{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:07:09Z","timestamp":1785434829410,"version":"3.56.0"},"reference-count":72,"publisher":"Cambridge University Press (CUP)","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"unspecified","delay-in-days":130,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Psychol. Med."],"published-print":{"date-parts":[[2026]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Clozapine is the only effective treatment for treatment-resistant schizophrenia, but concerns over blood dyscrasia and need for monitoring limit its use. Evidence suggests many hematological abnormalities may result from surveillance bias, with agranulocytosis being the primary adverse effect directly induced by clozapine. This systematic review (PROSPERO: CRD42024487199) investigates non-genetic risk factors associated with blood dyscrasia during clozapine treatment, focusing on neutropenia and agranulocytosis. Random-effect meta-analyses were performed on studies reporting quantitative risk data. Due to inconsistent neutropenia definitions, analyses used absolute neutrophil count (ANC) thresholds of &lt;2000\/mm\n                    <jats:sup>3<\/jats:sup>\n                    , &lt;1500\/mm\n                    <jats:sup>3<\/jats:sup>\n                    , and &lt;500\/mm\n                    <jats:sup>3<\/jats:sup>\n                    . Forty-four studies were included in the systematic review, 15 in meta-analyses. No significant association was found between agranulocytosis and female gender (OR = 1.48, 95% CI: 0.92\u20132.38; p = 0.106) or age (pooled standardized mean difference [SMD] = 0.32, 95% CI: \u20130.26 to 0.90, p = 0.285), whilst a modest inverse association with clozapine dose (SMD = \u20130.32, 95%CI: \u20130.50 to \u20130.14, p &lt; 0.001) and baseline white cell count (SMD = \u20130.21, 95%CI: \u20130.40 to \u20130.03, p = 0.026) was found. Neutropenia (ANC &lt; 2000\/mm\n                    <jats:sup>3<\/jats:sup>\n                    ) was positively associated with concomitant psychotropic use (OR = 2.15, 95% CI: 1.13\u20134.07, p = 0.019). Clozapine rechallenge studies revealed no significant associations with gender, age, duration of initial clozapine trial, or length of discontinuation period prior to rechallenge. No strong predictors of clozapine-associated blood dyscrasia were identified. Findings may be limited by study variability, surveillance bias, and lack of consistent differentiation between agranulocytosis and milder neutropenia, highlighting limitations in current evidence.\n                  <\/jats:p>","DOI":"10.1017\/s0033291726104371","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T10:33:42Z","timestamp":1778495622000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":0,"title":["Risk factors associated with blood dyscrasia during clozapine treatment: a systematic review and meta-analysis"],"prefix":"10.1017","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1980-3415","authenticated-orcid":false,"given":"Cecilia","family":"Casetta","sequence":"first","affiliation":[{"name":"Institute of Psychiatry at the Maudsley: King\u2019s College London Institute of Psyc"},{"id":[{"id":"https:\/\/ror.org\/015803449","id-type":"ROR","asserted-by":"publisher"}],"name":"SLAM: South London and Maudsley NHS Foundation Trust"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Loane","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry at the Maudsley: King\u2019s College London Institute of Psyc"},{"id":[{"id":"https:\/\/ror.org\/015803449","id-type":"ROR","asserted-by":"publisher"}],"name":"SLAM: South London and Maudsley NHS Foundation Trust"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Taylor","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/015803449","id-type":"ROR","asserted-by":"publisher"}],"name":"SLAM: South London and Maudsley NHS Foundation Trust"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1218-675X","authenticated-orcid":false,"given":"Richard","family":"Emsley","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry at the Maudsley: King\u2019s College London Institute of Psyc"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6754-1018","authenticated-orcid":false,"given":"James Hunter","family":"MacCabe","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry at the Maudsley: King\u2019s College London Institute of Psyc"},{"id":[{"id":"https:\/\/ror.org\/015803449","id-type":"ROR","asserted-by":"publisher"}],"name":"SLAM: South London and Maudsley NHS Foundation Trust"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"S0033291726104371_r17","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.188.3.255"},{"key":"S0033291726104371_r35","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01322-w"},{"key":"S0033291726104371_r53","doi-asserted-by":"publisher","DOI":"10.1017\/S204579602200066X"},{"key":"S0033291726104371_r16","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200103000-00004"},{"key":"S0033291726104371_r42","doi-asserted-by":"publisher","DOI":"10.1089\/cap.2011.0136"},{"key":"S0033291726104371_r66","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajp.2021.102745"},{"key":"S0033291726104371_r68","doi-asserted-by":"publisher","DOI":"10.1007\/s40801-023-00377-z"},{"key":"S0033291726104371_r41","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-9964(97)00057-1"},{"key":"S0033291726104371_r62","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2015.15030332"},{"key":"S0033291726104371_r24","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-018-4881-0"},{"key":"S0033291726104371_r37","first-page":"164","article-title":"Neutropenia and agranulocytosis in Chinese patients prescribed clozapine","volume":"25","author":"Lau","year":"2015","journal-title":"East Asian Archives of Psychiatry"},{"key":"S0033291726104371_r20","doi-asserted-by":"publisher","DOI":"10.1503\/jpn.200208"},{"key":"S0033291726104371_r43","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2017.08.041"},{"key":"S0033291726104371_r45","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050628"},{"key":"S0033291726104371_r63","doi-asserted-by":"publisher","DOI":"10.1177\/02698811241262767"},{"key":"S0033291726104371_r65","doi-asserted-by":"publisher","DOI":"10.30773\/pi.2020.0376"},{"key":"S0033291726104371_r21","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(14)70245-7"},{"key":"S0033291726104371_r32","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2023.08.001"},{"key":"S0033291726104371_r71","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/JCP.0000000000000537","article-title":"Relation of the allelic variants of multidrug resistance gene to agranulocytosis associated with clozapine","volume":"36","author":"Yagcioglu","year":"2016a","journal-title":"Erratum. Journal of Clinical Psychopharmacology"},{"key":"S0033291726104371_r10","doi-asserted-by":"publisher","DOI":"10.1097\/YIC.0000000000000060"},{"key":"S0033291726104371_r38","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2016.05.002"},{"key":"S0033291726104371_r50","doi-asserted-by":"publisher","DOI":"10.1111\/acps.12898"},{"key":"S0033291726104371_r54","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"S0033291726104371_r73","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-023-04659-2"},{"key":"S0033291726104371_r69","doi-asserted-by":"publisher","DOI":"10.4067\/S0717-92272017000200002"},{"key":"S0033291726104371_r52","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.2024.104"},{"key":"S0033291726104371_r60","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2024.111104"},{"key":"S0033291726104371_r3","first-page":"137","article-title":"Agranulocytosis: Incidence and risk factors","volume":"55","author":"Alvir","year":"1994","journal-title":"The Journal of Clinical Psychiatry"},{"key":"S0033291726104371_r51","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(23)00343-7"},{"key":"S0033291726104371_r47","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.14m09326"},{"key":"S0033291726104371_r55","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0000000000000512"},{"key":"S0033291726104371_r15","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500423"},{"key":"S0033291726104371_r6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199307153290303"},{"key":"S0033291726104371_r2","unstructured":"European Medicines Agency (EMA). (2025) Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC), 7\u201310 July 2025."},{"key":"S0033291726104371_r59","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfab154"},{"key":"S0033291726104371_r8","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.169.4.483"},{"key":"S0033291726104371_r18","unstructured":"National Institute for Health and Care Excellence (NICE), 2014 (updated 2024). Psychosis and schizophrenia in adults: prevention and management (Clinical guideline CG178). Available at: https:\/\/www.nice.org.uk\/guidance\/cg178."},{"key":"S0033291726104371_r12","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-024-02818-7"},{"key":"S0033291726104371_r26","first-page":"429","article-title":"Clozapine-induced transient white blood count disorders","volume":"55","author":"Hummer","year":"1994","journal-title":"The Journal of Clinical Psychiatry"},{"key":"S0033291726104371_r40","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-199200071-00003"},{"key":"S0033291726104371_r58","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021243"},{"key":"S0033291726104371_r64","doi-asserted-by":"publisher","DOI":"10.1038\/s41537-022-00232-0"},{"key":"S0033291726104371_r29","doi-asserted-by":"publisher","DOI":"10.1038\/s41397-022-00281-9"},{"key":"S0033291726104371_r48","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.175.6.576"},{"key":"S0033291726104371_r34","article-title":"Relationship between clozapine-induced inflammation and eosinophilia: A retrospective cohort study","author":"Kikuchi","year":"2024","journal-title":"Schizophrenia Bulletin"},{"key":"S0033291726104371_r19","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2017.06.068"},{"key":"S0033291726104371_r39","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291719000369"},{"key":"S0033291726104371_r23","doi-asserted-by":"publisher","DOI":"10.1590\/1516-4446-2021-1765"},{"key":"S0033291726104371_r70","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000391"},{"key":"S0033291726104371_r4","first-page":"311","article-title":"Do white-cell count spikes predict agranulocytosis in clozapine recipients?","volume":"31","author":"Alvir","year":"1995","journal-title":"Psychopharmacology Bulletin"},{"key":"S0033291726104371_r22","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-023-02589-7"},{"key":"S0033291726104371_r36","first-page":"233","article-title":"Blood dyscrasias in clozapine-treated patients in Italy","volume":"85","author":"Lambertenghi Deliliers","year":"2000","journal-title":"Haematologica"},{"key":"S0033291726104371_r72","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0000000000000495"},{"key":"S0033291726104371_r67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajp.2019.03.002"},{"key":"S0033291726104371_r30","first-page":"12","article-title":"Clozapine- and non-clozapine-associated neutropenia in patients with schizophrenia: A retrospective cohort study","author":"Johannsen","year":"2022","journal-title":"Therapeutic Advances in Psychopharmacology"},{"key":"S0033291726104371_r57","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(24)00097-X"},{"key":"S0033291726104371_r1","doi-asserted-by":"publisher","DOI":"10.1007\/s11096-014-9967-0"},{"key":"S0033291726104371_r25","first-page":"287","article-title":"Transient neutropenia induced by clozapine","volume":"28","author":"Hummer","year":"1992","journal-title":"Psychopharmacology Bulletin"},{"key":"S0033291726104371_r46","doi-asserted-by":"publisher","DOI":"10.1097\/YIC.0000000000000270"},{"key":"S0033291726104371_r28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2021.06.041"},{"key":"S0033291726104371_r49","doi-asserted-by":"publisher","DOI":"10.1038\/s44220-025-00554-9"},{"key":"S0033291726104371_r13","doi-asserted-by":"publisher","DOI":"10.5694\/j.1326-5377.1998.tb141414.x"},{"key":"S0033291726104371_r11","first-page":"466","article-title":"High risk of eosinophilia in women treated with clozapine","volume":"54","author":"Banov","year":"1993","journal-title":"The Journal of Clinical Psychiatry"},{"key":"S0033291726104371_r33","first-page":"101","article-title":"Seizures EEG abnormalities, and clinical response during clozapine therapy in Japanese patients with schizophrenia","volume":"1","author":"Kikuchi","year":"2014","journal-title":"International Journal of Neuropsychopharmacology"},{"key":"S0033291726104371_r61","volume-title":"Stata statistical software: Release 18","year":"2023"},{"key":"S0033291726104371_r44","doi-asserted-by":"publisher","DOI":"10.1002\/hup.2739"},{"key":"S0033291726104371_r14","doi-asserted-by":"publisher","DOI":"10.1097\/YIC.0000000000000108"},{"key":"S0033291726104371_r27","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.165.8.869"},{"key":"S0033291726104371_r31","doi-asserted-by":"publisher","DOI":"10.1002\/hup.779"},{"key":"S0033291726104371_r56","doi-asserted-by":"publisher","DOI":"10.1016\/j.phclin.2019.03.006"},{"key":"S0033291726104371_r5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199307153290303"},{"key":"S0033291726104371_r9","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.2024.236"}],"container-title":["Psychological Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S0033291726104371","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T10:33:46Z","timestamp":1778495626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S0033291726104371\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":72,"alternative-id":["S0033291726104371"],"URL":"https:\/\/doi.org\/10.1017\/s0033291726104371","relation":{},"ISSN":["0033-2917","1469-8978"],"issn-type":[{"value":"0033-2917","type":"print"},{"value":"1469-8978","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026]]},"assertion":[{"value":"\u00a9 The Author(s), 2026. Published by Cambridge University Press","name":"copyright","label":"Copyright","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http:\/\/creativecommons.org\/licenses\/by\/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.","name":"license","label":"License","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}],"article-number":"e142"}}