Editing Clozapine (section)

=== 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>