{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:43:06Z","timestamp":1787013786891,"version":"build-2736575974"},"reference-count":41,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,12,20]],"date-time":"2020-12-20T00:00:00Z","timestamp":1608422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["15Adk0310045h001"],"award-info":[{"award-number":["15Adk0310045h001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Psychiatr Scand"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      There is no report that statistically evaluates the therapeutic reference (350\u2013600\u00a0ng\/ml) and adverse drug reaction (ADR) range (&gt;1000\u00a0ng\/ml) of clozapine (CLZ) recommended by the\n                      <jats:italic>Arbeitsgemeinschaft f\u00fcr Neuropsychopharmakologie und Pharmakopsychiatrie<\/jats:italic>\n                      (\n                      <jats:italic>AGNP<\/jats:italic>\n                      ) consensus guidelines in an isolated and large sampling study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We administered CLZ to 131 Japanese patients with treatment\u2010resistant schizophrenia in a multicenter cross\u2010sectional study. Plasma CLZ concentrations were assayed by high\u2010performance liquid chromatography using trough sampling. The Brief Psychiatric Rating Scale (BPRS) and severe dose\u2010dependent ADR (sedation, myoclonus, and seizures) were analyzed statistically after adjusting for possible confounders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The daily CLZ dosage showed a moderately positive relationship with the plasma concentration (\n                      <jats:italic>r\u00a0=\u00a0<\/jats:italic>\n                      0.49,\n                      <jats:italic>p\u00a0&lt;\u00a0<\/jats:italic>\n                      0.001). Every 100\u00a0ng\/ml increase in plasma CLZ concentration improved the total BPRS score 1.95% (95% CI: 0.89\u20133.01,\n                      <jats:italic>p\u00a0&lt;\u00a0<\/jats:italic>\n                      0.001) and the odds ratio (OR) 1.38 (95% CI: 1.14\u20131.66,\n                      <jats:italic>p\u00a0=\u00a0<\/jats:italic>\n                      0.001) for BPRS response. Compared with concentrations below 350\u00a0ng\/ml CLZ, 350\u2013600\u00a0ng\/ml (11.12%; 95% CI: 2.52\u201319.72,\n                      <jats:italic>p\u00a0=\u00a0<\/jats:italic>\n                      0.012) and 600\u20131000\u00a0ng\/ml (11.05%; 95% CI: 2.40\u201319.71,\n                      <jats:italic>p\u00a0=\u00a0<\/jats:italic>\n                      0.013) showed significant improvement in the total BPRS score. Dosages above 1000\u00a0ng\/ml showed greater improvement (25.36%; 95% CI: 13.08\u201337.64,\n                      <jats:italic>p\u00a0&lt;\u00a0<\/jats:italic>\n                      0.001) of the total BPRS score but more severe ADRs than dosages below 1000\u00a0ng\/ml (OR: 31.72; 95% CI: 1.04\u2013968.81,\n                      <jats:italic>p\u00a0=\u00a0<\/jats:italic>\n                      0.048).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The AGNP therapeutic reference range (350\u2013600\u00a0ng\/ml) is useful, and a dose above 1000\u00a0ng\/ml is potentially more effective but carries the risk of severe ADRs in the central nervous system.<\/jats:p>\n                  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