Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study
Abstract
OBJECTIVE: Using national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation. METHOD: Through nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted. RESULTS: Three thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%. CONCLUSION: Cardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
People with mental illness now consume around half of all cigarettes sold.
“Resultantly, people with mental illness now consume around half of all cigarettes sold.201,259”
From The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness (2019) · cites this paper as [259]
Cites
The Danish Civil Registration System
Pedersen, C. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494810387965 · Cited by 4,713 · see citing works
The Danish National Patient Register
Lynge, E., Sandegaard, J. L., & Rebolj, M. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494811401482 · Cited by 3,968 · see citing works
The Danish National Prescription Registry
Wallach‐Kildemoes, H., Sørensen, H. T., & Hallas, J. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494810394717 · Cited by 2,470 · see citing works
The Danish Register of Causes of Death
Helweg‐Larsen, K. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494811399958 · Cited by 1,735 · see citing works
The Danish Psychiatric Central Research Register
Mors, O., Perto, G. P., & Mortensen, P. B. (2011) · Scandinavian Journal of Public Health · doi:10.1177/1403494810395825 · Cited by 1,589 · see citing works
Tiihonen, J., Lönnqvist, J., Wahlbeck, K., Klaukka, T., Niskanen, L., Tanskanen, A., & Haukka, J. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60742-x · Cited by 1,354 · see citing works
Sagar, S., Liu, P. P., & Cooper, L. T. (2012) · The Lancet · doi:10.1016/s0140-6736(11)60648-x · Cited by 743 · see citing works
Siskind, D. J., McCartney, L., Goldschlager, R., & Kisely, S. R. (2016) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.115.177261 · Cited by 605 · see citing works
Self-citationMyocarditis and cardiomyopathy associated with clozapine
Kilian, J. G., Kerr, K. M., Lawrence, C., & Celermajer, D. S. (1999) · The Lancet · doi:10.1016/s0140-6736(99)10385-4 · Cited by 541 · see citing works
Clozapine‐induced myocarditis, a widely overlooked adverse reaction
Ronaldson, K. J., Fitzgerald, P. B., & McNeil, J. J. (2015) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12416 · Cited by 315 · see citing works
Termination of Clozapine Treatment Due to Medical Reasons
Nielsen, J., Correll, C. U., Manu, P., & Kane, J. M. (2013) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.12r08064 · Cited by 232 · see citing works
Self-citationRonaldson, K. J., Fitzgerald, P. B., Taylor, A. J., Topliss, D. J., & McNeil, J. J. (2011) · Australian & New Zealand Journal of Psychiatry · doi:10.3109/00048674.2011.572852 · Cited by 231 · see citing works
Bresee, L. C., Majumdar, S., Patten, S., & Johnson, J. A. (2010) · Schizophrenia Research · doi:10.1016/j.schres.2009.12.016 · Cited by 187 · see citing works
Worldwide Differences in Regulations of Clozapine Use
Nielsen, J., Young, C., Ifteni, P. I., Kishimoto, T., Xiang, Y., Schulte, P. F. J., Correll, C. U., & Taylor, D. M. (2016) · CNS Drugs · doi:10.1007/s40263-016-0311-1 · Cited by 182 · see citing works
Self-citationMieno, M., Tanaka, N., Arai, T., et al. (2015) · Journal of Epidemiology · doi:10.2188/jea.je20150010 · Cited by 176 · see citing works
Myocarditis and Cardiomyopathy Associated with Clozapine Use in the United States
Grenade, L. L., Graham, D. P., & Trontell, A. E. (2001) · New England Journal of Medicine · doi:10.1056/nejm200107193450317 · Cited by 163 · see citing works
Second-Generation Antipsychotic Medications and Risk of Pneumonia in Schizophrenia
Kuo, C., Yang, S.-Y., Liao, Y., et al. (2012) · Schizophrenia Bulletin · doi:10.1093/schbul/sbr202 · Cited by 162 · see citing works
Clozapine for treatment-resistant bipolar disorder: a systematic review
Li, X., Tang, Y., Wang, C., & de León, J. (2014) · Bipolar Disorders · doi:10.1111/bdi.12272 · Cited by 147 · see citing works
The impact of clozapine on hospital use: a systematic review and meta-analysis
Land, R., Siskind, D., McArdle, P., Kisely, S., Winckel, K., & Hollingworth, S. A. (2017) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12700 · Cited by 141 · see citing works
Self-citationMyocarditis Related to Clozapine Treatment
Hägg, S., Spigset, O., BAHons, A. B., & Söderström, T. G. (2001) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200108000-00005 · Cited by 140 · see citing works
Systematic Review of Clozapine Cardiotoxicity
Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016) · Current Psychiatry Reports · doi:10.1007/s11920-016-0704-3 · Cited by 132 · see citing works
Karjalainen, J., & Heikkilä, J. (1999) · European Heart Journal · doi:10.1053/euhj.1998.1444 · Cited by 114 · see citing works
A systematic review of clozapine induced cardiomyopathy
Alawami, M., Wasywich, C. A., Cicović, A., & Kenedi, C. A. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.07.103 · Cited by 105 · see citing works
Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine
Wehmeier, P. M., Heiser, P., & Remschmidt, H. (2005) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/j.1365-2710.2004.00616_1.x · Cited by 71 · see citing works
Twenty year autopsy statistics of myocarditis incidence in Japan.
Wakafuji, S., & Okada, R. (1986) · Japanese Circulation Journal-english Edition · doi:10.1253/jcj.50.1288 · Cited by 61 · see citing works
Cardiovascular safety of antipsychotics: a clinical overview
Polcwiartek, C., Kragholm, K. H., Schjerning, O., Graff, C., & Nielsen, J. (2016) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2016.1161021 · Cited by 59 · see citing works
Self-citationEarly Recognition of Clozapine-Induced Myocarditis
Annamraju, S., Sheitman, B., Saik, S., et al. (2007) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e31814e5e68 · Cited by 50 · see citing works
Nonchemotherapy Drug-Induced Neutropenia and Agranulocytosis
Pick, A. M., & Nystrom, K. K. (2014) · Journal of Pharmacy Practice · doi:10.1177/0897190014546115 · Cited by 48 · see citing works
Clozapine Safety, 40 Years Later
Raja, M., & Raja, S. (2014) · Current Drug Safety · doi:10.2174/1574886309666140428115040 · Cited by 47 · see citing works
Echocardiographic monitoring for clozapine cardiac toxicity: lessons from real-world experience
Murch, S., Tran, N., Liew, D., et al. (2013) · Australasian Psychiatry · doi:10.1177/1039856213475684 · Cited by 44 · see citing works
Increased use of antibiotics in patients treated with clozapine
Nielsen, J., Foldager, L., & Meyer, J. M. (2009) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2009.03.002 · Cited by 42 · see citing works
Self-citationMyocarditis Associated with Clozapine Treatment
Degner, D., Bleich, S., Grohmann, R., et al. (2000) · Australian & New Zealand Journal of Psychiatry · doi:10.1080/j.1440-1614.2000.0822n.x · Cited by 39 · see citing works
Titrating clozapine amidst recommendations proposing high myocarditis risk and rapid titrations
de León, J., Tang, Y., Baptista, T., et al. (2015) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12421 · Cited by 39 · see citing works
Kelly, D. L., Wehring, H. J., Linthicum, J., Feldman, S. M., McMahon, R. P., Love, R. C., Wagner, T., Shim, J. C., & Fowler, D. R. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2008.10.020 · Cited by 28 · see citing works
Clozapine Induced Myopericarditis
Razminia, M., Salem, Y., Sivasubramaniam, D., et al. (2006) · American Journal of Therapeutics · doi:10.1097/01.mjt.0000212704.79248.3d · Cited by 26 · see citing works
Clozapine-induced myocarditis: Separating the wheat from the chaff
Winckel, K., Siskind, D. J., Hollingworth, S., et al. (2014) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867414554269 · Cited by 23 · see citing works
Self-citationMyocarditis associated with clozapine treatment
Degner, D., Bleich, S., Grohmann, R., et al. (2000) · Australian & New Zealand Journal of Psychiatry · doi:10.1046/j.1440-1614.2000.0822n.x · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Causes of premature mortality in schizophrenia: a review of literature published in 2018
Laursen, T. M. (2019) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000530 · Cited by 76 · see citing works
Treatment strategies for clozapine-induced sialorrhea: a systematic review and meta-analysis
Chen, S.-Y., Ravindran, G., Zhang, Q., Kisely, S., & Siskind, D. (2019) · CNS Drugs · doi:10.1007/s40263-019-00612-8 · Cited by 66 · see citing works
Self-citation
- Authors
- Rohde, C., Polcwiartek, C., Kragholm, K., Ebdrup, B. H., Siskind, D., & Nielsen, J.
- Affiliations
- Glostrup Hospital (DK)
- Aalborg University Hospital (DK)
- The University of Queensland (AU)
- Corresponding author
- Rohde, C.
- Venue
- Acta Psychiatrica Scandinavica
- Publisher
- Wiley
- Published
- 2017-10-24
- Volume
- 137
- Issue
- 1
- Pages
- 47-53
- ISSN
- 0001-690X (ISSN-L)
- 1600-0447
- OpenAlex
- W2765340093
- Cited by
- 71
- References
- 37
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 11 · 2023: 14 · 2022: 6 · 2021: 5 · 2020: 10 · 2019: 13 · 2018: 5
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Psychiatrica Scandinavica (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Funders
- Lundbeckfonden (R155-2013-16337)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Health and Mental Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Keywords
- clozapine, adverse cardiac events, myocarditis, pericarditis, cardiomyopathy, antipsychotic drugs, outpatients, mortality, pneumonia, stroke, drug safety
- MeSH terms
- Adult, Aged, Ambulatory Care, Bipolar Disorder, Clozapine, Denmark, Female, Humans, Male, Middle Aged, Cardiomyopathies, Myocarditis, Pericarditis, Psychotic Disorders, Registries, Schizophrenia, Antipsychotic Agents
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
