic challenge in psychiatry, affecting a substantial proportion of individuals diagnosed with major depressive disorder and contributing significantly to the overall burden of mental illness. Despite decades of research and the availability of numerous antidepressant agents, many patients fail to achieve full remission, which underscores the urgent need for more effective interventions. This review provides a comprehensive and up-to-date analysis of both established and novel strategies for the management of TRD, encompassing pharmacological augmentation approaches, a variety of neuromodulation techniques, the clinical application of psychedelic- assisted therapies, and the development of innovative compounds currently under investigation. Particular emphasis is placed on the therapeutic potential and clinical outcomes associated with ketamine, esketamine, and psilocybin, which have emerged as promising options for patients who do not respond to conventional treatments. In addition, the review explores future directions in TRD management, including the repurposing of agents such as lurasidone, pioglitazone, and minocycline, which may offer new mechanisms of action and improved tolerability. Finally, the discussion highlights the importance of adopting a personalized, evidence-based, and multidimensional treatment approach, with the goal of improving both short-term response rates and long-term functional recovery in individuals suffering from TRD.
References
Kajumba, M. M., Kakooza-Mwesige, A., Nakasujja, N., et al. (2024). Treatment-resistant depression: Molecular mechanisms and management. Molecular Biomedicine, 5, 43. https://doi.org/10.1186/s43556-024-00205-y
Caldiroli, A., Capuzzi, E., Tagliabue, I., Capellazzi, M., Marcatili, M., Mucci, F., Colmegna, F., Clerici, M., Buoli, M., & Dakanalis, A. (2021). Augmentative pharmacological strategies in treatment-resistant major depression: A comprehensive review. International Journal of Molecular Sciences, 22(23), 13070. https://doi.org/10.3390/ijms222313070
Diaz, A. P., Fernandes, B. S., Quevedo, J., Sanches, M., & Soares, J. C. (2022). Treatment- resistant bipolar depression: Concepts and challenges for novel interventions. Brazilian Journal of Psychiatry, 44(2), 178–186. https://doi.org/10.1590/1516-4446-2020-1627
Steffens, D. C. (2024). Treatment-resistant depression in older adults. New England Journal of Medicine, 390(7), 630–639. https://doi.org/10.1056/NEJMcp2305428
Pandarakalam, J. P. (2018). Challenges of treatment-resistant depression. Psychiatria Danubina, 30(3), 273–284. https://doi.org/10.24869/psyd.2018.273
Zhdanava, M., Pilon, D., Ghelerter, I., et al. (2021). The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. Journal of Clinical Psychiatry, 82(2), 20m13699. https://doi.org/10.4088/JCP.20m13699
Naguy, A., Pridmore, S., Alhazeem, H., & Alamiri, B. (2023). Treatment-resistant juvenile depression—A quicksand? Psychopharmacology Bulletin, 53(4), 54–56. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698857/
Nuñez, N. A., Joseph, B., Pahwa, M., et al. (2022). Augmentation strategies for treatment- resistant major depression: A systematic review and network meta-analysis. Journal of Affective Disorders, 302, 385–400. https://doi.org/10.1016/j.jad.2021.12.134
Moret, C. (2005). Combination/augmentation strategies for improving the treatment of depression. Neuropsychiatric Disease and Treatment, 1(4), 301–309. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424118/
Cuomo, A., Beccarini Crescenzi, B., Bolognesi, S., et al. (2020). S-adenosylmethionine (SAMe) in major depressive disorder (MDD): A clinician-oriented systematic review. Annals of General Psychiatry, 19, 50. https://doi.org/10.1186/s12991-020-00298-z
Philip, N. S., Carpenter, L. L., Tyrka, A. R., & Price, L. H. (2010). Pharmacologic approaches to treatment-resistant depression: A re-examination for the modern era. Expert Opinion on Pharmacotherapy, 11(5), 709–722. https://doi.org/10.1517/14656561003614781
Gałecki, P., & Bliźniewska-Kowalska, K. (2021). Treatment-resistant depression – Recommendations of the National Consultant in the field of psychiatry. Psychiatria Polska, 55(1), 7–21. https://doi.org/10.12740/PP/OnlineFirst/115208
Hicks, P., Hicks, X. P., Meyer, H., & Shisslak, C. (2010). How best to manage treatment- resistant depression? The Journal of Family Practice, 59(9), 490–497. https://pubmed.ncbi.nlm.nih.gov/20824225/
Rush, A. J. (2023). Challenges of research on treatment-resistant depression: A clinician’s
perspective. World Psychiatry, 22(3), 415–417. https://doi.org/10.1002/wps.21136
Karrouri, R., Hammani, Z., Benjelloun, R., & Otheman, Y. (2021). Major depressive disorder: Validated treatments and future challenges. World Journal of Clinical Cases, 9(31), 9350–9367. https://doi.org/10.12998/wjcc.v9.i31.9350
Kritzer, M. D., Peterchev, A. V., & Camprodon, J. A. (2023). Electroconvulsive therapy: Mechanisms of action, clinical considerations, and future directions. Harvard Review of Psychiatry, 31(3), 101–113. https://doi.org/10.1097/HRP.0000000000000365
Conelea, C. A., Philip, N. S., Yip, A. G., et al. (2017). Transcranial magnetic stimulation for treatment-resistant depression: Naturalistic treatment outcomes for younger versus older patients. Journal of Affective Disorders, 217, 42–47. https://doi.org/10.1016/j.jad.2017.03.063
Croarkin, P. E., Elmaadawi, A. Z., Aaronson, S. T., et al. (2021). Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: A double-blind, randomized, sham-controlled trial. Neuropsychopharmacology, 46(2), 462–469. https://doi.org/10.1038/s41386-020-00829-y
Kim, D. R., Wang, E., McGeehan, B., et al. (2019). Randomized controlled trial of transcranial magnetic stimulation in pregnant women with major depressive disorder. Brain Stimulation, 12(1), 96–102. https://doi.org/10.1016/j.brs.2018.09.005
Yavi, M., Lee, H., Henter, I. D., Park, L. T., & Zarate, C. A. Jr. (2022). Ketamine treatment for depression: A review. Discover Mental Health, 2(1), 9. https://doi.org/10.1007/s44192- 022-00012-3
Nikolin, S., Rodgers, A., Schwaab, A., et al. (2023). Ketamine for the treatment of major depression: A systematic review and meta-analysis. EClinicalMedicine, 62, 102127. https://doi.org/10.1016/j.eclinm.2023.102127
Halpape, K., Pashovitz, R., Wanson, A., Hooper, M., & Peters, E. M. (2025). Intranasal racemic ketamine maintenance therapy for patients with treatment-resistant depression: A naturalistic feasibility study. BMC Psychiatry, 25(1), 23. https://doi.org/10.1186/s12888-024- 06448-x
Jagtiani, A. (2024). Novel treatments of depression: Bridging the gap in current therapeutic approaches. Exploration of Neuroscience, 3, 272–286. https://doi.org/10.37349/en.2024.00049
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., et al. (2021). Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. American Journal of Psychiatry, 178(5), 383–399. https://doi.org/10.1176/appi.ajp.2020.20081251
Vasiliu, O. (2023). Esketamine for treatment‑resistant depression: A review of clinical evidence. Experimental and Therapeutic Medicine, 25(3), 111. https://doi.org/10.3892/etm.2023.11810
Esketamine hydrochloride for treatment-resistant depression. (2022). Australian Prescriber, 45(1), 27–28. https://doi.org/10.18773/austprescr.2021.061
Daly, E. J., Singh, J. B., Fedgchin, M., et al. (2018). Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 75(2), 139–148. https://doi.org/10.1001/jamapsychiatry.2017.3739
Jalloh, M. (2020). Esketamine (Spravato) for treatment-resistant depression. American Family Physician, 101(6), 339–340. https://pubmed.ncbi.nlm.nih.gov/32163257/
Borbély, É., Simon, M., Fuchs, E., Wiborg, O., Czéh, B., & Helyes, Z. (2022). Novel drug developmental strategies for treatment-resistant depression. British Journal of Pharmacology, 179(6), 1146–1186. https://doi.org/10.1111/bph.15753
Gałecki, P., Bliźniewska-Kowalska, K. M., Cubała, W. J., et al. (2024). Polish standard of treatment with racemic ketamine for patients with depressive disorders developed by a Working Group appointed by the National Consultant in the field of psychiatry. Psychiatria Polska, 58(3), 377–401. https://doi.org/10.12740/PP/189494
Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., et al. (2018). Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up.
Psychopharmacology, 235(2), 399–408. https://doi.org/10.1007/s00213-017-4771-x
Dougherty, R. F., Clarke, P., Atli, M., et al. (2023). Psilocybin therapy for treatment resistant depression: Prediction of clinical outcome by natural language processing.
Psychopharmacology. https://doi.org/10.1007/s00213-023-06432-5
Borissova, A., & Rucker, J. J. (2024). The development of psilocybin therapy for treatment- resistant depression: An update. BJPsych Bulletin, 48(1), 38–44. https://doi.org/10.1192/bjb.2023.25
Agin-Liebes, G., & Davis, A. K. (2022). Psilocybin for the treatment of depression: A promising new pharmacotherapy approach. Current Topics in Behavioral Neurosciences, 56, 125–140. https://doi.org/10.1007/7854_2021_282
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., et al. (2016). Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. The Lancet Psychiatry, 3(7), 619–627. https://doi.org/10.1016/S2215-0366(16)30065-7
Chiu, N. Y., & Chang, C. J. (2025). Efficacy and safety of adjunctive lurasidone in treatment resistant unipolar depression: An open-label single-arm pilot study. International Journal of Neuropsychopharmacology, 28(Suppl 1), i324–i325. https://doi.org/10.1093/ijnp/pyae059.578
Heresco-Levy, U., Gelfin, G., Bloch, B., et al. (2013). A randomized add-on trial of high- dose D-cycloserine for treatment-resistant depression. International Journal of Neuropsychopharmacology, 16(3), 501–506. https://doi.org/10.1017/S1461145712000910
Lin, K. W., Wroolie, T. E., Robakis, T., & Rasgon, N. L. (2015). Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry Research, 230(3), 846–852. https://doi.org/10.1016/j.psychres.2015.10.013
Husain, M. I., Cullen, C., Umer, M., et al. (2020). Minocycline as adjunctive treatment for treatment-resistant depression: Study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2). BMC Psychiatry, 20(1), 173. https://doi.org/10.1186/s12888- 020-02553-9
Russell, S. E., Skvarc, D. R., Mohebbi, M., et al. (2023). The impact of N-acetylcysteine on major depression: Qualitative observation and mixed methods analysis of participant change during a 12-week randomised controlled trial. Clinical Psychopharmacology and Neuroscience, 21(2), 320–331. https://doi.org/10.9758/cpn.2023.21.2.320
Vian, J., Pereira, C., Chavarria, V., et al. (2017). The renin-angiotensin system: A possible new target for depression. BMC Medicine, 15, 144. https://doi.org/10.1186/s12916-017- 0916-3
Akhondzadeh, S., Jafari, S., Raisi, F., et al. (2009). Clinical trial of adjunctive celecoxib treatment in patients with major depression: A double-blind and placebo-controlled trial. Depression and Anxiety, 26(7), 607–611. https://doi.org/10.1002/da.20589
Views:
20
Downloads:
3
Copyright (c) 2025 Ignacy Rożek, Wojciech Gąska, Izabela Lekan, Joanna Mazurek, Agnieszka Brzezińska, Weronika Tuszyńska, Alicja Sodolska, Michał Lenart, Barbara Madoń, Barbara Teresińska
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
