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Treatment-resistant schizophrenia (TRS) is the condition where symptoms remain after pharmacological intervention, resulting in long-lasting functional and social impairments. As the identification and treatment of a TRS patient requires previous failed treatments, early mechanisms of detection are needed in order to quicken the access to effective therapy, as well as improve treatment adherence. In this study, we aim to find a microRNA (miRNA) signature for TRS, as well as to shed some light on the molecular pathways potentially involved in this severe condition. To do this, we compared the blood miRNAs of schizophrenia patients that respond to medication and TRS patients, thus obtaining a 16-miRNA TRS profile. Then, we assessed the ability of this signature to separate responders and TRS patients using hierarchical clustering, observing that most of them are grouped correctly (~70% accuracy). We also conducted a network, pathway analysis, and bibliography search to spot molecular pathways potentially altered in TRS. We found that the response to stress seems to be a key factor in TRS and that proteins p53, SIRT1, MDM2, and TRIM28 could be the potential mediators of such responses. Finally, we suggest a molecular pathway potentially regulated by the miRNAs of the TRS profile.<\/jats:p>","DOI":"10.3390\/ijms24031891","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T02:51:37Z","timestamp":1674096697000},"page":"1891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["MiRNA Differences Related to Treatment-Resistant Schizophrenia"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8110-3567","authenticated-orcid":false,"given":"Daniel","family":"P\u00e9rez-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"NeuroEpigenetics Lab, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain"},{"name":"Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), \u00c1rea Sanitaria de Vigo-Hospital \u00c1lvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Ar\u00e1nzazu","family":"Penedo","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), \u00c1rea Sanitaria de Vigo-Hospital \u00c1lvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain"},{"name":"Grupo de Neurofarmacolog\u00eda de Las Adicciones y Los Trastornos Degenerativos (NEUROFAN), Universidad CEU San Pablo, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Rivera-Baltan\u00e1s","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), \u00c1rea Sanitaria de Vigo-Hospital \u00c1lvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonatiuh","family":"Pe\u00f1a-Centeno","sequence":"additional","affiliation":[{"name":"Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8546-1161","authenticated-orcid":false,"given":"Andre","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8170-0724","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Prieto-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"NeuroEpigenetics Lab, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain"},{"name":"Servicio de Neurolog\u00eda, Hospital Cl\u00ednico Universitario de Santiago, 15706 Santiago de Compostela, Spain"},{"name":"Grupo Trastornos del Movimiento, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Manuel","family":"Olivares","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), \u00c1rea Sanitaria de Vigo-Hospital \u00c1lvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain"},{"name":"Department of Psychiatry, \u00c1rea Sanitaria de Vigo, 36312 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6476-7206","authenticated-orcid":false,"given":"Hugo","family":"L\u00f3pez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"SING Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36213 Vigo, Spain"},{"name":"CINBIO, Department of Computer Science, ESEI-Escuela Superior de Ingenier\u00eda Inform\u00e1tica, Universidade de Vigo, 32004 Ourense, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9899-9569","authenticated-orcid":false,"given":"Roberto Carlos","family":"Ag\u00eds-Balboa","sequence":"additional","affiliation":[{"name":"NeuroEpigenetics Lab, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain"},{"name":"Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), \u00c1rea Sanitaria de Vigo-Hospital \u00c1lvaro Cunqueiro, SERGAS-UVIGO, CIBERSAM-ISCIII, 36213 Vigo, Spain"},{"name":"Servicio de Neurolog\u00eda, Hospital Cl\u00ednico Universitario de Santiago, 15706 Santiago de Compostela, Spain"},{"name":"Grupo Trastornos del Movimiento, Instituto de Investigaci\u00f3n Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Saha, S., Chant, D., Welham, J., and McGrath, J. 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