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Examination of mitochondria- and inflammasome-mediated mechanisms of clozapine-induced myocarditis using patient-derived iPSC cardiomyocytes

Molecular Psychiatry volume 30, pages 3491–3501 (2025)Cite this article

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Abstract

Clozapine is the only approved pharmacotherapy for treatment-resistant schizophrenia. However, widespread utilization of clozapine is constrained due to the potential for severe adverse effects, including myocarditis. Multiple mechanisms have been suggested to account for the cardiotoxic effects of clozapine, yet these investigations have not used cells derived from clozapine treated patients. In this study, cardiomyocytes that were derived from induced pluripotent stem cells generated from four patients with treatment-resistant schizophrenia with (n = 2) and without (n = 2) a history of clozapine-induced myocarditis were used to assess mitochondria- and NLRP3 inflammasome-mediated mechanisms of this severe adverse drug reaction. We found treatment of cardiomyocytes with a physiologically-relevant dose (2.8 µM) of clozapine for 24 h: (1) induced cardiac dysfunction, increased cytotoxicity, and apoptosis, (2) induced oxidative stress by elevating the level of reactive oxygen species and mitochondrial fragmentation, and (3) elevated levels of proinflammatory cytokines and activated the NLRP3 inflammasome. These effects were more pronounced in cardiomyocytes derived from individuals with a history of clozapine-induced myocarditis. Furthermore, pharmacological targeting of the mitochondria (elamipretide) and inflammasome (ustekinumab) attenuated these clozapine-induced cardiotoxic effects. Collectively, these results suggest a mitochondria- and NLRP3 inflammasome-mediated mechanism in the development of myocarditis associated with clozapine and support further evaluation of therapeutics that target mitochondria and NLRP3 signaling.

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Fig. 1: Contractile characteristics of iPSC-CMs.
Fig. 2: Cytotoxcitiy and apoptosis in iPSC-CMs before and after clozapine treatment.
Fig. 3: Mitochondrial morphology of iPSC-CMs before and after clozapine treatment as visualized by TOMM20 immunostaining.
Fig. 4: NLRP3 inflammasome and pro-inflamatory cytokine levels in iPSC-CMs before and after clozapine treatment.
Fig. 5: Characterization of iPSC-derived cardiomyocytes, cytotoxicity, apoptosis, mitochondrial structure and function, protein levels of NLRP3 and GSDMD, Caspase-1 activity, and pro-inflammatory cytokines release after clozapine and elamipretide or ustekinumab treatment for 24 h.
Fig. 6: Proposed mechanisms of clozapine-induced myocarditis in cardiomyocytes.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. All relevant data have been presented in this article. There was no data excluded from the analysis.

References

  1. Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry. 2007;18:39–60.

    Article  PubMed  Google Scholar 

  2. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001;158:518–26.

    Article  CAS  PubMed  Google Scholar 

  3. Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374:620–7.

    Article  PubMed  Google Scholar 

  4. de Leon J, Ruan C-J, Schoretsanitis G, De las Cuevas C. A rational use of clozapine based on adverse drug reactions, pharmacokinetics, and clinical pharmacopsychology. Psychother Psychosom. 2020;89:200–14.

    Article  PubMed  Google Scholar 

  5. Cooper LT. Myocarditis. N Engl J Med. 2009;360:1526–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Remington G, Lee J, Agid O, Takeuchi H, Foussias G, Hahn M, et al. Clozapine’s critical role in treatment resistant schizophrenia: ensuring both safety and use. Expert Opin Drug Saf. 2016;15:1193–203.

    Article  CAS  PubMed  Google Scholar 

  7. Bellissima BL, Tingle MD, Cicović A, Alawami M, Kenedi C. A systematic review of clozapine-induced myocarditis. Int J Cardiol. 2018;259:122–9.

    Article  PubMed  Google Scholar 

  8. Vaziri N, Marques D, Greenway SC, Bousman CA. The cellular mechanism of antipsychotic-induced myocarditis: a systematic review. Schizophr Res. 2023;261:206–15.

    Article  PubMed  Google Scholar 

  9. Bousman C, Greenway SC, Tarailo-Graovac M, Long Q, Sellmer R, Crockford D, et al. editors. The pharmacogenomics of clozapine-induced myocarditis (PROCLAIM) consortium. Neuropsychopharmacology. 2018: Nature publishing group macmillan building, 4, England.

  10. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry. 2011;45:458–65.

    Article  PubMed  Google Scholar 

  11. Churko JM, Burridge PW, Wu JC. Generation of human iPSCs from human peripheral blood mononuclear cells using non-integrative Sendai virus in chemically defined conditions. Methods Mol Biol. 2013;1036:81–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vaziri N, Marques D, Wang X, Machiraju P, Narang A, Vlahos K, et al. Generation of two human induced pluripotent stem cell lines from peripheral blood mononuclear cells of clozapine-tolerant and clozapine-induced myocarditis patients with treatment-resistant schizophrenia. Stem Cell Res. 2022;63:102877.

    Article  CAS  PubMed  Google Scholar 

  13. Machiraju P, Huang J, Iqbal F, Liu Y, Wang X, Bousman C, et al. Early inhibition of retinoic acid signaling rapidly generates cardiomyocytes expressing ventricular markers from human induced pluripotent stem cells. bioRxiv. 2019:856575.

  14. Zhang Q, Jiang J, Han P, Yuan Q, Zhang J, Zhang X, et al. Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res. 2011;21:579–87.

    Article  CAS  PubMed  Google Scholar 

  15. Titier K, Canal M, Déridet E, Abouelfath A, Gromb S, Molimard M, et al. Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice. Toxicol Appl Pharmacol. 2004;199:52–60.

    Article  CAS  PubMed  Google Scholar 

  16. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51:9–62.

    Article  CAS  PubMed  Google Scholar 

  17. Wu J, Hao S, Sun X-R, Zhang H, Li H, Zhao H, et al. Elamipretide (SS-31) ameliorates isoflurane-induced long-term impairments of mitochondrial morphogenesis and cognition in developing rats. Front Cell Neurosci. 2017;11:119.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chavez JD, Tang X, Campbell MD, Reyes G, Kramer PA, Stuppard R, et al. Mitochondrial protein interaction landscape of SS-31. Proc Natl Acad Sci. 2020;117:15363–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Szeto HH. First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171:2029–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Machiraju P, Wang X, Sabouny R, Huang J, Zhao T, Iqbal F, et al. SS-31 peptide reverses the mitochondrial fragmentation present in fibroblasts from patients with DCMA, a mitochondrial cardiomyopathy. Front Cardiovasc Med. 2019;6:167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rohani L, Machiraju P, Sabouny R, Meng G, Liu S, Zhao T, et al. Reversible mitochondrial fragmentation in iPSC-derived cardiomyocytes from children with DCMA, a mitochondrial cardiomyopathy. Can J Cardiol. 2020;36:554–63.

    PubMed  Google Scholar 

  22. Chetwood J, Gupta S, Subramaniam K, De Cruz P, Moore G, An Y, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis–national extended follow-up and a review of the literature. Expert Opin Drug Saf. 2024;23:449–56.

    Article  CAS  PubMed  Google Scholar 

  23. Gorski KS, Waller EL, Bjornton-Severson J, Hanten JA, Riter CL, Kieper WC, et al. Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists. Int Immunol. 2006;18:1115–26.

    Article  CAS  PubMed  Google Scholar 

  24. Sala L, Van Meer BJ, Tertoolen LG, Bakkers J, Bellin M, Davis RP, et al. MUSCLEMOTION: a versatile open software tool to quantify cardiomyocyte and cardiac muscle contraction in vitro and in vivo. Circ Res. 2018;122:e5–e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J Biol Chem. 1998;273:32608–13.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang F, Han L, Wang J, Shu M, Liu K, Zhang Y, et al. Clozapine induced developmental and cardiac toxicity on Zebrafish Embryos by elevating oxidative stress. Cardiovasc Toxicol. 2021;21:399–409.

    Article  PubMed  Google Scholar 

  27. Abdel-Wahab BA, Metwally ME. Clozapine-induced cardiotoxicity in rats: involvement of tumour necrosis factor alpha, NF-κβ and caspase-3. Toxicol Rep. 2014;1:1213–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Abdel-Wahab BA, Metwally ME. Clozapine-induced cardiotoxicity: role of oxidative stress, tumour necrosis factor alpha and NF-κβ. Cardiovasc Toxicol. 2015;15:355–65.

    Article  CAS  PubMed  Google Scholar 

  29. Hayes RD, Downs J, Chang C-K, Jackson RG, Shetty H, Broadbent M, et al. The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders. Schizophr Bull. 2015;41:644–55.

    Article  PubMed  Google Scholar 

  30. Yusufi B, Mukherjee S, Flanagan R, Paton C, Dunn G, Page E, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration. Int Clin Psychopharmacol. 2007;22:238–43.

    Article  PubMed  Google Scholar 

  31. Nilsson BM, Edström O, Lindström L, Wernegren P, Bodén R. Tachycardia in patients treated with clozapine versus antipsychotic long-acting injections. Int Clin Psychopharmacol. 2017;32:219–24.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J. 1994;35:745–50.

    Article  CAS  PubMed  Google Scholar 

  33. Scarabelli TM, Knight R, Stephanou A, Townsend P, Chen-Scarabelli C, Lawrence K, et al. Clinical implications of apoptosis in ischemic myocardium. Curr Probl Cardiol. 2006;31:181–264.

    Article  PubMed  Google Scholar 

  34. Liu P, Sole MJ. What is the relevance of apoptosis to the myocardium? Can J Cardiol. 1999;15:8B–10B.

    PubMed  Google Scholar 

  35. Shi Y. Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci. 2004;13:1979–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jarskog LF, Gilmore JH, Glantz LA, Gable KL, German TT, Tong RI, et al. Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics. Neuropsychopharmacology. 2007;32:95–102.

    Article  CAS  PubMed  Google Scholar 

  37. Arends M, Morris R, Wyllie A. Apoptosis. The role of the endonuclease. Am J Pathol. 1990;136:593.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yuan J, Lipinski M, Degterev A. Diversity in the mechanisms of neuronal cell death. Neuron. 2003;40:401–13.

    Article  CAS  PubMed  Google Scholar 

  39. Scheffer DdL, Garcia AA, Lee L, Mochly-Rosen D, Ferreira JCB. Mitochondrial fusion, fission, and mitophagy in cardiac diseases: challenges and therapeutic opportunities. Antioxid Redox Signal. 2022;36:844–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ben‐Shachar D. Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. J Neurochem. 2002;83:1241–51.

    Article  PubMed  Google Scholar 

  41. Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull. 2001;55:597–610.

    Article  CAS  PubMed  Google Scholar 

  42. Kohen R, Nyska A. Invited review: oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol. 2002;30:620–50.

    Article  CAS  PubMed  Google Scholar 

  43. Martín-Fernández B, Gredilla R. Mitochondria and oxidative stress in heart aging. Age. 2016;38:225–38.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hafez AA, Jamali Z, Khezri S, Salimi A. Thymoquinone reduces mitochondrial damage and death of cardiomyocytes induced by clozapine. Naunyn Schmiedebergs Arch Pharmacol. 2021;394:1675–84.

    Article  CAS  PubMed  Google Scholar 

  45. Mishra P, Samanta L. Oxidative stress and heart failure in altered thyroid states. Sci World J. 2012;2012:741861.

    Article  Google Scholar 

  46. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.

    Article  CAS  PubMed  Google Scholar 

  47. Kingston E, Tingle M, Bellissima BL, Helsby N, Burns K. CYP-catalysed cycling of clozapine and clozapine-N-oxide promotes the generation of reactive oxygen species in vitro. Xenobiotica. 2024;54:26–37.

    Article  CAS  PubMed  Google Scholar 

  48. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, et al. Mitochondrial‐targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013;12:763–71.

    Article  CAS  PubMed  Google Scholar 

  49. Liu Y, Yang W, Sun X, Xie L, Yang Y, Sang M, et al. SS31 ameliorates sepsis-induced heart injury by inhibiting oxidative stress and inflammation. Inflammation. 2019;42:2170–80.

    Article  CAS  PubMed  Google Scholar 

  50. Jeong S-Y, Seol D-W. The role of mitochondria in apoptosis. BMB Rep. 2008;41:11–22.

    Article  CAS  PubMed  Google Scholar 

  51. Li L, Gao P, Tang X, Liu Z, Cao M, Luo R, et al. CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity. Signal Transduct Target Ther. 2022;7:1–15.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009;10:241–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rauf A, Shah M, Yellon DM, Davidson SM. Role of caspase 1 in ischemia/reperfusion injury of the myocardium. J Cardiovasc Pharmacol. 2019;74:194–200.

    Article  CAS  PubMed  Google Scholar 

  54. Wang J-F, Min J-Y, Hampton TG, Amende I, Yan X, Malek S, et al. Clozapine-induced myocarditis: role of catecholamines in a murine model. Eur J Pharmacol. 2008;592:123–7.

    Article  CAS  PubMed  Google Scholar 

  55. Hu X, Ma R, Lu J, Zhang K, Xu W, Jiang H, et al. IL-23 promotes myocardial I/R injury by increasing the inflammatory responses and oxidative stress reactions. Cell Physiol Biochem. 2016;38:2163–72.

    Article  CAS  PubMed  Google Scholar 

  56. Afanasyeva M, Wang Y, Kaya Z, Stafford EA, Dohmen KM, Sadighi Akha AA, et al. Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-γ–independent pathway. Circulation. 2001;104:3145–51.

    Article  CAS  PubMed  Google Scholar 

  57. Jimenez-Tellez N, Greenway SC. Cellular models for human cardiomyopathy: what is the best option? World J Cardiol. 2019;11:221.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Musunuru K, Sheikh F, Gupta RM, Houser SR, Maher KO, Milan DJ, et al. Induced pluripotent stem cells for cardiovascular disease modeling and precision medicine: a scientific statement from the american heart association. Circ Genom Precis Med. 2018;11:e000043.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by William H. Davies Medical Research Scholarships, Calgary Chapter of the Schizophrenia Society of Alberta, Dr. S.K. Littman Graduate Award, Libin Cardiovascular Institute BRAIN CREATE Doctoral Scholarship, Maria Fotaki International Student Graduate Scholarship, and Alberta Children Hospital (ACHRI) graduate scholarship. The human iPSCs were obtained from Joseph C. Wu, MD, PhD, Stanford Cardiovascular Institute. We acknowledge the Hotchkiss Brain Institute Advanced Microscopy Platform and the Cumming School of Medicine for support and use of slide scanner microscope and Charbonneau Microscopy Facility for support and use of confocal microscope. C Pantelis was supported by a National Health and Medical Research Council (NHMRC) L3 Investigator Grant (1196508) and NHMRC Program Grant (ID: 1150083).

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Authors and Affiliations

  1. Department of Medical Genetics, University of Calgary, Calgary, AB, Canada

    Nazanin Vaziri, Timothy E. Shutt, Wasi Karim & Chad A. Bousman

  2. Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Timothy E. Shutt & Steven C. Greenway

  3. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Timothy E. Shutt, Thomas J. Raedler & Chad A. Bousman

  4. Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Timothy E. Shutt & Chad A. Bousman

  5. Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Timothy E. Shutt

  6. Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia

    Christos Pantelis

  7. Western Centre for Health Research & Education, University of Melbourne & Western Health, Sunshine Hospital, St Albans, VIC, Australia

    Christos Pantelis

  8. Monash Institute of Pharmaceutical Sciences (MIPS), Monash University, Parkville, VIC, Australia

    Christos Pantelis

  9. Adult Mental Health Rehabilitation Unit, Mental Health and Wellbeing Services, Western Health, Sunshine Hospital, St Albans, VIC, Australia

    Naveen Thomas & Mahesh Jayaram

  10. Department of Psychiatry, The University of Melbourne and Western Health, Western Centre for Health & Education, St Albans, VIC, Australia

    Mahesh Jayaram

  11. Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  12. Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  13. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway & Chad A. Bousman

  14. Department of Psychiatry, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

  15. Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

  16. Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

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Contributions

NV, CAB: Writing - Original Draft; CAB, SCG, TES: Conceptualization; NV: Methodology and Formal Analysis; TES, WK, TJR, CP, NT, MJ, SCG: Review & Editing.

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Correspondence to Chad A. Bousman.

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CAB is founder of Sequence2Script Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

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Examination of mitochondria- and inflammasome-mediated mechanisms of clozapine-induced myocarditis using patient-derived iPSC cardiomyocytes

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Vaziri, N., Shutt, T.E., Karim, W. et al. Examination of mitochondria- and inflammasome-mediated mechanisms of clozapine-induced myocarditis using patient-derived iPSC cardiomyocytes. Mol Psychiatry 30, 3491–3501 (2025). https://doi.org/10.1038/s41380-025-02935-z

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