Editing Clozapine (section)

==History==
Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant [[imipramine]].<ref name="Crilly_2007" /><ref name="Ellenbroek2012">{{cite book|url=https://books.google.com/books?id=08kGCAAAQBAJ&pg=PA144|title=Atypical Antipsychotics| vauthors = Ellenbroek BA, Cools AR |date=6 December 2012|publisher=Birkhäuser|isbn=978-3-0348-8448-8 |via=Google Books}}</ref> The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967, Wander AG was acquired by [[Sandoz Laboratories|Sandoz]].<ref name="Crilly_2007" /> Further trials took place in 1972 when clozapine was released in Switzerland and Austria as '''Leponex'''.<ref name="Crilly_2007" /> Two years later, it was released in West Germany and in Finland in 1975.<ref name="Crilly_2007" /> Early testing was performed in the United States around the same time.<ref name="Crilly_2007" /> In 1975, 16 cases of [[agranulocytosis]] leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern.<ref>{{cite journal | vauthors = Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva I | title = Letter: Clozapine and agranulocytosis | journal = Lancet | volume = 2 | issue = 7935 | pages = 611 | date = September 1975 | pmid = 51442 | doi = 10.1016/s0140-6736(75)90206-8 | s2cid = 54345964 }}</ref> Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period.<ref>{{cite journal | vauthors = Amsler HA, Teerenhovi L, Barth E, Harjula K, Vuopio P | title = Agranulocytosis in patients treated with clozapine. A study of the Finnish epidemic | journal = Acta Psychiatrica Scandinavica | volume = 56 | issue = 4 | pages = 241–248 | date = October 1977 | pmid = 920225 | doi = 10.1111/j.1600-0447.1977.tb00224.x | s2cid = 24782844 }}</ref> The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic variant in the region.<ref name="Griffith_1975">{{cite journal | vauthors = Griffith RW, Saameli K | title = Letter: Clozapine and agranulocytosis | journal = Lancet | volume = 2 | issue = 7936 | pages = 657 | date = October 1975 | pmid = 52022 | doi = 10.1016/S0140-6736(75)90135-X | s2cid = 53296036 }}</ref><ref name="Legge2019">{{cite journal | vauthors = Legge SE, Walters JT | title = Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective | journal = Pharmacogenomics | volume = 20 | issue = 4 | pages = 279–290 | date = March 2019 | pmid = 30767710 | pmc = 6563116 | doi = 10.2217/pgs-2018-0188 }}</ref><ref name="deWith2017">{{cite journal | vauthors = de With SA, Pulit SL, Staal WG, Kahn RS, Ophoff RA | title = More than 25 years of genetic studies of clozapine-induced agranulocytosis | journal = The Pharmacogenomics Journal | volume = 17 | issue = 4 | pages = 304–311 | date = July 2017 | pmid = 28418011 | doi = 10.1038/tpj.2017.6 | s2cid = 5007914 }}</ref> Whilst the drug continued to be manufactured by [[Sandoz]], and remained available in Europe, development in the U.S. halted.

Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalization, especially in [[state hospital]]s for those with treatment resistant schizophrenia, might often be measured in years rather than days.<ref name="Crilly_2007">{{cite journal | vauthors = Crilly J | title = The history of clozapine and its emergence in the US market: a review and analysis | journal = History of Psychiatry | volume = 18 | issue = 1 | pages = 39–60 | date = March 2007 | pmid = 17580753 | doi = 10.1177/0957154X07070335 | s2cid = 21086497 }}</ref> The role of clozapine in treatment-resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to [[chlorpromazine]] in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61&nbsp;mg +/− 14&nbsp;mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900&nbsp;mg/d)  or chlorpromazine (up to 1800&nbsp;mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas.<ref name="Kane_1988">{{cite journal | vauthors = Kane J, Honigfeld G, Singer J, Meltzer H | title = Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine | journal = Archives of General Psychiatry | volume = 45 | issue = 9 | pages = 789–796 | date = September 1988 | pmid = 3046553 | doi = 10.1001/archpsyc.1988.01800330013001 }}</ref> Following this study, the US [[Food and Drug Administration]] (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.<ref name="deWith2017" /><ref>{{cite book|title=The Psychopharmacologists|vauthors=Healy D|date=8 May 2018|publisher=CRC Press |isbn=978-0-203-73615-9|doi=10.1201/9780203736159}}</ref>

In December 2002, clozapine was approved in the US for people with schizophrenia or schizoaffective disorder judged to be at chronic risk for suicidal behavior.<ref>{{cite web|date=18 December 2002|title=Supplemental NDA Approval Letter for Clozaril, NDA 19-758 / S-047|url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf|url-status=dead|archive-url=https://web.archive.org/web/20131108024629/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf|archive-date=8 November 2013|access-date=23 November 2012|publisher=United States Food and Drug Administration}}</ref> In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.<ref>{{cite web|title=Letter to Novartis Pharmaceuticals Corporation|url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf|url-status=live|archive-url=https://web.archive.org/web/20110511063325/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf|archive-date=11 May 2011|access-date=20 September 2009}}</ref> In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared patient registry called The Clozapine Risk Evaluation and Mitigation Strategy (REMS) Registry.<ref>{{cite news|title=FDA Modifies REMS Program for Clozapine|work=www.raps.org|url=https://www.raps.org/news-and-articles/news-articles/2019/1/fda-modifies-rems-program-for-clozapine|access-date=14 August 2021}}</ref> As of 24 February 2025, the FDA no longer requires participation in the Clozapine REMS, but blood monitoring is still recommended.<ref>{{Cite web |date=24 February 2025 |title=Information on Clozapine |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine |website=Food and Drug Administration}}</ref> Despite the demonstrated safety of the 2005 FDA monitoring requirements, which have lower [[neutrophil]] levels and do not include total white cell counts, international monitoring has not been standardized.<ref>{{cite journal | vauthors = Sultan RS, Olfson M, Correll CU, Duncan EJ | title = Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring | journal = The Journal of Clinical Psychiatry | volume = 78 | issue = 8 | pages = e933–e939 | date = 25 October 2017 | pmid = 28742291 | pmc = 5669833 | doi = 10.4088/jcp.16m11152 }}</ref><ref name="Nielsen_2016" /><ref name="There Is Life After the UK Clozapin">{{cite journal | vauthors = Oloyede E, Casetta C, Dzahini O, Segev A, Gaughran F, Shergill S, Mijovic A, Helthuis M, Whiskey E, MacCabe JH, Taylor D | title = There Is Life After the UK Clozapine Central Non-Rechallenge Database | journal = Schizophrenia Bulletin | volume = 47 | issue = 4 | pages = 1088–1098 | date = July 2021 | pmid = 33543755 | pmc = 8266568 | doi = 10.1093/schbul/sbab006 }}</ref>