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Current pharmacological approaches often do not provide sufficient therapeutic results, prompting the need for innovative treatments. This review summarizes recent advances in TRD management, including non-pharmacological therapies such as transcranial magnetic stimulation, deep brain stimulation, electroconvulsive therapy, and vagus nerve stimulation, and describes their mechanisms of action. Novel pharmacotherapies, particularly glutamatergic modulators like ketamine and esketamine, have shown promising results with esketamine being available to eligible patients in Poland since 2023 within a drug program. Electroconvulsive therapy remains an effective treatment for TRD, usually with small side effects mainly including transient memory impairment, headache, or cardiovascular changes. Transcranial magnetic stimulation is a non-invasive procedure with proven efficacy; therefore several psychiatric organizations recommend it as a treatment option for major depressive disorder in their clinical guidelines. Deep brain stimulation is a relatively new treatment modality for TRD, with its primary risk being associated with the required neurosurgical procedure. Vagus nerve stimulation seems to be a promising adjunctive treatment for TRD, showing significant improvements in depressive symptoms, especially at higher electrical doses but with no side effects. While these treatments appear to have potential, personalized approaches are crucial for optimizing outcomes. Future research should focus on refining the techniques, improving safety profiles, and validating the long-term efficacy.<\/jats:p>","DOI":"10.1007\/s11357-025-01615-8","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T10:21:55Z","timestamp":1743157315000},"page":"5543-5558","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Innovative approaches in the treatment-resistant depression: exploring different therapeutic pathways"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4233-5374","authenticated-orcid":false,"given":"Anna","family":"\u0141ysik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9038-2940","authenticated-orcid":false,"given":"Katarzyna","family":"Logo\u0144","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1280-1046","authenticated-orcid":false,"given":"Aleksandra","family":"Szczygie\u0142","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3241-649X","authenticated-orcid":false,"given":"Julia","family":"Wo\u0142oszczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7710-3680","authenticated-orcid":false,"given":"Martyna","family":"Wrze\u015bniewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2316-2470","authenticated-orcid":false,"given":"Jerzy","family":"Leszek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"1615_CR1","unstructured":"Depression and Other Common Mental Disorders: Global Health Estimates. 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