{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T14:20:14Z","timestamp":1793974814691,"version":"4.8.0"},"reference-count":16,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Clozapine (CLZ) use is hampered by the risk of granulocyte toxicity, which is associated with the formation of nitrenium ions and the concurrent use of valproic acid (VPA). These highly reactive nitrenium ions cannot be measured in vivo. Instead, deactivated cysteinyl conjugates may potentially be detected. The aim of this study was to develop a novel method for identifying cysteinylated derivates of CLZ nitrenium ions to investigate the effect of VPA on their formation using therapeutic drug monitoring data.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>A population comprising 93 VPA comedicated and 162 control patients from a therapeutic drug monitoring (TDM) service in Oslo, Norway, was included. Reprocessing of ultraperformance liquid chromatography high-resolution mass spectra (UHPLC-HR-MS) of previously analyzed TDM samples, combined with the assessment of MS\/MS fragmentation patterns, was performed to identify the CLZ cysteinyl conjugates. Smoking, which induces CLZ metabolism, was assessed by detecting cotinine in the reprocessed mass spectra.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>By reprocessing the UHPLC-HR-MS files of the TDM analyses and reviewing the MS\/MS fragment profiles, four cysteinyl conjugates of CLZ were identified. The formations of CLZ cysteinyl (CLZ-Cys<jats:sup>1+<\/jats:sup>) and CLZ-<jats:italic toggle=\"yes\">N<\/jats:italic>-oxide cysteinyl (CLZ-NOX-Cys<jats:sup>1+<\/jats:sup>) were 1.5-fold (<jats:italic toggle=\"yes\">P<\/jats:italic> = 0.038) and 2.1-fold (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; 0.001) higher in VPA-treated patients than those in the controls. In agreement with previous studies, a 45% reduction in <jats:italic toggle=\"yes\">N<\/jats:italic>-desmethylclozapine formation was observed in VPA-treated patients (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; 0.001).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>A novel method for detecting cysteinyl conjugates of CLZ was developed. Application of this method indicated that VPA significantly increased the formation of CLZ-Cys<jats:sup>1+<\/jats:sup> metabolites, which might explain the granulocyte toxicity reported after adding VPA to CLZ treatment. The developed method opens new avenues for investigating CLZ toxicity, e.g. by correlating cysteinyl conjugates and granulocyte counts in patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/ftd.0000000000001177","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T08:09:41Z","timestamp":1706602181000},"page":"265-269","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":12,"title":["Novel Identification of Cysteinyl Derivatives of Toxic Clozapine Nitrenium Ions and the Effect of Valproic Acid on Metabolite Formation: A Study Using Reprocessed High-Resolution Mass Spectra of Analyzed Therapeutic Drug Monitoring Samples"],"prefix":"10.1097","volume":"46","author":[{"given":"Birgit M.","family":"Wollmann","sequence":"first","affiliation":[{"name":"Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aina G.","family":"Haugen","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; and"},{"name":"Department of Pharmacy, University of Oslo, Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-2751","authenticated-orcid":false,"given":"Espen","family":"Molden","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; and"},{"name":"Department of Pharmacy, University of Oslo, Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,1,26]]},"reference":[{"key":"R1-20250603","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s12888-015-0578-7","article-title":"An evaluation of variation in published estimates of schizophrenia prevalence from 1990\u25002013: a systematic literature review","volume":"15","author":"Simeone","year":"2015","journal-title":"BMC Psychiatry"},{"key":"R2-20250603","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/YIC.0b013e32836508e6","article-title":"The social and economic burden of treatment-resistant schizophrenia: a systematic literature review","volume":"29","author":"Kennedy","year":"2014","journal-title":"Int Clin Psychopharmacol"},{"key":"R3-20250603","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1017\/S2045796017000166","article-title":"Increased cardiovascular mortality in people with schizophrenia: a 24-year national register study","volume":"27","author":"Westman","year":"2018","journal-title":"Epidemiol Psychiatr Sci"},{"key":"R4-20250603","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1056\/NEJM199307153290303","article-title":"Clozapine-induced agranulocytosis. 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