{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:02:24Z","timestamp":1780628544034,"version":"3.54.1"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Treatment-resistant depression (TRD) remains one of the most urgent unmet needs in psychiatry, while its therapeutic pipeline is evolving rapidly. To characterize current development trajectories, we conducted a registry-anchored mapping of interventional trials in adults with major depressive disorder and treatment resistance (MDD-TRD), with the aim of defining the distribution of intervention types, endpoint choices, and key design features across the active trial landscape. Methods: We systematically searched ClinicalTrials.gov, the EU Clinical Trials Information System, and ISRCTN for interventional MDD-TRD trials registered up to 18 September 2025. After data cleaning and cross-registry deduplication, 237 unique trials were retained. Interventions were categorized through a taxonomy distinguishing device-based neuromodulation, pharmacological strategies, biologic\/novel agents, multimodal non-digital combinations, digital\u2013hybrid programs, psychotherapy, and lifestyle interventions, with classification anchored on structured registry intervention tags and whole-word matching across title and intervention text. Primary endpoints were flagged as standard when they explicitly referenced the Montgomery\u2013\u00c5sberg Depression Rating Scale or Hamilton Depression Rating Scale. We also examined developmental phase, sample size, and recurrent methodological features. Results: Device-based neuromodulation accounted for the largest share of the active pipeline (114\/237, 48.1%), followed by pharmacological strategies (86\/237, 36.3%), biologic\/novel agents (16\/237, 6.8%), and multimodal non-digital combinations (11\/237, 4.6%). Digital\u2013hybrid programs represented a small but distinctive stratum (5\/237, 2.1%), with the remaining records comprising lifestyle interventions (3\/237, 1.3%) and psychotherapy (2\/237, 0.8%). Standard clinician-rated primary endpoints were used in 63.3% of studies. Trial development was concentrated in mid-phase designs, whereas sample sizes were generally modest (median 49; interquartile range, 19\u201387). Across modalities, increasing attention was directed to durability of response, functioning, and patient-reported outcomes, with adaptive and enrichment-based designs appearing with greater frequency. Conclusions: The contemporary TRD trial ecosystem is structured around two co-active developmental tracks\u2014device-based neuromodulation and pharmacology with novel mechanisms\u2014accompanied by a smaller but measurably expanding biologic\/novel stratum and a still-marginal digital\u2013hybrid presence. This registry-based mapping provides a near-real-time overview of the field and may support future harmonization of trial endpoints and design standards.<\/jats:p>","DOI":"10.3390\/brainsci16060612","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:23:21Z","timestamp":1780622601000},"page":"612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Resistance to Redesign\u2014The Emerging Logic of Hybrid Care in Treatment-Resistant Depression"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9746-8237","authenticated-orcid":false,"given":"Federico","family":"Mucci","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Lucca Zone, Azienda USL Toscana Nord Ovest, 55100 Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0743-178X","authenticated-orcid":false,"given":"Riccardo","family":"Gurrieri","sequence":"additional","affiliation":[{"name":"Health Science Interdisciplinary Center, Sant\u2019Anna School of Advanced Studies, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siham","family":"Bouanani","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8863-9353","authenticated-orcid":false,"given":"Matteo","family":"Gambini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Russomanno","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4021-5829","authenticated-orcid":false,"given":"Donatella","family":"Marazziti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/wps.21120","article-title":"Treatment-resistant depression: Definition, prevalence, detection, management, and investigational interventions","volume":"22","author":"McIntyre","year":"2023","journal-title":"World Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chrenek, C., Duong, B., Khullar, A., McRee, C., Thomas, R., and Swainson, J. (2024). Use of ketamine for treatment-resistant depression: Updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1283733"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41398-024-03180-8","article-title":"Personalized use of ketamine and esketamine for treatment-resistant depression","volume":"14","author":"Medeiros","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gambini, M., Gurrieri, R., Russomanno, G., Cecchini, G., Mucci, F., Carbone, M.G., and Marazziti, D. (2025). Botulinum toxin: An unconventional tool for the treatment of depression?. Brain Sci., 15.","DOI":"10.20944\/preprints202508.0634.v1"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.clinph.2024.12.015","article-title":"Consensus review and considerations on TMS to treat depression","volume":"170","author":"Trapp","year":"2025","journal-title":"Clin. Neurophysiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3893","DOI":"10.1038\/s41380-024-02630-5","article-title":"Theta burst stimulation for depression: A systematic review and network and pairwise meta-analysis","volume":"29","author":"Kishi","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tao, X., Jing, Z.W., Yuan, W.K., Yun, G.H., Fang, X.J., and Sheng, L.M. (2025). A meta-analysis comparing the effectiveness and safety of rTMS versus theta burst stimulation for treatment-resistant depression. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1504727"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e2444306","DOI":"10.1001\/jamanetworkopen.2024.44306","article-title":"Transcranial direct current stimulation combined with repetitive transcranial magnetic stimulation for depression: A randomized clinical trial","volume":"7","author":"Zhou","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/s41386-023-01677-2","article-title":"How electroconvulsive therapy works in the treatment of depression: Is it the seizure, the electricity, or both?","volume":"49","author":"Deng","year":"2024","journal-title":"Neuropsychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1056\/NEJMoa2302399","article-title":"Ketamine versus ECT for nonpsychotic treatment-resistant major depression: A randomized non-inferiority trial","volume":"388","author":"Anand","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1001\/jamapsychiatry.2020.4364","article-title":"Internet-based cognitive behavioral therapy for depression: A systematic review and individual patient data network meta-analysis","volume":"78","author":"Karyotaki","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41746-022-00677-8","article-title":"A systematic review of digital and face-to-face cognitive behavioral therapy for depression","volume":"5","author":"Rzayeva","year":"2022","journal-title":"npj Digit. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1177\/07067437241245384","article-title":"CANMAT 2023 update of clinical guidelines for the management of major depressive disorder in adults","volume":"69","author":"Lam","year":"2024","journal-title":"Can. J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/S0140-6736(18)30295-2","article-title":"Effectiveness of theta burst versus high-frequency rTMS in depression (THREE-D): A randomized non-inferiority trial","volume":"391","author":"Blumberger","year":"2018","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.clinph.2020.10.003","article-title":"Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines","volume":"132","author":"Rossi","year":"2021","journal-title":"Clin. Neurophysiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.clinph.2019.11.002","article-title":"Evidence-based guidelines on the therapeutic use of rTMS (2014\u20132018 update)","volume":"131","author":"Lefaucheur","year":"2020","journal-title":"Clin. Neurophysiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1176\/appi.ajp.2021.20101429","article-title":"Stanford neuromodulation therapy (SNT): A double-blind randomized controlled trial","volume":"179","author":"Cole","year":"2022","journal-title":"Am. J. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41386-023-01599-z","article-title":"Accelerated TMS\u2014Moving quickly into the future of depression treatment","volume":"49","author":"Arulpragasam","year":"2024","journal-title":"Neuropsychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2516459","DOI":"10.1001\/jamanetworkopen.2025.16459","article-title":"Transcranial electrical stimulation for major depressive disorder: A systematic review and meta-analysis","volume":"8","author":"Ren","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/s41398-021-01560-y","article-title":"Comparative efficacy and cognitive function of magnetic seizure therapy vs electroconvulsive therapy for major depressive disorder: Systematic review and meta-analysis","volume":"11","author":"Chen","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cai, D.B., Cao, X.L., Zhong, B.L., and Xiang, Y.T. (2023). Comparison of efficacy and safety of magnetic seizure therapy vs modified electroconvulsive therapy for depression: Systematic review and meta-analysis. J. Pers. Med., 13.","DOI":"10.3390\/jpm13030449"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1056\/NEJMoa2206443","article-title":"Single-dose psilocybin for a treatment-resistant episode of major depression: A phase 2b randomized trial","volume":"387","author":"Goodwin","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1056\/NEJMe2210975","article-title":"Psilocybin in treatment-resistant depression","volume":"387","author":"Madras","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1080\/17512433.2021.1933434","article-title":"Blinding and expectancy confounds in psychedelic randomized controlled trials","volume":"14","author":"Muthukumaraswamy","year":"2021","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"pyaf023","DOI":"10.1093\/ijnp\/pyaf023","article-title":"Addressing blinding in classic psychedelic studies with low-dose active placebos","volume":"28","author":"Aday","year":"2025","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_26","first-page":"512","article-title":"Expectancy effects in psychedelic trials","volume":"9","author":"Szigeti","year":"2024","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"24m15449","DOI":"10.4088\/JCP.24m15449","article-title":"Results from a long-term observational follow-up study of a single dose of psilocybin for a treatment-resistant episode of major depressive disorder (COMP 004)","volume":"86","author":"Goodwin","year":"2025","journal-title":"J. Clin. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1001\/jama.2023.14530","article-title":"Single-dose psilocybin treatment for major depressive disorder: A randomized clinical trial","volume":"330","author":"Raison","year":"2023","journal-title":"JAMA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1056\/NEJMoa2032994","article-title":"Trial of psilocybin versus escitalopram for depression","volume":"384","author":"Giribaldi","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102799","DOI":"10.1016\/j.eclinm.2024.102799","article-title":"Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: Observational 6-month follow-up of a phase 2 double-blind randomised controlled trial","volume":"76","author":"Erritzoe","year":"2024","journal-title":"EClinicalMedicine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e078084","DOI":"10.1136\/bmj-2023-078084","article-title":"Efficacy of psilocybin for treating symptoms of depression: A systematic review and meta-analysis","volume":"385","author":"Metaxa","year":"2024","journal-title":"BMJ"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, L.J., Mo, Y., Shi, Z.M., Huang, X.B., Ning, Y.P., Wu, H.W., Yang, X.H., and Zheng, W. (2024). Psilocybin for major depressive disorder: A systematic review. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1416420"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.euroneuro.2023.07.011","article-title":"Psilocybin-assisted therapy for depression: A systematic review and dose\u2013response meta-analysis of human studies","volume":"76","author":"Perez","year":"2023","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"116337","DOI":"10.1016\/j.psychres.2024.116337","article-title":"Efficacy and safety of psilocybin in the treatment of major depressive disorder: A dose\u2013response network meta-analysis of randomized placebo-controlled clinical trials","volume":"344","author":"Swieczkowski","year":"2025","journal-title":"Psychiatry Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2524119","DOI":"10.1001\/jamanetworkopen.2025.24119","article-title":"Control group outcomes in trials of psilocybin, SSRIs, or esketamine for depression: A meta-analysis","volume":"8","author":"Hieronymus","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S2215-0366(24)00404-8","article-title":"Efficacy and effectiveness of therapist-guided internet versus face-to-face cognitive behavioural therapy for depression: A retrospective cohort study","volume":"12","author":"Saarni","year":"2025","journal-title":"Lancet Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e49660","DOI":"10.2196\/49660","article-title":"Blended psychological therapy for the treatment of psychological disorders in adult patients: Systematic review and meta-analysis","volume":"13","author":"Shepherd","year":"2024","journal-title":"Interact. J. Med. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e36577","DOI":"10.2196\/36577","article-title":"The clinical effectiveness of blended cognitive behavioral therapy compared with face-to-face cognitive behavioral therapy for adult depression: Randomized controlled noninferiority trial","volume":"24","author":"Mathiasen","year":"2022","journal-title":"J. Med. Internet Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s40501-023-00297-3","article-title":"The engagement problem: A review of engagement with digital mental health interventions and recommendations for a path forward","volume":"10","author":"Lipschitz","year":"2023","journal-title":"Curr. Treat. Options Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Boucher, E.M., and Raiker, J.S. (2024). Engagement and retention in digital mental health interventions: A narrative review. BMC Digit. Health, 2.","DOI":"10.1186\/s44247-024-00105-9"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.jad.2024.10.018","article-title":"Digital mental health interventions for the treatment of depression: A multiverse meta-analysis","volume":"369","author":"Plessen","year":"2025","journal-title":"J. Affect. Disord."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e301451","DOI":"10.1136\/bmjment-2024-301451","article-title":"Crosswalk between HRSD and MADRS outcomes for rTMS in patients with depression","volume":"28","author":"Chen","year":"2025","journal-title":"BMJ Ment. Health"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hengartner, M.P., Jakobsen, J.C., S\u00f8rensen, A., and Pl\u00f6derl, M. (2020). Efficacy of new-generation antidepressants assessed with MADRS vs HAMD: Meta-analysis of randomized placebo-controlled trials. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229381"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1176\/appi.ajp.159.9.1598","article-title":"Interrater reliability in clinical trials of depressive disorders","volume":"159","author":"Mulsant","year":"2002","journal-title":"Am. J. Psychiatry"},{"key":"ref_45","first-page":"1492","article-title":"Web-based training and rater reliability in multicenter depression trials","volume":"59","author":"Rosen","year":"2008","journal-title":"Psychiatr. Serv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1001\/2013.jamapsychiatry.4","article-title":"A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers","volume":"70","author":"Raison","year":"2013","journal-title":"JAMA Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41398-022-02064-z","article-title":"Predicting treatment response using EEG in major depressive disorder: A machine-learning meta-analysis","volume":"12","author":"Watts","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_48","first-page":"451","article-title":"TMS\u2013EEG biomarkers for psychiatry: Methodological readiness and clinical promise","volume":"9","author":"Farzan","year":"2024","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bofill Roig, M., Krotka, P., Burman, C.-F., Glimm, E., Gold, S.M., Hees, K., Jacko, P., Koenig, F., Magirr, D., and Mesenbrink, P. (2022). On model-based time trend adjustments in platform trials with non-concurrent controls. BMC Med. Res. Methodol., 22.","DOI":"10.1186\/s12874-022-01683-w"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1038\/s41591-024-03057-9","article-title":"Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety","volume":"30","author":"Tozzi","year":"2024","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e70025","DOI":"10.1002\/pst.70025","article-title":"Design considerations for a phase II platform trial in major depressive disorder","volume":"24","author":"Freitag","year":"2025","journal-title":"Pharm. Stat."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/6\/612\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T02:15:04Z","timestamp":1780625704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/6\/612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["brainsci16060612"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16060612","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}