{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:15:00Z","timestamp":1789845300591,"version":"4.0.1"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Medizinische Hochschule Hannover (MHH)"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neural Transm"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clozapine is a second-generation antipsychotic drug that offers superior treatment results in patients with schizophrenia but is also associated with significant risks. This study analyzes data on pharmacotherapy with clozapine and the associated adverse drug reactions (ADRs) in an inpatient setting including 38,349 patients. Data about the use of clozapine and reports of\u00a0severe ADRs within the period 1993\u20132016 were obtained from the multicentered observational pharmacovigilance program \u201cArzneimittelsicherheit in der Psychiatrie\u201d (AMSP). In total, 586\u00a0severe clozapine-associated ADRs were documented (1.53% of all patients exposed). Patients aged \u226565 years had a higher risk of ADRs than patients aged &lt;65 years (1.96 vs. 1.48%; <jats:italic>p\u2009=\u2009<\/jats:italic>0.021). Significantly more ADRs were attributed to clozapine alone (396; 67.6% of all 586 ADRs) than to a combination with other drugs. The most frequent ADRs were grand mal seizures (0.183% of all 38,349 patients exposed), delirium (0.180%), increased liver enzymes (0.120%), and agranulocytosis (0.107%). We detected 24 cases (0.063%) of clozapine-induced extrapyramidal symptoms, of which 8 (0.021%) were attributed to clozapine alone. Five ADRs resulted in death (0.013%): 2 due to agranulocytosis (41 cases total) (mortality\u2009=\u20094.88%) and 3 due to paralytic (sub)ileus (16 cases) (mortality\u2009=\u200918.75%). The median dose of clozapine in all patients treated was 300\u00a0mg\/day, in patients who developed ADRs 250\u00a0mg\/day. The main risk factor for an ADR was pre-existing damage of the affected organ system. Overall, the results of this study highlight the importance of alertness\u2014especially of frequently overlooked symptoms\u2014and appropriate monitoring during treatment with clozapine, even at low doses.<\/jats:p>","DOI":"10.1007\/s00702-024-02818-7","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T06:02:35Z","timestamp":1723528955000},"page":"1117-1134","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Clozapine-associated adverse drug reactions in 38,349 psychiatric inpatients: drug surveillance data from the AMSP project between 1993 and 2016"],"prefix":"10.1007","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9585-4744","authenticated-orcid":false,"given":"Lene","family":"Bleich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renate","family":"Grohmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2342-735X","authenticated-orcid":false,"given":"Waldemar","family":"Greil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Dabbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3870-3521","authenticated-orcid":false,"given":"Andreas","family":"Erfurth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-6907","authenticated-orcid":false,"given":"Sermin","family":"Toto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8678-7419","authenticated-orcid":false,"given":"Johanna","family":"Seifert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"2818_CR1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJM199307153290303","volume":"329","author":"JM Alvir","year":"1993","unstructured":"Alvir JM, Lieberman JA, Safferman AZ et al (1993) Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 329:162\u2013167. https:\/\/doi.org\/10.1056\/NEJM199307153290303","journal-title":"N Engl J Med"},{"key":"2818_CR2","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1111\/j.1600-0447.1977.tb00224.x","volume":"56","author":"HA Amsler","year":"1977","unstructured":"Amsler HA, Teerenhovi L, Barth E et al (1977) Agranulocytosis in patients treated with clozapine. A study of the Finnish epidemic. Acta Psychiatr Scand 56:241\u2013248. https:\/\/doi.org\/10.1111\/j.1600-0447.1977.tb00224.x","journal-title":"Acta Psychiatr Scand"},{"key":"2818_CR3","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1097\/YIC.0000000000000060","volume":"30","author":"MV Balda","year":"2015","unstructured":"Balda MV, Garay OU, Papale RM et al (2015) Clozapine-associated neutropenia and agranulocytosis in Argentina (2007\u20132012). Int Clin Psychopharmacol 30:109\u2013114. https:\/\/doi.org\/10.1097\/YIC.0000000000000060","journal-title":"Int Clin Psychopharmacol"},{"key":"2818_CR4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0364-7722(79)90068-7","volume":"3","author":"B Beckmann","year":"1979","unstructured":"Beckmann B, Hippius H, R\u00fcther E (1979) Treatment of schizophrenia. Prog Neuropsychopharmacol 3:47\u201352. https:\/\/doi.org\/10.1016\/0364-7722(79)90068-7","journal-title":"Prog Neuropsychopharmacol"},{"key":"2818_CR5","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s40266-013-0144-2","volume":"31","author":"D Bishara","year":"2014","unstructured":"Bishara D, Taylor D (2014) Adverse effects of clozapine in older patients: epidemiology, prevention and management. Drugs Aging 31:11\u201320. https:\/\/doi.org\/10.1007\/s40266-013-0144-2","journal-title":"Drugs Aging"},{"key":"2818_CR6","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1055\/s-2003-41201","volume":"36","author":"F Centorrino","year":"2003","unstructured":"Centorrino F, Albert MJ, Drago-Ferrante G et al (2003) Delirium during clozapine treatment: incidence and associated risk factors. Pharmacopsychiatry 36:156\u2013160. https:\/\/doi.org\/10.1055\/s-2003-41201","journal-title":"Pharmacopsychiatry"},{"key":"2818_CR7","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1007\/s13181-023-00963-1","volume":"19","author":"P Chandru","year":"2023","unstructured":"Chandru P, Gunja N (2023) Toxicity and adverse effects in clozapine-related presentations to a medical toxicology service in Western Sydney. J Med Toxicol 19:374\u2013380. https:\/\/doi.org\/10.1007\/s13181-023-00963-1","journal-title":"J Med Toxicol"},{"key":"2818_CR8","doi-asserted-by":"publisher","first-page":"831","DOI":"10.4103\/aian.AIAN_522_20","volume":"24","author":"S Choudhury","year":"2021","unstructured":"Choudhury S, Banerjee S, Chatterjee K et al (2021) Low-dose clozapine-induced agranulocytosis in patients with movement disorders-retrospective study from India. Ann Indian Acad Neurol 24:831\u2013832. https:\/\/doi.org\/10.4103\/aian.AIAN_522_20","journal-title":"Ann Indian Acad Neurol"},{"key":"2818_CR9","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/s0278-5846(01)00238-x","volume":"26","author":"S-J Chung","year":"2002","unstructured":"Chung S-J, Jeong S-H, Ahn Y-M et al (2002) A retrospective study of clozapine and electroencephalographic abnormalities in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 26:139\u2013144. https:\/\/doi.org\/10.1016\/s0278-5846(01)00238-x","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2818_CR10","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1007\/s40263-017-0481-5","volume":"31","author":"D Cohen","year":"2017","unstructured":"Cohen D (2017) Clozapine and Gastrointestinal Hypomotility. CNS Drugs 31:1083\u20131091. https:\/\/doi.org\/10.1007\/s40263-017-0481-5","journal-title":"CNS Drugs"},{"key":"2818_CR11","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/0006-3223(91)90329-k","volume":"29","author":"BM Cohen","year":"1991","unstructured":"Cohen BM, Keck PE, Satlin A, Cole JO (1991) Prevalence and severity of akathisia in patients on clozapine. Biol Psychiatry 29:1215\u20131219. https:\/\/doi.org\/10.1016\/0006-3223(91)90329-k","journal-title":"Biol Psychiatry"},{"key":"2818_CR12","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/s0006-3223(01)01271-9","volume":"50","author":"RR Conley","year":"2001","unstructured":"Conley RR, Kelly DL (2001) Management of treatment resistance in schizophrenia. Biol Psychiatry 50:898\u2013911. https:\/\/doi.org\/10.1016\/s0006-3223(01)01271-9","journal-title":"Biol Psychiatry"},{"key":"2818_CR14","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1007\/s11920-016-0704-3","volume":"18","author":"M Curto","year":"2016","unstructured":"Curto M, Girardi N, Lionetto L et al (2016) Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep 18:68. https:\/\/doi.org\/10.1007\/s11920-016-0704-3","journal-title":"Curr Psychiatry Rep"},{"key":"2818_CR15","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1097\/YIC.0000000000000108","volume":"31","author":"TL Demler","year":"2016","unstructured":"Demler TL, Morabito NE, Meyer CE, Opler L (2016) Maximizing clozapine utilization while minimizing blood dyscrasias: evaluation of patient demographics and severity of events. Int Clin Psychopharmacol 31:76\u201383. https:\/\/doi.org\/10.1097\/YIC.0000000000000108","journal-title":"Int Clin Psychopharmacol"},{"key":"2818_CR16","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s12888-022-03758-w","volume":"22","author":"MJ Doane","year":"2022","unstructured":"Doane MJ, Bessonova L, Friedler HS et al (2022) Weight gain and comorbidities associated with oral second-generation antipsychotics: analysis of real-world data for patients with schizophrenia or bipolar I disorder. BMC Psychiatry 22:114. https:\/\/doi.org\/10.1186\/s12888-022-03758-w","journal-title":"BMC Psychiatry"},{"key":"2818_CR17","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1080\/15622975.2018.1500030","volume":"20","author":"K Druschky","year":"2019","unstructured":"Druschky K, Bleich S, Grohmann R et al (2019) Seizure rates under treatment with antipsychotic drugs: data from the AMSP project. World J Biol Psychiatry 20:732\u2013741. https:\/\/doi.org\/10.1080\/15622975.2018.1500030","journal-title":"World J Biol Psychiatry"},{"key":"2818_CR18","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1001\/archpsyc.1988.01800250087012","volume":"45","author":"L Farde","year":"1988","unstructured":"Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71\u201376. https:\/\/doi.org\/10.1001\/archpsyc.1988.01800250087012","journal-title":"Arch Gen Psychiatry"},{"key":"2818_CR19","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1002\/mds.27372","volume":"33","author":"SH Fox","year":"2018","unstructured":"Fox SH, Katzenschlager R, Lim S-Y et al (2018) International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson\u2019s disease. Mov Disord 33:1248\u20131266. https:\/\/doi.org\/10.1002\/mds.27372","journal-title":"Mov Disord"},{"key":"2818_CR20","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1093\/ijnp\/pyz046","volume":"23","author":"M-E Friedrich","year":"2020","unstructured":"Friedrich M-E, Winkler D, Konstantinidis A et al (2020) Cardiovascular adverse reactions during antipsychotic treatment: results of AMSP, a drug surveillance program between 1993 and 2013. Int J Neuropsychopharmacol 23:67\u201375. https:\/\/doi.org\/10.1093\/ijnp\/pyz046","journal-title":"Int J Neuropsychopharmacol"},{"key":"2818_CR21","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1017\/S146114571100201X","volume":"15","author":"C Frogley","year":"2012","unstructured":"Frogley C, Taylor D, Dickens G, Picchioni M (2012) A systematic review of the evidence of clozapine\u2019s anti-aggressive effects. Int J Neuropsychopharmacol 15:1351\u20131371. https:\/\/doi.org\/10.1017\/S146114571100201X","journal-title":"Int J Neuropsychopharmacol"},{"key":"2818_CR22","doi-asserted-by":"publisher","first-page":"35S","DOI":"10.1016\/0893-133X(95)00203-P","volume":"14","author":"J Gerlach","year":"1996","unstructured":"Gerlach J, Lublin H, Peacock L (1996) Extrapyramidal symptoms during long-term treatment with antipsychotics: special focus on clozapine and D1 and D2 dopamine antagonists. Neuropsychopharmacology 14:35S-39S. https:\/\/doi.org\/10.1016\/0893-133X(95)00203-P","journal-title":"Neuropsychopharmacology"},{"key":"2818_CR23","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1136\/bmj.38330.470486.8F","volume":"330","author":"SS Gill","year":"2005","unstructured":"Gill SS, Rochon PA, Herrmann N et al (2005) Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. BMJ 330:445. https:\/\/doi.org\/10.1136\/bmj.38330.470486.8F","journal-title":"BMJ"},{"key":"2818_CR24","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/S0140-6736(15)60692-4","volume":"386","author":"Global Burden of Disease Study","year":"2013","unstructured":"Global Burden of Disease Study (2013) Collaborators (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990\u20132013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386:743\u2013800. https:\/\/doi.org\/10.1016\/S0140-6736(15)60692-4","journal-title":"Lancet"},{"key":"2818_CR25","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1007\/s00406-021-01241-3","volume":"271","author":"C Glocker","year":"2021","unstructured":"Glocker C, Grohmann R, Engel R et al (2021) Galactorrhea during antipsychotic treatment: results from AMSP, a drug surveillance program, between 1993 and 2015. Eur Arch Psychiatry Clin Neurosci 271:1425\u20131435. https:\/\/doi.org\/10.1007\/s00406-021-01241-3","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"2818_CR26","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s00702-023-02589-7","volume":"130","author":"C Glocker","year":"2023","unstructured":"Glocker C, Grohmann R, Burkhardt G et al (2023) Antipsychotic drug-induced neutropenia: results from the AMSP drug surveillance program between 1993 and 2016. J Neural Transm (vienna) 130:153\u2013163. https:\/\/doi.org\/10.1007\/s00702-023-02589-7","journal-title":"J Neural Transm (vienna)"},{"issue":"Suppl 1","key":"2818_CR27","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1055\/s-2004-815505","volume":"37","author":"R Grohmann","year":"2004","unstructured":"Grohmann R, Engel RR, R\u00fcther E, Hippius H (2004) The AMSP drug safety program: methods and global results. Pharmacopsychiatry 37(Suppl 1):S4-11. https:\/\/doi.org\/10.1055\/s-2004-815505","journal-title":"Pharmacopsychiatry"},{"key":"2818_CR28","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00406-013-0419-y","volume":"264","author":"R Grohmann","year":"2014","unstructured":"Grohmann R, Engel RR, M\u00f6ller H-J et al (2014) Flupentixol use and adverse reactions in comparison with other common first- and second-generation antipsychotics: data from the AMSP study. Eur Arch Psychiatry Clin Neurosci 264:131\u2013141. https:\/\/doi.org\/10.1007\/s00406-013-0419-y","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"2818_CR29","doi-asserted-by":"publisher","first-page":"234","DOI":"10.4103\/0253-7613.153441","volume":"47","author":"S Grover","year":"2015","unstructured":"Grover S, Sahoo S (2015) Clozapine induced akathisia: a case report and review of the evidence. Indian J Pharmacol 47:234\u2013235. https:\/\/doi.org\/10.4103\/0253-7613.153441","journal-title":"Indian J Pharmacol"},{"key":"2818_CR30","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1055\/s-2007-1014345","volume":"26","author":"W G\u00fcnther","year":"1993","unstructured":"G\u00fcnther W, Baghai T, Naber D et al (1993) EEG alterations and seizures during treatment with clozapine. A retrospective study of 283 patients. Pharmacopsychiatry 26:69\u201374. https:\/\/doi.org\/10.1055\/s-2007-1014345","journal-title":"Pharmacopsychiatry"},{"key":"2818_CR31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0287122","volume":"18","author":"M Hatano","year":"2023","unstructured":"Hatano M, Yamada K, Matsuzaki H et al (2023) Analysis of clozapine-induced seizures using the Japanese Adverse Drug Event Report database. PLoS ONE 18:e0287122. https:\/\/doi.org\/10.1371\/journal.pone.0287122","journal-title":"PLoS ONE"},{"key":"2818_CR32","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1080\/08039488.2018.1517189","volume":"72","author":"O Ingimarsson","year":"2018","unstructured":"Ingimarsson O, MacCabe JH, Sigurdsson E (2018) Constipation, ileus and medication use during clozapine treatment in patients with schizophrenia in Iceland. Nord J Psychiatry 72:497\u2013500. https:\/\/doi.org\/10.1080\/08039488.2018.1517189","journal-title":"Nord J Psychiatry"},{"key":"2818_CR33","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1097\/JGP.0b013e3182118318","volume":"20","author":"Z Ismail","year":"2012","unstructured":"Ismail Z, Wessels AM, Uchida H et al (2012) Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia. Am J Geriatr Psychiatry 20:53\u201360. https:\/\/doi.org\/10.1097\/JGP.0b013e3182118318","journal-title":"Am J Geriatr Psychiatry"},{"key":"2818_CR34","doi-asserted-by":"publisher","first-page":"161","DOI":"10.2165\/00003088-199324020-00005","volume":"24","author":"MW Jann","year":"1993","unstructured":"Jann MW, Grimsley SR, Gray EC, Chang WH (1993) Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet 24:161\u2013176. https:\/\/doi.org\/10.2165\/00003088-199324020-00005","journal-title":"Clin Pharmacokinet"},{"key":"2818_CR35","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1097\/JCP.0000000000000792","volume":"37","author":"G Joy","year":"2017","unstructured":"Joy G, Whiskey E, Bolstridge M et al (2017) Hearts and minds: real-life cardiotoxicity with clozapine in psychosis. J Clin Psychopharmacol 37:708\u2013712. https:\/\/doi.org\/10.1097\/JCP.0000000000000792","journal-title":"J Clin Psychopharmacol"},{"key":"2818_CR36","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.nurx.2005.12.003","volume":"3","author":"S Kapur","year":"2006","unstructured":"Kapur S, Agid O, Mizrahi R, Li M (2006) How antipsychotics work-from receptors to reality. NeuroRx 3:10\u201321. https:\/\/doi.org\/10.1016\/j.nurx.2005.12.003","journal-title":"NeuroRx"},{"key":"2818_CR37","doi-asserted-by":"publisher","first-page":"323","DOI":"10.9758\/cpn.2016.14.4.323","volume":"14","author":"N Kar","year":"2016","unstructured":"Kar N, Barreto S, Chandavarkar R (2016) Clozapine monitoring in clinical practice: beyond the mandatory requirement. Clin Psychopharmacol Neurosci 14:323\u2013329. https:\/\/doi.org\/10.9758\/cpn.2016.14.4.323","journal-title":"Clin Psychopharmacol Neurosci"},{"key":"2818_CR38","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.2147\/NDT.S69784","volume":"10","author":"YS Kikuchi","year":"2014","unstructured":"Kikuchi YS, Sato W, Ataka K et al (2014) Clozapine-induced seizures, electroencephalography abnormalities, and clinical responses in Japanese patients with schizophrenia. Neuropsychiatr Dis Treat 10:1973\u20131978. https:\/\/doi.org\/10.2147\/NDT.S69784","journal-title":"Neuropsychiatr Dis Treat"},{"key":"2818_CR39","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13030-020-00199-3","volume":"14","author":"K Kurisu","year":"2020","unstructured":"Kurisu K, Miyabe D, Furukawa Y et al (2020) Association between polypharmacy and the persistence of delirium: a retrospective cohort study. Biopsychosoc Med 14:25. https:\/\/doi.org\/10.1186\/s13030-020-00199-3","journal-title":"Biopsychosoc Med"},{"key":"2818_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.105306","volume":"163","author":"M Lavrador","year":"2021","unstructured":"Lavrador M, Castel-Branco MM, Cabral AC et al (2021) Association between anticholinergic burden and anticholinergic adverse outcomes in the elderly: Pharmacological basis of their predictive value for adverse outcomes. Pharmacol Res 163:105306. https:\/\/doi.org\/10.1016\/j.phrs.2020.105306","journal-title":"Pharmacol Res"},{"key":"2818_CR41","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1176\/appi.ajp.159.9.1534","volume":"159","author":"DL Leslie","year":"2002","unstructured":"Leslie DL, Rosenheck RA (2002) From conventional to atypical antipsychotics and back: dynamic processes in the diffusion of new medications. Am J Psychiatry 159:1534\u20131540. https:\/\/doi.org\/10.1176\/appi.ajp.159.9.1534","journal-title":"Am J Psychiatry"},{"key":"2818_CR42","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0140-6736(13)60733-3","volume":"382","author":"S Leucht","year":"2013","unstructured":"Leucht S, Cipriani A, Spineli L et al (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382:951\u2013962. https:\/\/doi.org\/10.1016\/S0140-6736(13)60733-3","journal-title":"Lancet"},{"key":"2818_CR43","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.3390\/jcm9061808","volume":"9","author":"N Lorenzo-Villalba","year":"2020","unstructured":"Lorenzo-Villalba N, Alonso-Ortiz MB, Maouche Y et al (2020) Idiosyncratic drug-induced neutropenia and agranulocytosis in elderly patients. J Clin Med 9:1808. https:\/\/doi.org\/10.3390\/jcm9061808","journal-title":"J Clin Med"},{"key":"2818_CR44","doi-asserted-by":"publisher","first-page":"118","DOI":"10.47102\/annals-acadmedsg.V39N2p118","volume":"39","author":"R Mahendran","year":"2010","unstructured":"Mahendran R, Hendricks M, Chan YH (2010) Weight gain in Asian patients on second-generation antipsychotics. Ann Acad Med Singap 39:118\u2013121","journal-title":"Ann Acad Med Singap"},{"key":"2818_CR45","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1176\/ajp.2006.163.4.600","volume":"163","author":"JP McEvoy","year":"2006","unstructured":"McEvoy JP, Lieberman JA, Stroup TS et al (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 163:600\u2013610. https:\/\/doi.org\/10.1176\/ajp.2006.163.4.600","journal-title":"Am J Psychiatry"},{"key":"2818_CR46","doi-asserted-by":"publisher","first-page":"135","DOI":"10.2147\/NDT.S12769","volume":"7","author":"ME McIlwain","year":"2011","unstructured":"McIlwain ME, Harrison J, Wheeler AJ, Russell BR (2011) Pharmacotherapy for treatment-resistant schizophrenia. Neuropsychiatr Dis Treat 7:135\u2013149. https:\/\/doi.org\/10.2147\/NDT.S12769","journal-title":"Neuropsychiatr Dis Treat"},{"key":"2818_CR47","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1007\/BF00449814","volume":"238","author":"HY Meltzer","year":"1989","unstructured":"Meltzer HY, Bastani B, Ramirez L, Matsubara S (1989) Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatry Neurol Sci 238:332\u2013339. https:\/\/doi.org\/10.1007\/BF00449814","journal-title":"Eur Arch Psychiatry Neurol Sci"},{"key":"2818_CR48","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1001\/archpsyc.60.1.82","volume":"60","author":"HY Meltzer","year":"2003","unstructured":"Meltzer HY, Alphs L, Green AI et al (2003) Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial (InterSePT). Arch Gen Psychiatry 60:82\u201391. https:\/\/doi.org\/10.1001\/archpsyc.60.1.82","journal-title":"Arch Gen Psychiatry"},{"key":"2818_CR49","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3109\/15622970009150593","volume":"1","author":"HJ M\u00f6ller","year":"2000","unstructured":"M\u00f6ller HJ (2000) State of the art of drug treatment of schizophrenia and the future position of the novel\/atypical antipsychotics. World J Biol Psychiatry 1:204\u2013214. https:\/\/doi.org\/10.3109\/15622970009150593","journal-title":"World J Biol Psychiatry"},{"key":"2818_CR50","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.4088\/jcp.v68n1115","volume":"68","author":"TA Moore","year":"2007","unstructured":"Moore TA, Buchanan RW, Buckley PF et al (2007) The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry 68:1751\u20131762. https:\/\/doi.org\/10.4088\/jcp.v68n1115","journal-title":"J Clin Psychiatry"},{"key":"2818_CR51","doi-asserted-by":"publisher","first-page":"514","DOI":"10.3390\/ph14060514","volume":"14","author":"N Moschny","year":"2021","unstructured":"Moschny N, Hefner G, Grohmann R et al (2021) Therapeutic drug monitoring of second- and third-generation antipsychotic drugs-influence of smoking behavior and inflammation on pharmacokinetics. Pharmaceuticals (basel) 14:514. https:\/\/doi.org\/10.3390\/ph14060514","journal-title":"Pharmaceuticals (basel)"},{"key":"2818_CR52","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/acps.12898","volume":"138","author":"N Myles","year":"2018","unstructured":"Myles N, Myles H, Xia S et al (2018) Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand 138:101\u2013109. https:\/\/doi.org\/10.1111\/acps.12898","journal-title":"Acta Psychiatr Scand"},{"key":"2818_CR53","doi-asserted-by":"publisher","first-page":"603","DOI":"10.4088\/JCP.12r08064","volume":"74","author":"J Nielsen","year":"2013","unstructured":"Nielsen J, Correll CU, Manu P, Kane JM (2013) Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry 74:603\u2013613. https:\/\/doi.org\/10.4088\/JCP.12r08064. (quiz 613)","journal-title":"J Clin Psychiatry"},{"key":"2818_CR54","doi-asserted-by":"publisher","first-page":"759","DOI":"10.4088\/jcp.v69n0509","volume":"69","author":"SE Palmer","year":"2008","unstructured":"Palmer SE, McLean RM, Ellis PM, Harrison-Woolrych M (2008) Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry 69:759\u2013768. https:\/\/doi.org\/10.4088\/jcp.v69n0509","journal-title":"J Clin Psychiatry"},{"key":"2818_CR55","doi-asserted-by":"publisher","first-page":"91","DOI":"10.2165\/00002018-200225020-00004","volume":"25","author":"F Pisani","year":"2002","unstructured":"Pisani F, Oteri G, Costa C et al (2002) Effects of psychotropic drugs on seizure threshold. Drug Saf 25:91\u2013110. https:\/\/doi.org\/10.2165\/00002018-200225020-00004","journal-title":"Drug Saf"},{"issue":"Suppl","key":"2818_CR56","doi-asserted-by":"publisher","first-page":"S105","DOI":"10.1007\/BF00442572","volume":"99","author":"M Schmauss","year":"1989","unstructured":"Schmauss M, Wolff R, Erfurth A, R\u00fcther E (1989) Tolerability of long term clozapine treatment. Psychopharmacology 99(Suppl):S105-108. https:\/\/doi.org\/10.1007\/BF00442572","journal-title":"Psychopharmacology"},{"key":"2818_CR57","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.euroneuro.2020.05.001","volume":"36","author":"M Schneider","year":"2020","unstructured":"Schneider M, Pauwels P, Toto S et al (2020) Severe weight gain as an adverse drug reaction of psychotropics: Data from the AMSP project between 2001 and 2016. Eur Neuropsychopharmacol 36:60\u201371. https:\/\/doi.org\/10.1016\/j.euroneuro.2020.05.001","journal-title":"Eur Neuropsychopharmacol"},{"key":"2818_CR58","doi-asserted-by":"publisher","first-page":"863","DOI":"10.3390\/ijms17060863","volume":"17","author":"A Shirazi","year":"2016","unstructured":"Shirazi A, Stubbs B, Gomez L et al (2016) Prevalence and predictors of clozapine-associated constipation: a systematic review and meta-analysis. Int J Mol Sci 17:863. https:\/\/doi.org\/10.3390\/ijms17060863","journal-title":"Int J Mol Sci"},{"key":"2818_CR59","doi-asserted-by":"publisher","first-page":"3267","DOI":"10.1038\/s41380-023-02203-y","volume":"28","author":"S Siafis","year":"2023","unstructured":"Siafis S, Wu H, Wang D et al (2023) Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis. Mol Psychiatry 28:3267\u20133277. https:\/\/doi.org\/10.1038\/s41380-023-02203-y","journal-title":"Mol Psychiatry"},{"key":"2818_CR60","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1111\/acps.13361","volume":"144","author":"D Siskind","year":"2021","unstructured":"Siskind D, Sharma M, Pawar M et al (2021) Clozapine levels as a predictor for therapeutic response: a systematic review and meta-analysis. Acta Psychiatr Scand 144:422\u2013432. https:\/\/doi.org\/10.1111\/acps.13361","journal-title":"Acta Psychiatr Scand"},{"key":"2818_CR61","doi-asserted-by":"publisher","first-page":"817","DOI":"10.3390\/ph15070817","volume":"15","author":"M Skokou","year":"2022","unstructured":"Skokou M, Karavia EA, Drakou Z et al (2022) Adverse drug reactions in relation to clozapine plasma levels: a systematic review. Pharmaceuticals (basel) 15:817. https:\/\/doi.org\/10.3390\/ph15070817","journal-title":"Pharmaceuticals (basel)"},{"key":"2818_CR62","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1111\/j.1742-7843.2007.00017.x","volume":"100","author":"E Spina","year":"2007","unstructured":"Spina E, de Leon J (2007) Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol 100:4\u201322. https:\/\/doi.org\/10.1111\/j.1742-7843.2007.00017.x","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"2818_CR63","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1176\/appi.ajp.2015.15030332","volume":"173","author":"TS Stroup","year":"2016","unstructured":"Stroup TS, Gerhard T, Crystal S et al (2016) Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. Am J Psychiatry 173:166\u2013173. https:\/\/doi.org\/10.1176\/appi.ajp.2015.15030332","journal-title":"Am J Psychiatry"},{"key":"2818_CR64","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1093\/ijnp\/pyz037","volume":"22","author":"S Toto","year":"2019","unstructured":"Toto S, Grohmann R, Bleich S et al (2019) Psychopharmacological treatment of schizophrenia over time in 30 908 inpatients: data from the AMSP study. Int J Neuropsychopharmacol 22:560\u2013573. https:\/\/doi.org\/10.1093\/ijnp\/pyz037","journal-title":"Int J Neuropsychopharmacol"},{"key":"2818_CR65","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/0924-977x(95)00057-v","volume":"6","author":"IA Treves","year":"1996","unstructured":"Treves IA, Neufeld MY (1996) EEG abnormalities in clozapine-treated schizophrenic patients. Eur Neuropsychopharmacol 6:93\u201394. https:\/\/doi.org\/10.1016\/0924-977x(95)00057-v","journal-title":"Eur Neuropsychopharmacol"},{"issue":"2","key":"2818_CR66","first-page":"157","volume":"55","author":"DS Umbricht","year":"1994","unstructured":"Umbricht DS, Pollack S, Kane JM (1994) Clozapine and weight gain. J Clin Psychiatry 55(2):157\u2013160","journal-title":"J Clin Psychiatry"},{"key":"2818_CR67","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2023.115539","volume":"330","author":"MZ van der Horst","year":"2023","unstructured":"van der Horst MZ, Meijer Y, de Boer N et al (2023) Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions. Psychiatry Res 330:115539. https:\/\/doi.org\/10.1016\/j.psychres.2023.115539","journal-title":"Psychiatry Res"},{"key":"2818_CR68","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1111\/acps.13267","volume":"143","author":"Y van der Zalm","year":"2021","unstructured":"van der Zalm Y, Foldager L, Termorshuizen F et al (2021) Clozapine and mortality: a comparison with other antipsychotics in a nationwide Danish cohort study. Acta Psychiatr Scand 143:216\u2013226. https:\/\/doi.org\/10.1111\/acps.13267","journal-title":"Acta Psychiatr Scand"},{"key":"2818_CR69","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1177\/2045125311405566","volume":"1","author":"S Varma","year":"2011","unstructured":"Varma S, Bishara D, Besag FMC, Taylor D (2011) Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol 1:47\u201366. https:\/\/doi.org\/10.1177\/2045125311405566","journal-title":"Ther Adv Psychopharmacol"},{"key":"2818_CR70","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41398-021-01613-2","volume":"11","author":"E Wagner","year":"2021","unstructured":"Wagner E, Siafis S, Fernando P et al (2021) Efficacy and safety of clozapine in psychotic disorders-a systematic quantitative meta-review. Transl Psychiatry 11:487. https:\/\/doi.org\/10.1038\/s41398-021-01613-2","journal-title":"Transl Psychiatry"},{"key":"2818_CR71","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.genhosppsych.2017.02.004","volume":"46","author":"S West","year":"2017","unstructured":"West S, Rowbotham D, Xiong G, Kenedi C (2017) Clozapine induced gastrointestinal hypomotility: a potentially life threatening adverse event. A review of the literature. Gen Hosp Psychiatry 46:32\u201337. https:\/\/doi.org\/10.1016\/j.genhosppsych.2017.02.004","journal-title":"Gen Hosp Psychiatry"},{"key":"2818_CR72","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1345\/aph.1K662","volume":"42","author":"AJ Wheeler","year":"2008","unstructured":"Wheeler AJ (2008) Treatment pathway and patterns of clozapine prescribing for schizophrenia in New Zealand. Ann Pharmacother 42:852\u2013860. https:\/\/doi.org\/10.1345\/aph.1K662","journal-title":"Ann Pharmacother"},{"key":"2818_CR73","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1007\/s00702-016-1573-y","volume":"123","author":"C Wohkittel","year":"2016","unstructured":"Wohkittel C, Gerlach M, Taurines R et al (2016) Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice. J Neural Transm (vienna) 123:1021\u20131031. https:\/\/doi.org\/10.1007\/s00702-016-1573-y","journal-title":"J Neural Transm (vienna)"},{"key":"2818_CR74","doi-asserted-by":"publisher","first-page":"3393","DOI":"10.1007\/s00213-022-06241-2","volume":"239","author":"J Wong","year":"2022","unstructured":"Wong J, Pang T, Cheuk NKW et al (2022) A systematic review on the use of clozapine in treatment of tardive dyskinesia and tardive dystonia in patients with psychiatric disorders. Psychopharmacology 239:3393\u20133420. https:\/\/doi.org\/10.1007\/s00213-022-06241-2","journal-title":"Psychopharmacology"},{"key":"2818_CR75","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1007\/s40263-021-00859-0","volume":"35","author":"Y Xu","year":"2021","unstructured":"Xu Y, Amdanee N, Zhang X (2021) Antipsychotic-induced constipation: a review of the pathogenesis, clinical diagnosis, and treatment. CNS Drugs 35:1265\u20131274. https:\/\/doi.org\/10.1007\/s40263-021-00859-0","journal-title":"CNS Drugs"}],"container-title":["Journal of Neural Transmission"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00702-024-02818-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00702-024-02818-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00702-024-02818-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T09:02:43Z","timestamp":1725181363000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00702-024-02818-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,13]]},"references-count":74,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["2818"],"URL":"https:\/\/doi.org\/10.1007\/s00702-024-02818-7","relation":{},"ISSN":["0300-9564","1435-1463"],"issn-type":[{"value":"0300-9564","type":"print"},{"value":"1435-1463","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,13]]},"assertion":[{"value":"14 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"S. Toto is the project manager of the AMSP program and a member of the advisory board for Otsuka and Janssen-Cilag and has received speaker\u2019s honoraria from Janssen-Cilag, Lundbeck\/Otsuka, Recordati Pharma GmbH, ROVI, and Servier. D. Dabbert has received speaker\u2019s honoraria from Aristo. A. Erfurth has received honoraria for advisory board membership and\/or speaker fees from Angelini, Boehringer Ingelheim, Germania, Janssen, Lundbeck, Mylan, Neuraxpharm, Recordati, Rovi and Sandoz. All other authors state they have no competing interests to declare that are relevant to the content of this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The AMSP project and the evaluation of the collected data were authorized by AMSP representatives from Germany, Austria, and Switzerland and the ethics committees of the Ludwig-Maximilians-University of Munich and Hannover Medical School (Nr. 8100_BO_S_2018). This study adheres to the Declaration of Helsinki and its later adaptions. The AMSP program in no way interferes with the treatment of hospitalized patients due to its nature of being an observational post-marketing drug surveillance program. Moreover, data used in this study was obtained from the anonymized data bank of the AMSP program and therefore, individual patients cannot be retraced.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}