{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T04:31:16Z","timestamp":1792297876114,"version":"4.4.0"},"reference-count":357,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Treatment-resistant schizophrenia (TRS) affects up to one in three individuals with schizophrenia and is associated with a significant clinical, social, and economic burden. Different from treatment-responsive forms, TRS appears to involve other biological mechanisms extending beyond dopaminergic dysfunctions. This review outlines current knowledge on the molecular and cellular basis of TRS, focusing on alterations in glutamate signaling, imbalances between excitatory and inhibitory activity, disruptions in D-amino acid metabolism, and evidence of neuroinflammation, oxidative stress, and mitochondrial or endoplasmic reticulum dysfunction. Data from genomics, proteomics, metabolomics, preclinical models, and postmortem studies suggest that TRS may have a peculiar neurobiological substrate. Further, multimodal brain imaging studies reveal differences in brain structure, white matter integrity, and network connectivity when compared to treatment-responsive individuals. Altogether, these findings support a shift from the traditional dopamine hypothesis toward a more comprehensive model that includes multiple immune, metabolic, and synaptic factors. Understanding the possible interplay of these complex mechanisms may lead to the identification of potential biomarkers that may help to predict antipsychotic response, as well as the development of more targeted treatments. Early recognition and a deeper biological insight into TRS are essential for improving care and guiding personalized therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26178598","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:18:57Z","timestamp":1756977537000},"page":"8598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Underpinning of Treatment-Resistant Schizophrenia: A Putative Different Neurobiology from Treatment-Responsive Schizophrenia"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2751-5683","authenticated-orcid":false,"given":"Annarita","family":"Barone","sequence":"first","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5301-405X","authenticated-orcid":false,"given":"Licia","family":"Vellucci","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"},{"name":"Department of Translational Medical Sciences, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8944-414X","authenticated-orcid":false,"given":"Mariateresa","family":"Ciccarelli","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6938-9120","authenticated-orcid":false,"given":"Marta","family":"Matrone","sequence":"additional","affiliation":[{"name":"NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department, Faculty of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy"},{"name":"Department of Mental Health Protection and Promotion, Unit of Addiction Pathology, ASL Rieti, 02100 Rieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0422-3415","authenticated-orcid":false,"given":"Giuseppe","family":"De Simone","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"},{"name":"Bipolar and Depressive Disorders Unit, Hosp\u00ectal Clinic de Barcelona. c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Departament de Medicina, Facultat de Medicina i Ci\u00e8ncies de la Salut, Institut de Neuroci\u00e8ncies, Universitat de Barcelona (UB), c. Casanova, 143, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4938-7627","authenticated-orcid":false,"given":"Federica","family":"Iannotta","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7051-5013","authenticated-orcid":false,"given":"Felice","family":"Iasevoli","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"de Bartolomeis","sequence":"additional","affiliation":[{"name":"Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples \u201cFederico II\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref_1","first-page":"Lu21112ah2","article-title":"Patient Functioning, Life Engagement, and Treatment Goals in Schizophrenia","volume":"83","author":"Correll","year":"2022","journal-title":"J. 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