{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T06:11:47Z","timestamp":1765260707409,"version":"3.46.0"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T00:00:00Z","timestamp":1765065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"crossref","award":["075-15-2025-463"],"award-info":[{"award-number":["075-15-2025-463"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia (TRS). However, it is effective in only about 40% of patients and is associated with numerous adverse drug reactions. Personalization of clozapine therapy is therefore of critical importance in clinical psychiatry. MiRNA expression may serve as a promising exploratory marker for understanding individual variability in clozapine efficacy and safety. Methods: In this study, we determined the complete miRNA expression profile in TRS patients before initiation of clozapine and after four weeks of treatment. Results: In 15 inpatients with TRS receiving 4-week clozapine monotherapy, PANSS total decreased from 98.8 \u00b1 13.19 to 80.47 \u00b1 14.63 (p = 0.001). The most frequent adverse drug reactions were hypersalivation (n = 13), drowsiness\/sedation (n = 12), and prolonged sleep (n = 12). We detected 24 differentially expressed miRNAs after clozapine. Changes in hsa-miR-129-5p, hsa-miR-6068, and hsa-miR-6814-5p correlated with improvements in positive symptoms; hsa-miR-128-1-5p tracked general psychopathology; and hsa-miR-6814-5p aligned with global improvement (lower PANSS total, higher PSP). Safety signals included associations of hsa-miR-4472 with asthenia\/fatigue and prolonged sleep, hsa-miR-4510 with prolonged sleep, hsa-miR-615-3p and hsa-miR-4715-3p with tachycardia, and hsa-miR-329-1-5p with weight gain. Conclusions: Because miRNAs regulate the expression of a wide range of genes, including those involved in clozapine\u2019s efficacy and safety, these findings underscore the need for further studies integrating pharmacoepigenetic and pharmacogenetic biomarkers. Our preliminary findings suggest that specific miRNAs could be candidate biomarkers associated with clozapine response in TRS, although these results require validation in larger and controlled studies.<\/jats:p>","DOI":"10.3390\/cimb47121020","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:21:43Z","timestamp":1765182103000},"page":"1020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Personalizing Clozapine in Treatment-Resistant Schizophrenia: The Role of MicroRNA Biomarkers\u2014A Pilot Study"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2314-7174","authenticated-orcid":false,"given":"Dmitry N.","family":"Sosin","sequence":"first","affiliation":[{"name":"Psychiatric Hospital No. 1 Named After N.A. Alexeev of the Department of Health of Moscow, 117152 Moscow, Russia"},{"name":"Federal State Budgetary Research Institution Russian Research Center of Surgery Named After Academician B.V. Petrovsky, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5391-0786","authenticated-orcid":false,"given":"Aiperi K.","family":"Khasanova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare, Russian Federation, 125993 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2711-748X","authenticated-orcid":false,"given":"Roman A.","family":"Illarionov","sequence":"additional","affiliation":[{"name":"D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3512-2557","authenticated-orcid":false,"given":"Anastasia K.","family":"Popova","sequence":"additional","affiliation":[{"name":"D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9307-4994","authenticated-orcid":false,"given":"Karin B.","family":"Mirzaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution Russian Research Center of Surgery Named After Academician B.V. Petrovsky, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare, Russian Federation, 125993 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7465-4504","authenticated-orcid":false,"given":"Andrey S.","family":"Glotov","sequence":"additional","affiliation":[{"name":"D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint-Petersburg, Russia"},{"name":"Department of Genetics and Biotechnology, Saint Petersburg State University, 199034 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-3964","authenticated-orcid":false,"given":"Sergey N.","family":"Mosolov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare, Russian Federation, 125993 Moscow, Russia"},{"name":"Moscow Research Institute of Psychiatry, Branch of the V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Ministry of Health, Russian Federation, 107076 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry A.","family":"Sychev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution Russian Research Center of Surgery Named After Academician B.V. Petrovsky, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare, Russian Federation, 125993 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0140-6736(21)01730-X","article-title":"Schizophrenia","volume":"399","author":"Jauhar","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2147\/NDT.S61672","article-title":"Towards a framework for treatment effectiveness in schizophrenia","volume":"10","author":"Juckel","year":"2014","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ying, J., Chew, Q.H., McIntyre, R.S., and Sim, K. (2023). 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