{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:19:32Z","timestamp":1791310772911,"version":"4.3.1"},"reference-count":33,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Psychiatry Clin Neurosci"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Clozapine\u2010induced agranulocytosis (CIA) is traditionally considered an idiosyncratic, dose\u2010independent reaction. However, emerging evidence suggests that clozapine\u2010related inflammatory events may exhibit dose\u2010dependent characteristics, leading us to hypothesize that CIA risk may similarly relate to early cumulative exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using Japan's nationwide Clozaril Patient Monitoring Service database (2009\u20132024), the 30\u2010day cumulative dose following initiation was calculated for all treated patients. Participants were stratified into quartiles (Q1\u2013Q4). CIA was defined as two consecutive absolute neutrophil counts &lt;500\/mm\n                      <jats:sup>3<\/jats:sup>\n                      . The incidence of CIA was compared across quartiles using Kaplan\u2013Meier survival curves and Cox proportional hazards models adjusted for age and sex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 18,189 patients (mean age 42.9 [SD 12.7]; 46.4% female), 138 (0.76%) developed CIA, with no cases occurring within the first 30\u2009days. The incidence rates of CIA in Q1, Q2, Q3, and Q4 were 0.44%, 0.66%, 0.74%, and 1.20%, respectively. Compared with Q1, hazard ratios (HRs) over 180\u2009days were 1.78 (95% confidence interval [CI] 0.96\u20133.30;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0659), 2.01 (95% CI 1.10\u20133.66;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0233), and 3.07 (95% CI 1.74\u20135.42;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001) for Q2, Q3, and Q4, respectively. Male sex and age &gt;40\u2009years were identified as independent risk factors.\n                      <jats:italic>E<\/jats:italic>\n                      \u2010values for Q4 HR were 5.59 (point estimate) and 2.88 (95% CI), indicating high robustness against unmeasured confounders such as co\u2010medications.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Higher early cumulative clozapine exposure was associated with increased CIA risk. These findings suggest that early exposure may serve as a clinically relevant marker of CIA risk, although causal inference is limited and further research is needed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/pcn.70092","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T03:50:46Z","timestamp":1781581846000},"page":"765-772","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Association between initial 30\u2010day cumulative clozapine dose and risk of agranulocytosis: A nationwide register\u2010based cohort study"],"prefix":"10.1111","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1184-8918","authenticated-orcid":false,"given":"Yuki","family":"Kikuchi","sequence":"first","affiliation":[{"name":"Department of Psychiatry Graduate School of Medicine, Tohoku University  Sendai Japan"},{"name":"Department of Psychiatry Kodama Hospital  Ishinomaki 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Medicine, Dokkyo Medical University  Mibu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3073-4588","authenticated-orcid":false,"given":"Ken","family":"Inada","sequence":"additional","affiliation":[{"name":"The Japanese Society of Clinical Neuropsychopharmacology  Tokyo Japan"},{"name":"Department of Psychiatry Kitasato University School of Medicine  Sagamihara Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2628-880X","authenticated-orcid":false,"given":"Hiroaki","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Graduate School of Medicine, Tohoku University  Sendai Japan"},{"name":"The Japanese Society of Clinical Neuropsychopharmacology  Tokyo Japan"},{"name":"Department of Psychiatry Tohoku University Hospital  Sendai 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