Editing Clozapine (section)

=== Neutropenia and agranulocytosis ===
{{main|Agranulocytosis}}
Clozapine use has been associated with neutropenia, and as a result clozapine therapy is typically done with stringent blood monitoring.<ref name="medicines.org.uk" />  However, meta-analysis of controlled trial data fails to show that clozapine has a stronger association with neutropenia than other antipsychotic medications, or to find a difference in rates of agranulocytosis before and after 1990 (at which point mandatory monitoring was introduced).<ref>{{cite journal | vauthors = Ingimarsson O, MacCabe JH, Haraldsson M, Jónsdóttir H, Sigurdsson E | title = Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland | journal = BMC Psychiatry | volume = 16 | issue = 1 | pages = 441 | date = December 2016 | pmid = 27955666 | pmc = 5153901 | doi = 10.1186/s12888-016-1167-0 | doi-access = free }}</ref><ref name="A meta-analysis of controlled studi">{{cite journal | vauthors = Myles N, Myles H, Xia S, Large M, Bird R, Galletly C, Kisely S, Siskind D | title = A meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia | journal = The Australian and New Zealand Journal of Psychiatry | volume = 53 | issue = 5 | pages = 403–412 | date = May 2019 | pmid = 30864459 | doi = 10.1177/0004867419833166 }}</ref>  Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia.<ref>{{cite journal |vauthors=Vermeulen JM, van Rooijen G, van de Kerkhof MP, Sutterland AL, Correll CU, de Haan L |date=March 2019 |title=Clozapine and Long-Term Mortality Risk in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years |journal=Schizophrenia Bulletin |volume=45 |issue=2 |pages=315–329 |doi=10.1093/schbul/sby052 |pmc=6403051 |pmid=29697804}}</ref> The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700.<ref name="Li_2020" /> The association between clozapine use and specific blood dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland.<ref name="Griffith_1975" /> At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited.<ref name="Crilly_2007" />

Clozapine Induced [[Neutropenia]] (CIN) occurs in approximately 3.8% of cases and Clozapine Induced [[Agranulocytosis]] (CIA) in 0.4%.<ref name="Myles_2018" /> These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory [[absolute neutrophil count]] (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS).<ref>{{cite web|title=A Guide for Patients and Caregivers: What You Need to Know About Clozapine and Neutropenia|url=https://www.clozapinerems.com/CpmgClozapineUI/rems/pdf/resources/Clozapine_REMS_Guide_Patients_Caregivers.pdf |archive-url=https://web.archive.org/web/20171222184248/https://www.clozapinerems.com/CpmgClozapineUI/rems/pdf/resources/Clozapine_REMS_Guide_Patients_Caregivers.pdf |archive-date=22 December 2017 |url-status=live|access-date=14 September 2021|website=Clozapine REMS|publisher=Clozapine REMS Program}}</ref> The exact schedules and blood count thresholds vary internationally<ref name="Nielsen_2016" /> and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. and Australasia for some time.<ref>{{cite journal | vauthors = Whiskey E, Dzahini O, Ramsay R, O'Flynn D, Mijovic A, Gaughran F, MacCabe J, Shergill S, Taylor D | title = Need to bleed? Clozapine haematological monitoring approaches a time for change | journal = International Clinical Psychopharmacology | volume = 34 | issue = 5 | pages = 264–268 | date = September 2019 | pmid = 30882426 | doi = 10.1097/yic.0000000000000258 | s2cid = 81977064 | url = https://kclpure.kcl.ac.uk/portal/en/publications/need-to-bleed(f1dea2eb-0cc6-452b-acab-84e047cb6554).html }}</ref> The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated.<ref name="Li_2020" /> Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.<ref name="Myles_2018" /> After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still.<ref name="Li_2020" /> When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction.<ref name="Myles_2018">{{cite journal | vauthors = Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, Bird R, Siskind D | title = Meta-analysis examining the epidemiology of clozapine-associated neutropenia | journal = Acta Psychiatrica Scandinavica | volume = 138 | issue = 2 | pages = 101–109 | date = August 2018 | pmid = 29786829 | doi = 10.1111/acps.12898 | s2cid = 29157011 }}</ref><ref name="Li_2020">{{cite journal | vauthors = Li XH, Zhong XM, Lu L, Zheng W, Wang SB, Rao WW, Wang S, Ng CH, Ungvari GS, Wang G, Xiang YT | title = The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies | journal = Psychological Medicine | volume = 50 | issue = 4 | pages = 583–594 | date = March 2020 | pmid = 30857568 | doi = 10.1017/S0033291719000369 | s2cid = 75137940 }}</ref> However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of [[white blood cell]] called [[granulocyte]]s. Clozapine carries a [[Boxed warning|black box warning]] for drug-induced agranulocytosis, although meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia fails to show a specific clozapine related risk, which is contrary to the previously accepted beliefs.<ref name="A meta-analysis of controlled studi"/> Rapid [[point-of-care tests]] may simplify the monitoring for agranulocytosis.<ref name="pmid31692521">{{cite journal | vauthors = Kalaria SN, Kelly DL | title = Development of point-of-care testing devices to improve clozapine prescribing habits and patient outcomes | journal = Neuropsychiatric Disease and Treatment | volume = 15 | pages = 2365–2370 | date = 2019 | pmid = 31692521 | pmc = 6708436 | doi = 10.2147/NDT.S216803 | doi-access = free }}</ref>

==== Pharmacogenetics and Mechanism of Clozapine Related Blood Dyscrasias ====
CIA is a type B idiosyncratic adverse drug reaction (ADR). It is unrelated to the mode of therapeutic action, and there is no evidence that it is dose dependent and is one of many non-chemotherapy drugs with the potential to induce an idiosyncratic drug-induced agranulocytosis (IDIN). The mechanisms of CIA have not been fully elucidated but are thought to involve a combination of toxic, immunological and genetic factors, combined with oxidised drug metabolites and HLA-activating T helper cells, which induce B cells to produce drug-dependent neutrophil antibodies.<ref name="Non-chemotherapy drug-induced neutr">{{cite journal | vauthors = Curtis BR | title = Non-chemotherapy drug-induced neutropenia: key points to manage the challenges | journal = Hematology. American Society of Hematology. Education Program | volume = 2017 | issue = 1 | pages = 187–193 | date = December 2017 | pmid = 29222255 | doi = 10.1182/asheducation-2017.1.187 | pmc = 6142577 }}</ref> Severe life-threatening CIA has a distinctive pattern, with a continuous and rapid fall to zero or near-zero ANC within 2–15 days, followed by a prolonged nadir of a similar duration.<ref name="Distinctive pattern of neutrophil c">{{cite journal | vauthors = Taylor D, Vallianatou K, Whiskey E, Dzahini O, MacCabe J | title = Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis | journal = Schizophrenia | volume = 8 | issue = 1 | pages = 21 | date = March 2022 | pmid = 35288577 | doi = 10.1038/s41537-022-00232-0 | pmc = 8920060 }}</ref> Genetic linkage studies have identified specific HLA types and transporter genes as conferring increased risk, but the pharmacogenetics has not yet progressed so as to make testing sufficiently predictive to be used clinically, and the identified genetic risk factors are not generalisable across ethnic groups.<ref>{{Cite journal | vauthors = Konte B, Walters J, Giegling I, Legge S, Cohen D, Pirmohamed M, Tiihonen J, Hartmann A, Bogers JP, Van der Weide J, Van der Weide K |date=2019 |title=HLA-DQB1 6672G&gt;C Influences the Risk of Clozapine-Induced Agranulocytosis in Individuals of European Ancestry |journal=European Neuropsychopharmacology |volume=29 |pages=S866 |doi=10.1016/j.euroneuro.2017.08.154 |issn=0924-977X}}</ref><ref>{{cite journal | vauthors = Ogese MO, Lister A, Jenkins RE, Meng X, Alfirevic A, Douglas L, Mcloughlin R, Silva E, Park BK, Pirmohamed M, Naisbitt DJ | title = Characterization of Clozapine-Responsive Human T Cells | journal = Journal of Immunology | volume = 205 | issue = 9 | pages = 2375–2390 | date = November 2020 | pmid = 32989092 | doi = 10.4049/jimmunol.2000646 }}</ref> Overall, IDINs now have a mortality estimated at 5%; this is a marked improvement compared with previous levels, owing to early recognition and the introduction of hematopoietic growth factors such as G-CSF (granulocyte colony stimulating factor).

Clozapine-induced neutropenia (CIN) and CIA are often regarded as synonymous, with the belief that CIN is a precursor to the more serious dyscrasia. However, there is little if any evidence to support this idea. Instead, it seems that the two are distinct, with most cases of CIN being incidental findings and artefacts of increased blood monitoring.<ref name="Understanding clozapine-related blo">{{cite journal | vauthors = Silva E, Legge S, Casetta C, Whiskey E, Oloyede E, Gee S | title = Understanding clozapine-related blood dyscrasias. Developments, genetics, ethnicity and disparity: it's a CIN | journal = BJPsych Bulletin | pages = 1–6 | date = June 2024 | pmid = 38828731 | doi = 10.1192/bjb.2024.38 }}</ref>

==== International Variation and Cost effectiveness of Monitoring ====
There is very significant international variation in the frequency of full blood count (for neutrophil counts) monitoring including both the thresholds for increased monitoring and for clozapine withdrawal as well as the duration and frequency of blood testing. The most extreme variation is between Iceland, where clozapine is given without full blood monitoring, and with no demonstrable increase in risk and Japan, where the thresholds and frequency is highest. Likewise there are differences between the US thresholds and those in the UK. The US and UK thresholds for clozapine monitoring were identical until 2015, at which point the US Food and Drug Administration (FDA) approved a reduction of 0.5 × 10<sup>−9</sup>/L for each ANC range and removed the requirement for white blood cell, eosinophil and platelet monitoring completely. The frequency used in many parts of mainland Europe and the reduced US thresholds and alternate, extended intervals in monitoring used in the Netherlands have had no demonstrable increase in risk.<ref>{{cite journal | vauthors = Oloyede E, Blackman G, Whiskey E, Bachmann C, Dzahini O, Shergill S, Taylor D, McGuire P, MacCabe J | title = Clozapine haematological monitoring for neutropenia: a global perspective | journal = Epidemiology and Psychiatric Sciences | volume = 31 | pages = e83 | date = November 2022 | pmid = 36426600 | doi = 10.1017/s204579602200066x | pmc = 9714212 }}</ref><ref>{{cite journal | vauthors = Ingimarsson O, MacCabe JH, Haraldsson M, Jónsdóttir H, Sigurdsson E | title = Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland | journal = BMC Psychiatry | volume = 16 | issue = 1 | pages = 441 | date = December 2016 | pmid = 27955666 | doi = 10.1186/s12888-016-1167-0 | doi-access = free | pmc = 5153901 }}</ref><ref name="Understanding clozapine-related blo"/> The rationale for monitoring after the first 18 weeks of treatment is questionable, given that monthly blood sampling is highly unlikely to detect the sudden and profound falls in ANC that accompany agranulocytosis<ref name="Distinctive pattern of neutrophil c"/> and the economic analysis of the cost effectiveness of the current clozapine monitoring schedules shows that these are of highly questionable utility.<ref>{{cite journal | vauthors = Girardin FR, Poncet A, Blondon M, Rollason V, Vernaz N, Chalandon Y, Dayer P, Combescure C | title = Monitoring white blood cell count in adult patients with schizophrenia who are taking clozapine: a cost-effectiveness analysis | journal = The Lancet. Psychiatry | volume = 1 | issue = 1 | pages = 55–62 | date = June 2014 | pmid = 26360402 | doi = 10.1016/s2215-0366(14)70245-7 }}</ref> Similarly several other drugs, for example carbimazole, which is   commonly used in medical practice and with very similar risks of agranulocytosis is  used without mandatory FBC monitoring.<ref name="Non-chemotherapy drug-induced neutr"/><ref>{{cite journal | vauthors = Vicente N, Cardoso L, Barros L, Carrilho F | title = Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management | journal = Drugs in R&D | volume = 17 | issue = 1 | pages = 91–96 | date = March 2017 | pmid = 28105610 | doi = 10.1007/s40268-017-0172-1 | pmc = 5318340 }}</ref>

==== Clozapine rechallenge ====
A clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off.<ref name="There Is Life After the UK Clozapin" /> Other approaches have included the use of other drugs to support neutrophil counts including [[Lithium (medication)|lithium]] or [[granulocyte colony-stimulating factor]] (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.<ref name="Myles">{{cite journal | vauthors = Myles N, Myles H, Clark SR, Bird R, Siskind D | title = Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations | journal = The Australian and New Zealand Journal of Psychiatry | volume = 51 | issue = 10 | pages = 980–989 | date = October 2017 | pmid = 28747065 | doi = 10.1177/0004867417720516 | doi-access = free }}</ref><ref name="LallyJ">{{cite journal | vauthors = Lally J, Malik S, Krivoy A, Whiskey E, Taylor DM, Gaughran FP, Flanagan RJ, Mijovic A, MacCabe JH | title = The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review | journal = Journal of Clinical Psychopharmacology | volume = 37 | issue = 5 | pages = 600–604 | date = October 2017 | pmid = 28817489 | doi = 10.1097/JCP.0000000000000767 | s2cid = 41269943 | url = https://kclpure.kcl.ac.uk/portal/en/publications/the-use-of-granulocyte-colonystimulating-factor-in-clozapine-rechallenge(123168da-3735-4007-886f-6087bef72040).html | access-date = 22 September 2021 | archive-date = 14 May 2023 | archive-url = https://web.archive.org/web/20230514220903/https://kclpure.kcl.ac.uk/portal/en/publications/the-use-of-granulocyte-colonystimulating-factor-in-clozapine-rechallenge(123168da-3735-4007-886f-6087bef72040).html | url-status = dead }}</ref><ref>{{cite journal | vauthors = Silva E, Higgins M, Hammer B, Stephenson P | title = Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital | journal = Therapeutic Advances in Psychopharmacology | volume = 11 | pages = 20451253211015070 | date = January 2021 | pmid = 34221348 | doi = 10.1177/20451253211015070 | pmc = 8221694 }}</ref><ref>{{cite journal | vauthors = Silva E, Higgins M, Hammer B, Stephenson P | title = Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide | journal = BMC Psychiatry | volume = 20 | issue = 1 | pages = 279 | date = June 2020 | pmid = 32503471 | doi = 10.1186/s12888-020-02592-2 | doi-access = free | pmc = 7275543 }}</ref>