Editing Clozapine (section)

==Medical uses==

=== Schizophrenia ===
The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark multicenter double blind study<ref>{{cite web |title=clozapine (CHEBI:3766) |url=https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3766 |access-date=1 October 2021 |website=www.ebi.ac.uk}}</ref> in which clozapine (up to 900&nbsp;mg/d) showed marked benefits compared to chlorpromazine (up to 1800&nbsp;mg/d) in a group of patients with protracted psychosis who had already shown an inadequate response to at least three previous antipsychotics including a prior single blind trial of haloperidol (mean 61+/− 14&nbsp;mg/d for six weeks).<ref name="Kane_1988" /> While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalization.<ref name="Taipale_2020" /><ref name="Masuda_2019" /><ref name="NIHR Evidence_2019">{{Cite journal |date=2 October 2019 |title='Last resort' antipsychotic remains the gold standard for treatment-resistant schizophrenia |url=https://evidence.nihr.ac.uk/alert/last-resort-antipsychotic-remains-the-gold-standard-for-treatment-resistant-schizophrenia |journal=NIHR Evidence |type=Plain English summary |doi=10.3310/signal-000826 |s2cid=241225484}}</ref> In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs.<ref name="Lancet2013">{{cite journal
 |vauthors=Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM |date=September 2013 |title=Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis |journal=Lancet |volume=382 |issue=9896 |pages=951–962 |doi=10.1016/S0140-6736(13)60733-3 |pmid=23810019 |s2cid=32085212}}</ref> In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it.<ref name="Taylor_2000" /> In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.<ref name="Waserman 666–668" />{{Unreliable medical source|reason=[[WP:MEDRS|Dated ref from year 2000, survey on 130 patients.]]|date=July 2022}} UK studies into the perspectives of people taking clozapine and their families following treatment with and discontinuation of clozapine describe significant stress and fearfulness of clozapine being stopped.<ref>{{cite journal | vauthors = Oloyede E, Dunnett D, Taylor D, Clark I, MacCabe JH, Whiskey E, Onwumere J | title = The lived experience of clozapine discontinuation in patients and carers following suspected clozapine-induced neutropenia | journal = BMC Psychiatry | volume = 23 | issue = 1 | pages = 413 | date = June 2023 | pmid = 37291505 | pmc = 10249299 | doi = 10.1186/s12888-023-04902-w | doi-access = free }}</ref><ref>{{cite journal | vauthors = Southern J, Elliott P, Maidment I | title = What are patients' experiences of discontinuing clozapine and how does this impact their views on subsequent treatment? | journal = BMC Psychiatry | volume = 23 | issue = 1 | pages = 353 | date = May 2023 | pmid = 37217959 | pmc = 10204301 | doi = 10.1186/s12888-023-04851-4 | doi-access = free }}</ref>

Clozapine is usually used for people diagnosed with [[schizophrenia]] who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. The US FDA authorisation also includes clozapine for the treatment of people exhibiting suicidal behaviour who have schizophrenia or schizoaffective disorder.<ref name="CDER" /> It is also used for the treatment of psychosis in [[Parkinson's disease]].<ref name="medicines.org.uk">{{cite web |title=Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) |url=https://www.medicines.org.uk/emc/product/4411/smpc |access-date=14 September 2021 |website=www.medicines.org.uk}}</ref><ref name="National Institute for Health and Care Excellence (Great Britain)">{{cite book|author=National Institute for Health and Care Excellence (Great Britain)|title=Parkinson's disease in adults : diagnosis and management : full guideline|oclc=1105250833}}</ref> It is regarded as the [[Gold standard therapy|gold-standard]] treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by [[systematic review]]s and [[meta-analysis]].<ref name="Hasan_2012">{{cite journal | vauthors = Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ | title = World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance | journal = The World Journal of Biological Psychiatry | volume = 13 | issue = 5 | pages = 318–378 | date = July 2012 | pmid = 22834451 | doi = 10.3109/15622975.2012.696143 | s2cid = 20370225 }}</ref><ref name="Buchanan_2010">{{cite journal | vauthors = Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W | title = The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements | journal = Schizophrenia Bulletin | volume = 36 | issue = 1 | pages = 71–93 | date = January 2010 | pmid = 19955390 | pmc = 2800144 | doi = 10.1093/schbul/sbp116 }}</ref><ref name="Gaebel_2005">{{cite journal | vauthors = Gaebel W, Weinmann S, Sartorius N, Rutz W, McIntyre JS | title = Schizophrenia practice guidelines: international survey and comparison | journal = The British Journal of Psychiatry | volume = 187 | issue = 3 | pages = 248–255 | date = September 2005 | pmid = 16135862 | doi = 10.1192/bjp.187.3.248 | doi-access = free }}</ref><ref name="Kuipers_2014">{{cite journal | vauthors = Kuipers E, Yesufu-Udechuku A, Taylor C, Kendall T | title = Management of psychosis and schizophrenia in adults: summary of updated NICE guidance | journal = BMJ | volume = 348 | pages = g1173 | date = February 2014 | pmid = 24523363 | doi = 10.1136/bmj.g1173 | s2cid = 44282161 | url = http://www.bmj.com/cgi/content/short/348/mar19_4/g2234 }}</ref><ref name="Howes_2017">{{cite journal | vauthors = Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA, Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P, Fleischacker WW, Gadelha A, Gaughran F, Glenthøj BY, Graff-Guerrero A, Hallak JE, Honer WG, Kennedy J, Kinon BJ, Lawrie SM, Lee J, Leweke FM, MacCabe JH, McNabb CB, Meltzer H, Möller HJ, Nakajima S, Pantelis C, Reis Marques T, Remington G, Rossell SL, Russell BR, Siu CO, Suzuki T, Sommer IE, Taylor D, Thomas N, Üçok A, Umbricht D, Walters JT, Kane J, Correll CU | title = Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology | journal = The American Journal of Psychiatry | volume = 174 | issue = 3 | pages = 216–229 | date = March 2017 | pmid = 27919182 | pmc = 6231547 | doi = 10.1176/appi.ajp.2016.16050503 }}</ref><ref name="Galletly_2016">{{cite journal | vauthors = Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, Kulkarni J, McGorry P, Nielssen O, Tran N | title = Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders | journal = The Australian and New Zealand Journal of Psychiatry | volume = 50 | issue = 5 | pages = 410–472 | date = May 2016 | pmid = 27106681 | doi = 10.1177/0004867416641195 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Essali A, Al-Haj Haasan N, Li C, Rathbone J | title = Clozapine versus typical neuroleptic medication for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000059 | date = January 2009 | volume = 2009 | pmid = 19160174 | pmc = 7065592 | doi = 10.1002/14651858.CD000059.pub2 | collaboration = Cochrane Schizophrenia Group }}</ref><ref>{{cite journal | vauthors = Siskind D, McCartney L, Goldschlager R, Kisely S | title = Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis | journal = The British Journal of Psychiatry | volume = 209 | issue = 5 | pages = 385–392 | date = November 2016 | pmid = 27388573 | doi = 10.1192/bjp.bp.115.177261 | doi-access = free }}</ref> While the guidelines reserve clozapine for individuals in whom two other antipsychotics have already been tried, evidence indicates that clozapine might instead be used as a second-line medication.<ref name="Kahn_2018">{{cite journal | vauthors = Kahn RS, Winter van Rossum I, Leucht S, McGuire P, Lewis SW, Leboyer M, Arango C, Dazzan P, Drake R, Heres S, Díaz-Caneja CM, Rujescu D, Weiser M, Galderisi S, Glenthøj B, Eijkemans MJ, Fleischhacker WW, Kapur S, Sommer IE | title = Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study | journal = The Lancet. Psychiatry | volume = 5 | issue = 10 | pages = 797–807 | date = October 2018 | pmid =  30115598 | doi = 10.1016/S2215-0366(18)30252-9 | s2cid = 52014623 | url = https://kclpure.kcl.ac.uk/portal/en/publications/amisulpride-and-olanzapine-followed-by-openlabel-treatment-with-clozapine-in-firstepisode-schizophrenia-and-schizophreniform-disorder-optimise(e2ac95c9-d392-41b5-9392-6c9bbdfac360).html }}</ref> Clozapine treatment has been demonstrated to produce improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia.<ref name="Masuda_2019">{{cite journal | vauthors = Masuda T, Misawa F, Takase M, Kane JM, Correll CU | title = Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics: A Systematic Review and Meta-analysis of Cohort Studies | journal = JAMA Psychiatry | volume = 76 | issue = 10 | pages = 1052–1062 | date = October 2019 | pmid = 31365048 | pmc = 6669790 | doi = 10.1001/jamapsychiatry.2019.1702 }}</ref><ref name="NIHR Evidence_2019" /><ref name=":9">{{cite journal | vauthors = Nyakyoma K, Morriss R | title = Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study | journal = Psychopharmacology Bulletin | volume = 43 | issue = 2 | pages = 67–81 | date = 2010 | pmid = 21052043 }}</ref><ref name=":10">{{cite journal | vauthors = Siskind D, Reddel T, MacCabe JH, Kisely S | title = The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study | journal = Psychopharmacology | volume = 236 | issue = 6 | pages = 1931–1935 | date = June 2019 | pmid = 30715572 | doi = 10.1007/s00213-019-5179-6 | s2cid = 59603040 | url = https://kclpure.kcl.ac.uk/portal/en/publications/the-impact-of-clozapine-initiation-and-cessation-on-psychiatric-hospital-admissions-and-bed-days(f8558f24-c0c7-4187-a9ca-fce9592341de).html }}</ref> Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.<ref>{{cite journal | vauthors = Gaszner P, Makkos Z | title = Clozapine maintenance therapy in schizophrenia | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 28 | issue = 3 | pages = 465–469 | date = May 2004 | pmid = 15093952 | doi = 10.1016/j.pnpbp.2003.11.011 | s2cid = 36098336 | doi-access = free }}</ref> Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,<ref name="Taipale_2020">{{cite journal | vauthors = Taipale H, Tanskanen A, Mehtälä J, Vattulainen P, Correll CU, Tiihonen J | title = 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20) | journal = World Psychiatry | volume = 19 | issue = 1 | pages = 61–68 | date = February 2020 | pmid = 31922669 | pmc = 6953552 | doi = 10.1002/wps.20699 }}</ref><ref>{{cite journal | vauthors = Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J | title = 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) | journal = Lancet | volume = 374 | issue = 9690 | pages = 620–627 | date = August 2009 | pmid = 19595447 | doi = 10.1016/S0140-6736(09)60742-X | s2cid = 27282281 }}</ref> with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide.<ref>{{cite journal | vauthors = Taipale H, Lähteenvuo M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J | title = Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia | journal = Schizophrenia Bulletin | volume = 47 | issue = 1 | pages = 23–30 | date = January 2021 | pmid = 33428766 | pmc = 7824993 | doi = 10.1093/schbul/sbaa111 }}</ref> Clozapine has a significant anti-aggressive effect.<ref name="Brown_2014" /><ref>{{cite journal | vauthors = Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB | title = Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder | journal = Archives of General Psychiatry | volume = 63 | issue = 6 | pages = 622–629 | date = June 2006 | pmid = 16754835 | doi = 10.1001/archpsyc.63.6.622 | doi-access = free }}</ref><ref>{{cite journal|vauthors=Dalal B, Larkin E, Leese M, Taylor PJ|date=June 1999|title=Clozapine treatment of long-standing schizophrenia and serious violence: a two-year follow-up study of the first 50 patients treated with clozapine in Rampton high security hospital |journal=Criminal Behaviour and Mental Health|language=en|volume=9|issue=2|pages=168–178|doi=10.1002/cbm.304}}</ref><ref>{{cite journal | vauthors = Topiwala A, Fazel S | title = The pharmacological management of violence in schizophrenia: a structured review | journal = Expert Review of Neurotherapeutics | volume = 11 | issue = 1 | pages = 53–63 | date = January 2011 | pmid = 21158555 | doi = 10.1586/ern.10.180 | s2cid = 2190383 }}</ref><ref>{{cite journal | vauthors = Frogley C, Taylor D, Dickens G, Picchioni M | title = A systematic review of the evidence of clozapine's anti-aggressive effects | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 9 | pages = 1351–1371 | date = October 2012 | pmid = 22339930 | doi = 10.1017/S146114571100201X | doi-access = free }}</ref> Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found.<ref>{{cite journal| vauthors = Thomson LD |date=July 2000|title=Management of schizophrenia in conditions of high security |journal=Advances in Psychiatric Treatment|volume=6|issue=4|pages=252–260|doi=10.1192/apt.6.4.252|issn=1355-5146|doi-access=free}}</ref><ref name="Silva 231–239" /><ref name="Clozapine rechallenge and initiatio">{{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 | pmc = 7275543 | doi = 10.1186/s12888-020-02592-2 | doi-access = free }}</ref><ref name="Till_2019" /><ref name="FISHER 7–15" /><ref name="Kasinathan" /><ref>{{cite journal| vauthors = Swinton M, Haddock A |date=January 2000|title=Clozapine in Special Hospital: a retrospective case-control study |journal=The Journal of Forensic Psychiatry|volume=11|issue=3|pages=587–596|doi=10.1080/09585180010006205|s2cid=58172685|issn=0958-5184}}</ref><ref name="Silva 20451253211015070" /><ref>{{cite journal|date=December 1996|title=Schizophrenia, Violence, Clozapine and Risperidone: a Review |journal=British Journal of Psychiatry|volume=169|issue=S31|pages=21–30|doi=10.1192/s0007125000298589|s2cid=199026883 |issn=0007-1250}}</ref> In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm.<ref name="Swinton_2001" /><ref name="Haw_2011" /><ref name="Brown_2014">{{cite journal | vauthors = Brown D, Larkin F, Sengupta S, Romero-Ureclay JL, Ross CC, Gupta N, Vinestock M, Das M | title = Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital | journal = CNS Spectrums | volume = 19 | issue = 5 | pages = 391–402 | date = October 2014 | pmid = 24698103 | pmc = 4255317 | doi = 10.1017/S1092852914000157 }}</ref> Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention.<ref name="Silva 231–239">{{Cite journal|vauthors=Silva E, Till A, Adshead G|date=July 2017|title=Ethical dilemmas in psychiatry: When teams disagree|journal=BJPsych Advances|volume=23|issue=4|pages=231–239|doi=10.1192/apt.bp.116.016147|doi-access=free}}</ref><ref>{{cite journal | vauthors = Henry R, Massey R, Morgan K, Deeks J, Macfarlane H, Holmes N, Silva E | title = Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series | journal = BJPsych Bulletin | volume = 44 | issue = 6 | pages = 239–243 | date = December 2020 | pmid = 32081110 | pmc = 7684781 | doi = 10.1192/bjb.2020.6 }}</ref><ref name="Till_2019">{{cite journal | vauthors = Till A, Selwood J, Silva E | title = The assertive approach to clozapine: nasogastric administration | journal = BJPsych Bulletin | volume = 43 | issue = 1 | pages = 21–26 | date = February 2019 | pmid = 30223913 | pmc = 6327298 | doi = 10.1192/bjb.2018.61 }}</ref><ref>{{cite journal | vauthors = Casetta C, Oloyede E, Whiskey E, Taylor DM, Gaughran F, Shergill SS, Onwumere J, Segev A, Dzahini O, Legge SE, MacCabe JH | title = A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis | journal = The British Journal of Psychiatry | volume = 217 | issue = 3 | pages = 506–513 | date = September 2020 | pmid = 32605667 | doi = 10.1192/bjp.2020.115 | s2cid = 220287156 | url = https://orca.cardiff.ac.uk/134637/3/Manuscript%2Brevised3_no-highlight.pdf }}</ref><ref>{{cite journal | vauthors = Lokshin P, Lerner V, Miodownik C, Dobrusin M, Belmaker RH | title = Parenteral clozapine: five years of experience | journal = Journal of Clinical Psychopharmacology | volume = 19 | issue = 5 | pages = 479–480 | date = October 1999 | pmid = 10505595 | doi = 10.1097/00004714-199910000-00018 }}</ref><ref>{{cite journal | vauthors = Schulte PF, Stienen JJ, Bogers J, Cohen D, van Dijk D, Lionarons WH, Sanders SS, Heck AH | title = Compulsory treatment with clozapine: a retrospective long-term cohort study | journal = International Journal of Law and Psychiatry | volume = 30 | issue = 6 | pages = 539–545 | date = November 2007 | pmid = 17928054 | doi = 10.1016/j.ijlp.2007.09.003 }}</ref><ref name="Kasinathan">{{cite journal|vauthors=Kasinathan J, Mastroianni T|date=December 2007|title=Evaluating the use of enforced clozapine in an Australian forensic psychiatric setting: two cases|journal=BMC Psychiatry|volume=7|issue=S1|pages=13|doi=10.1186/1471-244x-7-s1-p13|issn=1471-244X|pmc=3332745 |doi-access=free }}</ref><ref>{{cite journal| vauthors = McLean G, Juckes L |date=1 December 2001|title=Parenteral Clozapine (Clozaril) |journal=Australasian Psychiatry|language=en|volume=9|issue=4|pages=371|doi=10.1046/j.1440-1665.2001.0367a.x|s2cid=73372315|issn=1039-8562}}</ref><ref name="FISHER 7–15">{{cite journal | vauthors = Fisher WA | title = Elements of successful restraint and seclusion reduction programs and their application in a large, urban, state psychiatric hospital | journal = Journal of Psychiatric Practice | volume = 9 | issue = 1 | pages = 7–15 | date = January 2003 | pmid = 15985912 | doi = 10.1097/00131746-200301000-00003 | s2cid = 2926142 }}</ref><ref>{{cite journal | vauthors = Mossman D, Lehrer DS | title = Conventional and atypical antipsychotics and the evolving standard of care | journal = Psychiatric Services | volume = 51 | issue = 12 | pages = 1528–1535 | date = December 2000 | pmid = 11097649 | doi = 10.1176/appi.ps.51.12.1528 }}</ref> Clozapine has also been used off-label to treat [[catatonia]] with success in over 80% of cases.<ref>{{cite journal | vauthors = Pompili M, Lester D, Dominici G, Longo L, Marconi G, Forte A, Serafini G, Amore M, Girardi P | title = Indications for electroconvulsive treatment in schizophrenia: a systematic review | journal = Schizophrenia Research | volume = 146 | issue = 1–3 | pages = 1–9 | date = May 2013 | pmid = 23499244 | doi = 10.1016/j.schres.2022.09.021 | s2cid = 252276294 | doi-access = free }}</ref>

=== Bipolar disorder ===
On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for [[bipolar disorder]].<ref>{{cite journal | vauthors = Li XB, Tang YL, Wang CY, de Leon J | title = Clozapine for treatment-resistant bipolar disorder: a systematic review | journal = Bipolar Disorders | volume = 17 | issue = 3 | pages = 235–247 | date = May 2015 | pmid = 25346322 | doi = 10.1111/bdi.12272 | s2cid = 22689570 | url = https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1027&context=psychiatry_facpub }}</ref><ref>{{cite journal | vauthors = Goodwin GM | title = Evidence-based guidelines for treating bipolar disorder: revised second edition--recommendations from the British Association for Psychopharmacology | journal = Journal of Psychopharmacology | volume = 23 | issue = 4 | pages = 346–388 | date = June 2009 | pmid = 19329543 | doi = 10.1177/0269881109102919 | s2cid = 27827654 }}</ref><ref>{{cite journal | vauthors = Bastiampillai T, Gupta A, Allison S, Chan SK | title = NICE guidance: why not clozapine for treatment-refractory bipolar disorder? | journal = The Lancet. Psychiatry | volume = 3 | issue = 6 | pages = 502–503 | date = June 2016 | pmid = 27262046 | doi = 10.1016/s2215-0366(16)30081-5 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O'Donovan C, McIntosh D, Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese JR, Vieta E, Malhi G, Post RM, Berk M | title = Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder | journal = Bipolar Disorders | volume = 20 | issue = 2 | pages = 97–170 | date = March 2018 | pmid = 29536616 | pmc = 5947163 | doi = 10.1111/bdi.12609 }}</ref> A long term follow-up study showed efficacy in terms of both psychiatric and somatic hospitialisation, but with bipolar disorder this effect was not as strong as with some other treatments (olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37–0.80), haloperidol LAI (aHR = 0.62, 0.47–0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52–0.85), lithium (aHR = 0.74, 95% CI 0.71–0.76) and clozapine (aHR = 0.75, 95% CI 0.64–0.87)).<ref>{{cite journal | vauthors = Lähteenvuo M, Paljärvi T, Tanskanen A, Taipale H, Tiihonen J | title = Real-world effectiveness of pharmacological treatments for bipolar disorder: register-based national cohort study | journal = The British Journal of Psychiatry | volume = 223 | issue = 4 | pages = 456–464 | date = October 2023 | pmid = 37395140 | pmc = 10866673 | doi = 10.1192/bjp.2023.75 }}</ref> Bipolar disorder is an off-label indication for clozapine.<ref name="CDER" />

=== Initiation ===
Whilst clozapine is usually initiated in hospital setting community initiation is also available.<ref>{{cite journal |vauthors=Flanagan RJ, Lally J, Gee S, Lyon R, [[Susanna Every-Palmer|Every-Palmer S]] |date=October 2020 |title=Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals |journal=British Medical Bulletin |volume=135 |issue=1 |pages=73–89 |doi=10.1093/bmb/ldaa024 |pmc=7585831 |pmid=32885238}}</ref><ref name="Beck_2014">{{cite journal | vauthors = Beck K, McCutcheon R, Bloomfield MA, Gaughran F, Reis Marques T, MacCabe J, Selvaraj S, Taylor D, Howes OD | title = The practical management of refractory schizophrenia--the Maudsley Treatment REview and Assessment Team service approach | journal = Acta Psychiatrica Scandinavica | volume = 130 | issue = 6 | pages = 427–438 | date = December 2014 | pmid = 25201058 | doi = 10.1111/acps.12327 | s2cid = 36409113 }}</ref> Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to [[extrapyramidal symptoms]] of other antipsychotics or psychosis in Parkinson's disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.<ref>{{Cite web|title=Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)|url=https://www.medicines.org.uk/emc/product/4411/smpc#gref|access-date=15 September 2021|website=www.medicines.org.uk}}</ref>

Baseline tests usually also include; a physical examination including baseline weight, [[waist circumference]] and [[Body mass index|BMI]], assessments of [[Assessment of kidney function|renal function]] and [[Liver function tests|liver function]], an [[Electrocardiography|ECG]] and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include [[C-reactive protein|C reactive protein]] (CRP) and [[troponin]]. In Australia and New Zealand pre-clozapine [[echocardiogram]]s are also commonly performed.<ref name="Taylor_2019">{{Cite book|title=The Maudsley prescribing guidelines in psychiatry|vauthors=Taylor D, Barnes TR, Young AH|date=2019|isbn=978-1-119-44260-8|edition=13th|location=Hoboken, NJ | publisher = Wiley |oclc=1029071684}}</ref> A number of service protocols are available and there are variations in the extent of pre-clozapine work ups. Some might also include [[fasting lipids]], [[HBA1c|HbA1c]] and [[prolactin]]. At the [[Maudsley Hospital]] in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; [[Magnetic resonance imaging of the brain|MRI brain]] imaging, [[thyroid function tests]], [[Vitamin B12|B12]], [[folate]] and [[serum calcium]] levels, infection screening for blood borne viruses including [[Hepatitis C|Hepatitis B and C]], [[HIV]] and [[syphilis]] as well as screening for autoimmune psychosis by [[Anti-NMDA receptor encephalitis|anti-NMDA]], [[Anti-VGKC-complex encephalitis|anti-VGKC]] and [[Anti-nuclear antibody]] screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and [[Ventricular natriuretic peptide|BNP]], and for [[neuroleptic malignant syndrome]], a [[Creatine kinase|CK]] level may also be drawn.<ref name="Beck_2014" />

Other clozapine initiation schedules exist. In 2023 the Treatment Response and Resistance in Psychosis Working Group published consensus guidelines on clozapine optimisation including initiation.<ref>{{cite journal | vauthors = Wagner E, Kane JM, Correll CU, Howes O, Siskind D, Honer WG, Lee J, Falkai P, Schneider-Axmann T, Hasan A | title = Clozapine Combination and Augmentation Strategies in Patients With Schizophrenia -Recommendations From an International Expert Survey Among the Treatment Response and Resistance in Psychosis (TRRIP) Working Group | journal = Schizophrenia Bulletin | volume = 46 | issue = 6 | pages = 1459–1470 | date = December 2020 | pmid = 32421188 | pmc = 7846085 | doi = 10.1093/schbul/sbaa060 }}</ref> The Team Daniel ([https://www.teamdanielrunningforrecovery.org/help-hope Dr Laitman's regimen]) includes a much slower than usual  titration (25&nbsp;mg increments per week rather than per day) combined with the prescription of a variety of other medications to manage side effects such as nausea, hypersalivation, acid reflux, tachycardia, nocturnal enuresis, metformin and lamotrigine.

The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5&nbsp;mg/d, increasing stepwise typically, to doses in the range of 250–350&nbsp;mg per day, at which point an assessment of response will be performed.<ref name="Taylor_2019" /> In the UK, the average clozapine dose is 450&nbsp;mg/d.<ref>{{cite journal | vauthors = Taylor D, Mace S, Mir S, Kerwin R | title = A prescription survey of the use of atypical antipsychotics for hospital inpatients in the United Kingdom | journal = International Journal of Psychiatry in Clinical Practice | volume = 4 | issue = 1 | pages = 41–46 | date = January 2000 | pmid = 24927311 | doi = 10.1080/13651500052048749 | s2cid = 25337120 }}</ref><ref>{{cite journal | vauthors = Sharma A | title = Maintenance doses for clozapine: past and present | journal = BJPsych Bulletin | volume = 42 | issue = 5 | pages = 217 | date = October 2018 | pmid = 30345070 | pmc = 6189983 | doi = 10.1192/bjb.2018.64 }}</ref> But response is highly variable and some patients respond at much lower doses, and vice versa. A genome wide association study from the MRC Centre for Neuropsychiatric Genetics and Genomics in Cardiff, UK has shown  significant interethnic variation in clozapine metabolism due to variation in the frequency of CYP alleles involved in clozapine metabolism such as UGT1A and CYP1A1/1A2. This found  faster average clozapine metabolism in people of sub-Saharan African ancestry than in those of European ancestry and that individuals with east Asian or southwest Asian ancestry were more likely to be slow clozapine metabolisers than those with European ancestry.<ref>{{cite journal | vauthors = Pardiñas AF, Kappel DB, Roberts M, Tipple F, Shitomi-Jones LM, King A, Jansen J, Helthuis M, Owen MJ, O'Donovan MC, Walters JT | title = Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data | journal = The Lancet. Psychiatry | volume = 10 | issue = 3 | pages = 209–219 | date = March 2023 | pmid = 36804072 | pmc = 10824469 | doi = 10.1016/s2215-0366(23)00002-0 }}</ref>

=== Clozapine response and treatment optimization ===
As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week.<ref>{{cite journal | vauthors = Suzuki T, Remington G, Arenovich T, Uchida H, Agid O, Graff-Guerrero A, Mamo DC | title = Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia | journal = The British Journal of Psychiatry | volume = 199 | issue = 4 | pages = 275–280 | date = October 2011 | pmid = 22187729 | doi = 10.1192/bjp.bp.110.083907 | s2cid = 2382648 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kapur S, Arenovich T, Agid O, Zipursky R, Lindborg S, Jones B | title = Evidence for onset of antipsychotic effects within the first 24 hours of treatment | journal = The American Journal of Psychiatry | volume = 162 | issue = 5 | pages = 939–946 | date = May 2005 | pmid = 15863796 | doi = 10.1176/appi.ajp.162.5.939 }}</ref> That said responses, especially those which are partial, can be delayed.<ref>{{cite book | vauthors = Remington G | chapter = Augmenting Clozapine Response in Treatment-Resistant Schizophreni a|date=2010 |title = Therapy-Resistant Schizophrenia |series= Advances in Biological Psychiatry|volume=26|pages=129–151|place=Basel |publisher=KARGER |doi= 10.1159/000319813| doi-broken-date = 11 November 2024|isbn=978-3-8055-9511-7 }}</ref> Quite what an adequate trial of clozapine is, is uncertain, but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L.<ref>{{cite journal | vauthors = Schulte P | title = What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia | journal = Clinical Pharmacokinetics | volume = 42 | issue = 7 | pages = 607–618 | date = 2003 | pmid = 12844323 | doi = 10.2165/00003088-200342070-00001 | s2cid = 25525638 }}</ref><ref>{{cite journal | vauthors = Conley RR, Carpenter WT, Tamminga CA | title = Time to clozapine response in a standardized trial | journal = The American Journal of Psychiatry | volume = 154 | issue = 9 | pages = 1243–1247 | date = September 1997 | pmid = 9286183 | doi = 10.1176/ajp.154.9.1243 | doi-access = free }}</ref> There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900&nbsp;mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary [[polypharmacy]] is a general principle in drug treatment. However, what constitutes "unnecessary" is important, because antipsychotics are associated with [[metabolic syndrome]] and a corresponding increased risk of [[type 2 diabetes]] and [[atherosclerotic cardiovascular disease]], especially with long-term treatment. Polypharmacy with metformin, along with [[statin]]s and [[ACE inhibitor]]s, have the potential to significantly attenuate this risk.<ref>Psychiatry Online. (2012). Metformin for treatment of antipsychotic-induced weight gain and metabolic disturbances: A meta-analysis. Retrieved from https://psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2012.12050591</ref><ref>NMCD Journal. (2021). The use of statins and ACE inhibitors to reduce cardiovascular risk in patients on antipsychotic therapy. Retrieved from https://www.nmcd-journal.com/article/S0939-4753%2821%2900556-1/pdf</ref> However, statins may increase blood glucose levels themselves, therefore necessitating polypharmacy with metformin whenever a statin is initiated. Together, this combination may have the potential to negate the negative metabolic and cardiovascular effects associated with antipsychotics, but further research is needed.<ref>Nomura, I., Kishi, T., Ikuta, T., & Iwata, N. (2018). Statin add-on therapy in the antipsychotic treatment of schizophrenia: A meta-analysis. Psychiatry research, 260, 41–47. https://doi.org/10.1016/j.psychres.2017.11.033</ref>

==== Optimizing blood sampling ====
The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available.<ref name="Clozapine rechallenge and initiatio" />

====Benign ethnic neutropenia====

Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds.  Ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection, is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry.<ref>{{cite journal | vauthors = Atallah-Yunes SA, Ready A, Newburger PE | title = Benign ethnic neutropenia | journal = Blood Reviews | volume = 37 | pages = 100586 | date = September 2019 | pmid = 31255364 | pmc = 6702066 | doi = 10.1016/j.blre.2019.06.003 }}</ref> A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations.<ref>{{cite journal | vauthors = Haddy TB, Rana SR, Castro O | title = Benign ethnic neutropenia: what is a normal absolute neutrophil count? | journal = The Journal of Laboratory and Clinical Medicine | volume = 133 | issue = 1 | pages = 15–22 | date = January 1999 | pmid = 10385477 | doi = 10.1053/lc.1999.v133.a94931 }}</ref> For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use, as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 10<sup>9</sup>/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima.<ref name="Silva 20451253211015070">{{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 | pmc = 8221694 | doi = 10.1177/20451253211015070 }}</ref><ref name="Nielsen_2016">{{cite journal | vauthors = Nielsen J, Young C, Ifteni P, Kishimoto T, Xiang YT, Schulte PF, Correll CU, Taylor D | title = Worldwide Differences in Regulations of Clozapine Use | journal = CNS Drugs | volume = 30 | issue = 2 | pages = 149–161 | date = February 2016 | pmid = 26884144 | doi = 10.1007/s40263-016-0311-1 | s2cid = 23395968 }}</ref><ref>{{cite journal | vauthors = Rajagopal S | title = Clozapine, agranulocytosis, and benign ethnic neutropenia | journal = Postgraduate Medical Journal | volume = 81 | issue = 959 | pages = 545–546 | date = September 2005 | pmid = 16143678 | pmc = 1743348 | doi = 10.1136/pgmj.2004.031161 }}</ref> But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The [[Duffy antigen system|Duffy]]–Null polymorphism, which protects against some types of malaria, is predictive of BEN.<ref>{{cite journal | vauthors = Reich D, Nalls MA, Kao WH, Akylbekova EL, Tandon A, Patterson N, Mullikin J, Hsueh WC, Cheng CY, Coresh J, Boerwinkle E, Li M, Waliszewska A, Neubauer J, Li R, Leak TS, Ekunwe L, Files JC, Hardy CL, Zmuda JM, Taylor HA, Ziv E, Harris TB, Wilson JG | title = Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene | journal = PLOS Genetics | volume = 5 | issue = 1 | pages = e1000360 | date = January 2009 | pmid = 19180233 | pmc = 2628742 | doi = 10.1371/journal.pgen.1000360 | doi-access = free }}</ref><ref name="tandfonline.com">{{Cite journal | vauthors = Silva E |date=28 August 2024 |title=Childhood onset violence and early onset schizophrenia. A molecular diagnosis of 15q13.2-13.3 duplication syndrome and the effects on insight and engagement |url=https://www.tandfonline.com/doi/full/10.1080/14789949.2024.2396348 |journal=The Journal of Forensic Psychiatry & Psychology |volume=35 |issue=6 |language=en |pages=984–995 |doi=10.1080/14789949.2024.2396348 |issn=1478-9949}}</ref> In the UK the Royal College of Psychiatrists recommends consideration of Duffy typing when using or considering clozapine for people with Black or Middle Eastern ancestry, in the UK this can be requested from the International Blood Group Reference laboratory based in Bristol.<ref name="tandfonline.com"/>