Editing Clozapine (section)

===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>