Correspondence
Myocarditis and Cardiomyopathy Associated with Clozapine Use in the United States
N Engl J Med 2001; 345:224-225July 19, 2001
- Article
To the Editor:
We summarize cases of myocarditis and cardiomyopathy reported to the Food and Drug Administration (FDA) in patients treated with the atypical antipsychotic medication clozapine. Because it carries risks of agranulocytosis and seizures, clozapine is indicated for patients with severe schizophrenia who have no response to or who cannot tolerate standard antipsychotic agents. Between the U.S. approval of clozapine in September 1989 and December 2, 1999, the FDA received reports of 28 cases of myocarditis, including 18 deaths, and 41 cases of cardiomyopathy, including 10 deaths, that were temporally associated with the use of clozapine and that met at least one of the criteria described in Table 1Table 1
Cardiomyopathy and Myocarditis Associated with the Use of Clozapine in the United States..1,2 Thirteen of the 18 deaths from myocarditis were confirmed at autopsy.As compared with patients who died of myocarditis, those who survived tended to have been treated for a shorter time (median, 2 weeks vs. 4 weeks) and to have taken a lower daily dose (median, 225 mg vs. 450 mg); the lower median dose may reflect a shorter duration of treatment, since the dose is titrated early in its administration. In contrast, among patients with cardiomyopathy, the median dose (450 mg and 400 mg) and the duration of therapy (8 months and 10 months) were similar in those who survived and those who died.
Data provided by the U.S. Clozaril National Registry indicated that through December 1999 a total of 189,405 persons had been exposed to clozapine. Assuming that all patients had taken clozapine for at least one month and including only the 5 cases with autopsy-confirmed myocarditis during the first month of therapy, we estimated that the incidence of fatal myocarditis in the first month of therapy was 321 per million person-years of observation. This greatly exceeds the background rate of 4 per million per year.3 Although the risk of fatal myocarditis is greatest in the first month of treatment with clozapine, it is not limited to this period, and patients may be at increased risk as long as they are taking the drug.
Although clozapine therapy continues to have a role in severe schizophrenia that cannot be managed effectively with other medications, physicians should be aware of the associations between the use of clozapine and these cardiac complications. Having a high index of clinical suspicion in the case of patients with cardiac symptoms may prevent life-threatening disease.
(The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the FDA or the U.S. government.)
3 ReferencesLois La Grenade, M.D., M.P.H.
David Graham, M.D., M.P.H.
Anne Trontell, M.D., M.P.H.
Food and Drug Administration, Rockville, MD 20857
lagrenadel@cder.fda. gov 1
Killian JG ,Kerr K ,Lawrence C ,Celermajer DS . Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-1845
CrossRef | Web of Science | Medline2
Clozapine and sudden death. Lancet 2000;355:841-843
Medline3
Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence, and mortality estimates for over 200 conditions. Vol. 2 of Global burden of disease and injury series. Cambridge, Mass.: Harvard University Press, 1996:1-33.
- Citing Articles (32)
Citing Articles
1
Carlo Rostagno, Sandro Domenichetti, Francesca Pastorelli, Gian Franco Gensini. (2011) Usefulness of NT-Pro-BNP and Echocardiography in the Diagnosis of Subclinical Clozapine-Related Cardiotoxicity. Journal of Clinical Psychopharmacology 31:6, 712-716
CrossRef2
Iria Grande, Alexandre Pons, Immaculada Baeza, Ángela Torras, Miguel Bernardo. (2011) QTc prolongation: is clozapine safe? Study of 82 cases before and after clozapine treatment. Human Psychopharmacology: Clinical and Experimentaln/a-n/a
CrossRef3
Veronica Scurti, Marilena Romero, Gianni Tognoni. (2011) A plea for a more epidemiological and patient-oriented pharmacovigilance. European Journal of Clinical Pharmacology
CrossRef4
Carlo Rostagno, Sandro Domenichetti, Francesca Pastorelli, Gian Franco Gensini. (2011) Clozapine associated cardiomyopathy: a cluster of 3 cases. Internal and Emergency Medicine 6:3, 281-283
CrossRef5
Kathlyn J. Ronaldson, Paul B. Fitzgerald, Andrew J. Taylor, Duncan J. Topliss, John J. McNeil. (2011) Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. Schizophrenia Research 128:1-3, 161-165
CrossRef6
Mohamed A. M. Khalaf, Tarek M. AbdelRahman, Mohamed F. Abbas. (2011) Values of Using QTc and N-Terminal Fragment of B-Type Natriuretic Peptide as Markers for Early Detection of Acute Antipsychotic Drugs-Induced Cardiotoxicity. Cardiovascular Toxicology 11:1, 10-17
CrossRef7
Giuseppina Novo, Pasquale Assennato, Stefano Augugliaro, Giovanni Fazio, Gianfranco Ciaramitaro, Giuseppe Coppola, Michele Farinella, Antonino Rotolo, Salvatore Novo. (2010) Midventricular dyskinesia during clozapine treatment?. Journal of Cardiovascular Medicine 11:8, 619-621
CrossRef8
Marina Grgas, Carl F. Washburn, Charles F. Caley. (2010) Clozapine-Induced Myocarditis. Journal of Clinical Psychopharmacology 30:1, 91-92
CrossRef9
Hans-Jürgen Möller, Michael Riedel. 2009. Side effect burden of antipsychotic medication. , 231-259.
CrossRef10
Rafael Stryjer, Igor Timinsky, Ilya Reznik, Abraham Weizman, Baruch Spivak. (2009) β-Adrenergic Antagonists for the Treatment of Clozapine-Induced Sinus Tachycardia. Clinical Neuropharmacology 32:5, 290-292
CrossRef11
Rodrigo D. Paz, Sonia Tardito, Marco Atzori, Kuei Y. Tseng. (2008) Glutamatergic dysfunction in schizophrenia: From basic neuroscience to clinical psychopharmacology. European Neuropsychopharmacology 18:11, 773-786
CrossRef12
Ju-Feng Wang, Jiang-Yong Min, Thomas G. Hampton, Ivo Amende, Xinhua Yan, Sohail Malek, Walter H. Abelmann, Alan I. Green, John Zeind, James P. Morgan. (2008) Clozapine-induced myocarditis: Role of catecholamines in a murine model. European Journal of Pharmacology 592:1-3, 123-127
CrossRef13
Carlo Rostagno, Gianni Di Norscia, Gian Framco Placidi, Gian Franco Gensini. (2008) Beta-blocker and angiotensin-converting enzyme inhibitor may limit certain cardiac adverse effects of clozapine. General Hospital Psychiatry 30:3, 280-283
CrossRef14
Paul Mackin. (2008) Cardiac side effects of psychiatric drugs. Human Psychopharmacology: Clinical and Experimental 23:S1, S3-S14
CrossRef15
Milou-Daniel Drici, Silvia Priori. (2007) Cardiovascular risks of atypical antipsychotic drug treatment. Pharmacoepidemiology and Drug Safety 16:8, 882-890
CrossRef16
Michael Berk, Joanna Fitzsimons, Timothy Lambert, Christos Pantelis, Jayashri Kulkarni, David Castle, Elizabeth W Ryan, Sean Jespersen, Pat McGorry, Gregor Berger, Bill Kuluris, Tom Callaly, Seetal Dodd. (2007) Monitoring the Safe Use of Clozapine. CNS Drugs 21:2, 117-127
CrossRef17
Sungwon Roh, Dong Hyun Ahn, Jung Hyun Nam, Byung Hwan Yang, Bang Hun Lee, Yang Suk Kim. (2006) Cardiomyopathy Associated With Clozapine.. Experimental and Clinical Psychopharmacology 14:1, 94-98
CrossRef18
J DOHERTY, P BELL, D KING. (2006) Implications for anaesthesia in a patient established on clozapine treatment. International Journal of Obstetric Anesthesia 15:1, 59-62
CrossRef19
Joanna Fitzsimons, Michael Berk, Timothy Lambert, Michel Bourin, Seetal Dodd. (2005) A review of clozapine safety. Expert Opinion on Drug Safety 4:4, 731-744
CrossRef20
Hans Stampfer, Peter Swanepoel. (2005) Severe tachycardia following low-dose clozapine treatment. Australasian Psychiatry 13:1, 80-82
CrossRef21
P. M. Wehmeier, P. Heiser, H. Remschmidt. (2005) Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine. Journal of Clinical Pharmacy and Therapeutics 30:1, 91-96
CrossRef22
David B. Merrill, G. William Dec, Donald C. Goff. (2005) Adverse Cardiac Effects Associated With Clozapine. Journal of Clinical Psychopharmacology 25:1, 32-41
CrossRef23
Jonathan Reinders, William Parsonage, Diana Lange, Julia M. Potter, Sally Plever. (2004) Clozapine-related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service. Australian and New Zealand Journal of Psychiatry 38:11-12, 915-922
CrossRef24
Vittorio Fineschi, Margherita Neri, Irene Riezzo, Emanuela Turillazzi. (2004) Sudden cardiac death due to hypersensitivity myocarditis during clozapine treatment. International Journal of Legal Medicine 118:5, 307-309
CrossRef25
K. S. Vaddadi, E. Soosai, G. Vaddadi. (2003) Low blood selenium concentrations in schizophrenic patients on clozapine. British Journal of Clinical Pharmacology 55:3, 307-309
CrossRef26
A GREEN, C CANUSO, M BRENNER, J WOJCIK. (2003) Detection and management of comorbidity in patients with schizophrenia. Psychiatric Clinics of North America 26:1, 115-139
CrossRef27
Harry J. Witchel, Jules C. Hancox, David J. Nutt. (2003) Psychotropic Drugs, Cardiac Arrhythmia, and Sudden Death. Journal of Clinical Psychopharmacology 23:1, 58-77
CrossRef28
O. Freudenreich. (2003) Clinical Experience With the Management of Schizophrenia in the General Hospital. Psychosomatics 44:1, 12-23
CrossRef29
Syed Rizwanuddin Ahmad. (2003) Adverse Drug Event Monitoring at the Food and Drug Administration. Your Report Can Make a Difference. Journal of General Internal Medicine 18:1, 57-60
CrossRef30
(2002) Current Awareness. Pharmacoepidemiology and Drug Safety 11:1, 79-94
CrossRef31
&NA;. (2001) Fatal cardiomyopathy and myocarditis with clozapine. Reactions Weekly &NA;:862, 4
CrossRef32
&NA;. (2001) Fatal cardiomyopathy and myocarditis with clozapine. Inpharma Weekly &NA;:1298, 19
CrossRef
