Editing Clozapine (section)

== Adverse effects ==
Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries [[boxed warning]]s, including severe [[neutropenia]] (low levels of neutrophils); [[orthostatic hypotension]] (low blood pressure upon changing positions), including [[bradycardia|slow heart rate]] and [[Syncope (medicine)|fainting]]; seizures;  [[myocarditis]] (inflammation of the heart); and risk of death when used in elderly people with dementia-related psychosis.<ref name="Clozaril FDA label" /> Lowering of the [[seizure threshold]] may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.<ref name="MCQ" />

Common effects include [[constipation]], bed-wetting, night-time [[drooling]], [[muscle stiffness]], [[sedation]], [[tremor]]s, orthostatic hypotension, high blood sugar, and [[weight gain]]. The risk of developing [[extrapyramidal symptoms]], such as [[tardive dyskinesia]], is below that of typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.<ref name="MCQ">{{Cite web|title=Clozapine|url=https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril|url-status=live|archive-url=https://web.archive.org/web/20131110214051/https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril|archive-date=10 November 2013|work=Pharmacology: MCQs|via=Google Sites}}</ref> Sexual problems, such as [[retrograde ejaculation]] and [[priapism]], have been reported while taking clozapine.<ref name="Clozaril FDA label" /> Rare adverse effects include periorbital edema and hematological malignancy.<ref>{{cite journal | vauthors = Teodoro T, Nogueira V, Aldeias J, Teles Martins M, Salgado J | title = Clozapine Associated Periorbital Edema in First Episode Psychosis: A Case Report of a Rare Adverse Effect in Treatment-Resistant Schizophrenia | journal = Journal of Clinical Psychopharmacology | date = September 2022 | volume = 42 | issue = 6 | pages = 594–596 | pmid = 36066404 | doi = 10.1097/JCP.0000000000001600| s2cid = 252088054 }}</ref><ref>{{cite journal | vauthors = Hu Y, Gao L, Zhou L, Liu W, Wei C, Liu B, Sun Q, Tian W, Chu RY, Song S, Cheng FW, Chan JK, Ng AP, Lo HK, Lee KC, Chang WC, Wong WC, Chan EW, Wong IC, Chai Y, Lai FT | title = Rare but elevated incidence of hematological malignancy after clozapine use in schizophrenia: A population cohort study | journal = PLoS Medicine | volume = 21 | issue = 12 | pages = e1004457 | date = December 2024 | pmid = 39636825 | doi = 10.1371/journal.pmed.1004457 | veditors = Fazel S | doi-access = free | pmc = 11620352 }}</ref> Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.<ref>{{cite journal | vauthors = Nielsen J, Correll CU, Manu P, Kane JM | title = Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 6 | pages = 603–13; quiz 613 | date = June 2013 | pmid = 23842012 | doi = 10.4088/JCP.12r08064 | doi-access = free }}</ref>

=== Mortality ===
The overall all cause mortality for people with serious psychotic illnesses such as schizophrenia who are prescribed clozapine is lower than those who take other treatments and much lower than those who take no drug treatments at all. Reductions are particularly marked for death by suicide but also from all natural causes. This is demonstrated by studies which have used whole-population databases, such as those completed in Sweden, Finland, Denmark and Taiwan and following [[systematic review]] and [[meta-analysis]].<ref>{{cite journal | vauthors = Correll CU, Solmi M, Croatto G, Schneider LK, Rohani-Montez SC, Fairley L, Smith N, Bitter I, Gorwood P, Taipale H, Tiihonen J | title = Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors | journal = World Psychiatry | volume = 21 | issue = 2 | pages = 248–271 | date = June 2022 | pmid = 35524619 | doi = 10.1002/wps.20994 | pmc = 9077617 }}</ref><ref>{{cite journal | vauthors = Fernandez-Egea E, Flanagan RJ, Taylor D, Gaughran F, Lawrie SM, Jenkins C, Smith S, Howes OD, MacCabe JH | title = Mortality associated with clozapine: what is the evidence? | journal = The British Journal of Psychiatry | volume = 225 | issue = 3 | pages = 357–359 | date = September 2024 | pmid = 39354861 | doi = 10.1192/bjp.2024.88 }}</ref>

=== 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>

===Cardiac toxicity===
Clozapine can rarely cause [[myocarditis]] and [[cardiomyopathy]]. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on.<ref>{{cite journal | vauthors = Siskind D, Sidhu A, Cross J, Chua YT, Myles N, Cohen D, Kisely S | title = Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy | journal = The Australian and New Zealand Journal of Psychiatry | volume = 54 | issue = 5 | pages = 467–481 | date = May 2020 | pmid = 31957459 | doi = 10.1177/0004867419898760 | s2cid = 210831575 }}</ref> First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically [[C-reactive protein]] (CRP) increases with the onset of fever, and rises in the cardiac enzyme, [[troponin]], occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness.<ref>{{cite journal | vauthors = Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ | title = A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls | journal = The Australian and New Zealand Journal of Psychiatry | volume = 45 | issue = 6 | pages = 458–465 | date = June 2011 | pmid = 21524186 | doi = 10.3109/00048674.2011.572852 | s2cid = 26627093 }}</ref> Signs of [[heart failure]] are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate.<ref>{{cite journal | vauthors = Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeil JJ | title = Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study | journal = Schizophrenia Research | volume = 141 | issue = 2–3 | pages = 173–178 | date = November 2012 | pmid = 23010488 | doi = 10.1016/j.schres.2012.08.018 | s2cid = 25720157 }}</ref> A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives.<ref>{{cite journal | vauthors = Segev A, Iqbal E, McDonagh TA, Casetta C, Oloyede E, Piper S, Plymen CM, MacCabe JH | title = Clozapine-induced myocarditis: electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy | journal = The British Journal of Psychiatry | volume = 219 | issue = 6 | pages = 644–651 | date = December 2021 | pmid = 35048875 | pmc = 8636612 | doi = 10.1192/bjp.2021.58 | s2cid = 236297166 }}</ref> Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published.<ref>{{cite journal | vauthors = Griffin JM, Woznica E, Gilotra NA, Nucifora FC | title = Clozapine-Associated Myocarditis: A Protocol for Monitoring Upon Clozapine Initiation and Recommendations for How to Conduct a Clozapine Rechallenge | journal = Journal of Clinical Psychopharmacology | volume = 41 | issue = 2 | pages = 180–185 | date = March 2021 | pmid = 33587399 | doi = 10.1097/JCP.0000000000001358 | s2cid = 231926010 }}</ref> A systematic review of rechallenge after myocarditis has shown success in over 60% of reported cases.<ref>{{cite journal | vauthors = Richardson N, Greenway SC, Bousman CA | title = Clozapine-induced myocarditis and patient outcomes after drug rechallenge following myocarditis: A systematic case review | journal = Psychiatry Research | volume = 305 | pages = 114247 | date = November 2021 | pmid = 34715441 | doi =10.1016/j.psychres.2021.114247 | s2cid = 237461869 }}</ref>

===Gastrointestinal hypomotility===
Another underrecognized and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe [[constipation]], [[fecal impaction]], paralytic [[ileus]], [[bowel obstruction]], acute megacolon, [[ischemia]] or [[necrosis]].<ref>{{cite journal | vauthors = Palmer SE, McLean RM, Ellis PM, Harrison-Woolrych M | title = Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases | journal = The Journal of Clinical Psychiatry | volume = 69 | issue = 5 | pages = 759–768 | date = May 2008 | pmid = 18452342 | doi = 10.4088/JCP.v69n0509 }}</ref> Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when [[gastrointestinal tract|gastrointestinal]] function is measured objectively using [[radiopaque]] markers.<ref>{{cite journal | vauthors = Every-Palmer S, Nowitz M, Stanley J, Grant E, Huthwaite M, Dunn H, Ellis PM | title = Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study | journal = eBioMedicine | volume = 5 | pages = 125–134 | date = March 2016 | pmid = 27077119 | pmc = 4816835 | doi = 10.1016/j.ebiom.2016.02.020 }}</ref> Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis.<ref>{{cite journal | vauthors = Cohen D, Bogers JP, van Dijk D, Bakker B, Schulte PF | title = Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy | journal = The Journal of Clinical Psychiatry | volume = 73 | issue = 10 | pages = 1307–1312 | date = October 2012 | pmid = 23140648 | doi = 10.4088/JCP.11r06977 }}</ref> A [[Cochrane (organisation)|Cochrane review]] found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other [[antipsychotic]] medication.<ref>{{cite journal | vauthors = Every-Palmer S, Newton-Howes G, Clarke MJ | title = Pharmacological treatment for antipsychotic-related constipation | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD011128 | date = January 2017 | pmid = 28116777 | pmc = 6465073 | doi = 10.1002/14651858.CD011128.pub2 }}</ref> Monitoring bowel function and the preemptive use of [[laxative]]s for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae.<ref>{{cite journal | vauthors = Every-Palmer S, Ellis PM, Nowitz M, Stanley J, Grant E, Huthwaite M, Dunn H | title = The Porirua Protocol in the Treatment of Clozapine-Induced Gastrointestinal Hypomotility and Constipation: A Pre- and Post-Treatment Study | journal = CNS Drugs | volume = 31 | issue = 1 | pages = 75–85 | date = January 2017 | pmid = 27826741 | doi = 10.1007/s40263-016-0391-y | s2cid = 46825178 }}</ref>

===Hypersalivation===
Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30–80%).<ref name="Syed Cochrane 2008" /> The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day.<ref name="Syed Cochrane 2008" /> While clozapine is a [[muscarinic]] antagonist at the [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]], [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]], [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]], and [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] receptors, clozapine is a full agonist at the [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] subset. Because M<sub>4</sub> is highly expressed in the [[salivary gland]], its M<sub>4</sub> agonist activity is thought to be responsible for hypersalivation.<ref>{{cite web |url=http://www.medscape.com/viewarticle/409612_2 |title=Treatment of Clozapine-Induced Sialorrhea |access-date=8 February 2010 |url-status=live |archive-url=https://web.archive.org/web/20120209042338/http://www.medscape.com/viewarticle/409612_2 |archive-date=9 February 2012}}</ref> clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication.<ref name="Syed Cochrane 2008" /> Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as [[Scopolamine|hyoscine]],<ref>{{cite journal | vauthors = Segev A, Evans A, Hodsoll J, Whiskey E, Sheriff RS, Shergill S, MacCabe JH | title = Hyoscine for clozapine-induced hypersalivation: a double-blind, randomized, placebo-controlled cross-over trial | journal = International Clinical Psychopharmacology | volume = 34 | issue = 2 | pages = 101–107 | date = March 2019 | pmid = 30614850 | doi = 10.1097/YIC.0000000000000251 | s2cid = 58554168 | url = https://kclpure.kcl.ac.uk/portal/en/publications/hyoscine-for-clozapineinduced-hypersalivation(0575f794-ce85-4b57-81aa-14fb64045b3c).html }}</ref> [[diphenhydramine]]<ref name="Syed Cochrane 2008">{{cite journal | vauthors = Syed R, Au K, Cahill C, Duggan L, He Y, Udu V, Xia J | title = Pharmacological interventions for clozapine-induced hypersalivation | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD005579 | date = July 2008 | pmid = 18646130 | pmc = 4160791 | doi = 10.1002/14651858.CD005579.pub2 | veditors = Syed R }}</ref> and topical anticholinergic medications like [[ipratropium bromide]].<ref name="Bird et al 2011 Review" /> Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.<ref name="Bird et al 2011 Review">{{cite journal | vauthors = Bird AM, Smith TL, Walton AE | title = Current treatment strategies for clozapine-induced sialorrhea | journal = The Annals of Pharmacotherapy | volume = 45 | issue = 5 | pages = 667–675 | date = May 2011 | pmid = 21540404 | doi = 10.1345/aph.1P761 | s2cid = 42222976 }}</ref>

===Central nervous system===
CNS side effects include [[drowsiness]], [[vertigo]], [[headache]], [[tremor]], [[Syncope (medicine)|syncope]], [[sleep disturbances]], [[nightmares]], restlessness, [[akinesia]], [[Psychomotor agitation|agitation]], [[seizures]], [[rigidity (neurology)|rigidity]], [[akathisia]], [[confusion]], [[Fatigue (medical)|fatigue]], [[insomnia]], [[hyperkinesia]], [[weakness]], [[lethargy]], [[ataxia]], [[slurred speech]], [[Depression (mood)|depression]], [[myoclonic jerks]], and [[anxiety (mood)|anxiety]]. Rarely seen are [[delusions]], [[hallucinations]], [[delirium]], [[amnesia]], [[libido]] increase or decrease, [[paranoia]] and [[irritability]], [[Electroencephalography#Abnormal activity|abnormal EEG]], worsening of [[psychosis]], [[paresthesia]], [[status epilepticus]], and [[Obsessive–compulsive disorder|obsessive compulsive symptoms]]. Similar to other [[antipsychotics]], clozapine rarely has been known to cause [[neuroleptic malignant syndrome]].<ref>{{Cite web|url=https://www.rxlist.com/script/main/notfoundstatic.asp?refurl=/cgi/generic/clozapine_ad.htm|archive-url=https://web.archive.org/web/20071104074526/http://www.rxlist.com/cgi/generic/clozapine_ad.htm|url-status=dead|title=ClozarilSide Effects & Drug Interactions|archive-date=4 November 2007|website=RxList|access-date=4 June 2020}}</ref>

===Urinary incontinence===
Clozapine is linked to [[urinary incontinence]],<ref name="Raja">{{cite journal | vauthors = Raja M | title = Clozapine safety, 35 years later | journal = Current Drug Safety | volume = 6 | issue = 3 | pages = 164–184 | date = July 2011 | pmid = 22122392 | doi = 10.2174/157488611797579230 }}</ref> though its appearance may be under-recognized.<ref>{{cite journal | vauthors = Barnes TR, Drake MJ, Paton C | title = Nocturnal enuresis with antipsychotic medication | journal = The British Journal of Psychiatry | volume = 200 | issue = 1 | pages = 7–9 | date = January 2012 | pmid = 22215862 | doi = 10.1192/bjp.bp.111.095737 | doi-access = free }}</ref> This side-effect may be amendable to [[bethanechol]].<ref>Dadlani N, Austin M. Bethanechol and Aripiprazole for the management of refractory urinary incontinence in a patient on Clozapine. Aust N Z J Psychiatry. 2016 Feb;50(2):182. doi: 10.1177/0004867415583878. Epub 2015 Apr 28. [//www.ncbi.nlm.nih.gov/pubmed/25922356?dopt=Abstract PMID 25922356].</ref>

===Withdrawal effects===
Abrupt withdrawal may lead to [[cholinergic]] [[rebound effects]], such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation.<ref>{{cite journal | vauthors = Stevenson E, Schembri F, Green DM, Burns JD | title = Serotonin syndrome associated with clozapine withdrawal | journal = JAMA Neurology | volume = 70 | issue = 8 | pages = 1054–1055 | date = August 2013 | pmid = 23753931 | doi = 10.1001/jamaneurol.2013.95 | doi-access = free }}</ref> Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis.<ref>{{cite journal | vauthors = Wadekar M, Syed S | title = Clozapine-withdrawal catatonia | journal = Psychosomatics | volume = 51 | issue = 4 | pages = 355–355.e2 | date = July 2010 | pmid = 20587767 | doi = 10.1176/appi.psy.51.4.355 }}</ref> Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.<ref name="Ahmed-1998">{{cite journal | vauthors = Ahmed S, Chengappa KN, Naidu VR, Baker RW, Parepally H, Schooler NR | title = Clozapine withdrawal-emergent dystonias and dyskinesias: a case series | journal = The Journal of Clinical Psychiatry | volume = 59 | issue = 9 | pages = 472–477 | date = September 1998 | pmid = 9771818 | doi = 10.4088/JCP.v59n0906 }}</ref><ref name="Szafrański-">{{cite journal | vauthors = Szafrański T, Gmurkowski K | title = [Clozapine withdrawal. A review] | journal = Psychiatria Polska | volume = 33 | issue = 1 | pages = 51–67 | year = 1999 | pmid = 10786215 }}</ref>

===Weight gain and diabetes===
In addition to [[hyperglycemia]], significant [[weight gain]] is frequently experienced by patients treated with clozapine.<ref>{{cite journal | vauthors = Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J, Mintz J, Marder SR | title = Novel antipsychotics: comparison of weight gain liabilities | journal = The Journal of Clinical Psychiatry | volume = 60 | issue = 6 | pages = 358–363 | date = June 1999 | pmid = 10401912 | doi = 10.4088/JCP.v60n0602 }}</ref> Impaired glucose metabolism and [[obesity]] have been shown to be constituents of the [[metabolic syndrome]] and may increase the risk of [[cardiovascular disease]]. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other [[atypical antipsychotics]].<ref name="pmid17848919">{{cite journal | vauthors = Nasrallah HA | title = Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles | journal = Molecular Psychiatry | volume = 13 | issue = 1 | pages = 27–35 | date = January 2008 | pmid = 17848919 | doi = 10.1038/sj.mp.4002066 | s2cid = 205678886 }}</ref> For people who gain weight because of clozapine, taking [[metformin]] may reportedly improve three of the five components of the metabolic syndrome: waist circumference, fasting glucose, and fasting triglycerides.<ref>{{cite journal | vauthors = Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S | title = Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0156208 | date = 15 June 2016 | pmid = 27304831 | pmc = 4909277 | doi = 10.1371/journal.pone.0156208 | bibcode = 2016PLoSO..1156208S | veditors = Holscher C | doi-access = free }}</ref>

=== Pneumonia ===
International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events.<ref>{{cite journal | vauthors = De Leon J, Sanz EJ, De Las Cuevas C | title = Data From the World Health Organization's Pharmacovigilance Database Supports the Prominent Role of Pneumonia in Mortality Associated With Clozapine Adverse Drug Reactions | journal = Schizophrenia Bulletin | volume = 46 | issue = 1 | pages = 1–3 | date = January 2020 | pmid = 31901099 | pmc = 6942151 | doi = 10.1093/schbul/sbz093 }}</ref> The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation or the immune effects of clozapine's effects on the resolution of inflammation.<ref>{{cite journal | vauthors = Ponsford M, Castle D, Tahir T, Robinson R, Wade W, Steven R, Bramhall K, Moody M, Carne E, Ford C, Farewell D, Williams P, El-Shanawany T, Jolles S | title = Clozapine is associated with secondary antibody deficiency | journal = The British Journal of Psychiatry | volume = 214 | issue = 2 | pages = 83–89 | date = September 2018 | pmid = 30259827 | pmc = 6429246 | doi = 10.1192/bjp.2018.152 }}</ref><ref>{{cite journal | vauthors = Okada M, Fukuyama K, Shiroyama T, Murata M | title = A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43 | journal = International Journal of Molecular Sciences | volume = 21 | issue = 19 | pages = 7019 | date = September 2020 | pmid = 32987640 | pmc = 7583770 | doi = 10.3390/ijms21197019 | doi-access = free }}</ref>

=== Overdose ===
{{Expand section|date=August 2019}}
Symptoms of overdose can be variable, but often include; [[sedation]], [[confusion]], [[tachycardia]], [[seizure]]s and [[ataxia]]. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000&nbsp;mg have been survived.<ref name="Keck et al">{{cite journal | vauthors = Keck PE, McElroy SL | title = Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications | journal = The Journal of Clinical Psychiatry | volume = 63 | issue = Suppl 4 | pages = 3–11 | date = 2002 | pmid = 11913673 }}</ref><ref name="pmid9754851">{{cite journal | vauthors = Broich K, Heinrich S, Marneros A | title = Acute clozapine overdose: plasma concentration and outcome | journal = Pharmacopsychiatry | volume = 31 | issue = 4 | pages = 149–151 | date = July 1998 | pmid = 9754851 | doi = 10.1055/s-2007-979318 | s2cid = 28623410 }}</ref>