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However, the molecular and cellular mechanisms that underlie its efficacy remain largely unclear. We previously generated induced pluripotent stem cell (iPSC) lines from a unique pair of monozygotic twins with TRS. One twin responded to clozapine (CLZ\u2010res), while the other did not (CLZ\u2010non\u2010res). Building on our previous study of these twins, we included healthy controls and focused on the early developmental stages of neuronal differentiation. To investigate the phenotypic differences in the developmental stages of neural cells between patient\u2010derived cells, we differentiated each iPSC line\u2014from both patients and healthy individuals\u2014into neural stem cells (NSCs) and subsequently induced the differentiation of NSCs into neurons. Our results demonstrated that NSCs derived from patients' iPSC lines exhibited impaired neuronal differentiation, with a more pronounced reduction in differentiation observed in CLZ\u2010non\u2010res cells than in CLZ\u2010res cells. RNA sequencing analysis revealed significant differences in the expression of genes involved in neuronal development between CLZ\u2010res and CLZ\u2010non\u2010res cells. These findings suggest that the differences in neuronal development may contribute to the variability in clozapine responsiveness. Although this study is limited to a single twin pair, this unique human model provides valuable insights into the molecular and cellular mechanisms underlying differential clozapine responses, offering a promising framework for the development of effective treatments for patients with TRS.<\/jats:p>","DOI":"10.1002\/npr2.70097","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:40:41Z","timestamp":1774248041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Neuronal Development in\n                    <scp>iPSC<\/scp>\n                    \u2010Derived Neural Stem Cells From Monozygotic Twin Cases With Treatment\u2010Resistant Schizophrenia and Discordant Responses to Clozapine"],"prefix":"10.1002","volume":"46","author":[{"given":"Shotaro","family":"Kawano","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences Tokyo University of Agriculture  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Katayama","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences Tokyo University of Agriculture  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences Tokyo University of Agriculture  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Endo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Department of Bioscience, Graduate School of Life Sciences Tokyo University of Agriculture  Tokyo 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