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Isolated nausea and vomiting as the cardinal presenting symptoms of clozapine-induced myocarditis: a case report



Clozapine is an atypical antipsychotic proven to be superior in the treatment of treatment-resistant schizophrenia. Myocarditis is a rare, but well-known complication of treatment with clozapine. Only few cases have been reported in which nausea and vomiting were prominent symptoms. This is the first described report in which nausea and vomiting were the only presenting symptoms of clozapine-induced myocarditis.

Case presentation

We report a case of a 58-year-old woman, suffering from schizoaffective disorder, who is being treated with clozapine. Two weeks after initiation of clozapine, she developed nausea and vomiting, in absence of any other clinical symptoms. Laboratory examination and magnetic resonance imaging confirmed the diagnosis of clozapine-induced myocarditis. Clozapine was discontinued and the patient recovered fully.


This case emphasizes the importance of recognizing myocarditis as a cause of isolated nausea and vomiting in patients treated with clozapine. Early recognition improves clinical outcome and reduces mortality.

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Clozapine is the most effective treatment in patients suffering from psychotic disorders. Furthermore, it is the only antipsychotic agent that reduces death from suicide [1]. However, clozapine is the most notorious antipsychotic agent associated with the development of myocarditis. Clozapine-induced myocarditis is a rare but life-threatening condition; mortality rates range from 10 to 30% [2,3,4,5].

Myocarditis is defined as an inflammation of the heart muscle (myocardium) and has various causes [6]. The most common cause of myocarditis is viral infection, particularly parvovirus B19 and herpes simplex virus [7]. Other types of infections, auto-immune diseases, and hypersensitivity or toxic reactions to drugs can cause this condition as well [6]. Due to underdiagnoses and a lack of shared standardized diagnostic approach worldwide, the true incidence of myocarditis remains unclear [8]. In patients using clozapine the reported incidence worldwide varies from < 0.1 to 3.2% [4, 5, 9]. In Australia incidence rates up to 8.5% are reported, possibly due to genetic factors, geographical differences and/or greater awareness and monitoring [10,11,12]. Bellissima et al. (2018) found in their systematic review that in 87% of cases, symptoms of myocarditis displayed in the first 30 days of treatment [13]. Almost half of these patients developed symptoms in the first 12 days of treatment. However, some cases have been described in which patients developed clozapine-induced myocarditis 2 years after starting this therapy [3]. The risk of developing clozapine-induced myocarditis does not appear to be dose-dependent [13].

The pathophysiological mechanism of clozapine-induced myocarditis has not been elucidated. In 1999 Kilian et al. suggested that clozapine-induced myocarditis results from an IgE-mediated hypersensitivity reaction, since the development of eosinophil infiltrates and damaged myocytes corresponds to the time path of a type 1 allergic reaction and duration of the clozapine treatment [4]. Such eosinophilic drug reactions in the myocardium have also been described by methyldopa, hydrochlorothiazide, azithromycin, furosemide, benzodiazepines and tricyclic antidepressants [14,15,16]. Histologically, a pattern of interstitial infiltration with prominent eosinophilitis can be found [17]. Wang et al. (2008) studied clozapine-induced myocarditis in mice and found increased levels of pro-inflammatory cytokines, as was hypothesized before by previous research [18,19,20]. Furthermore, a significant dose-related increase in myocardial inflammation correlated with plasma catecholamine levels was found, as well as release of TNF-alpha. These findings might provide future treatment options, such as beta-adrenergic blocking agents.

It is known that the clinical presentation of myocarditis can vary widely. Most reported symptoms are shortness of breath (42%), chest pain (37%), flu-like symptoms (18%), cough (12%), and gastrointestinal discomfort (11%) [13]. Here, we report a case in which nausea and vomiting were the only signs leading to the diagnosis of clozapine-induced myocarditis. A systematic literature search provided no previous published reports where these symptoms were the only cardinal presenting signs. For this reason, this is the first case report describing nausea and vomiting as the only presenting symptoms of clozapine-induced myocarditis.

Case presentation

A 58-year-old woman with a history of schizoaffective disorder, was admitted to our hospital for treatment of a psychotic episode with depressive symptoms, characterized by anxiety, nihilistic and paranoid delusions, depressive mood, bradyphrenia, and inability to complete activities of daily living. She did not experience hallucinations or suicidal thoughts. The patient’s medical history revealed no relevant diseases other than renal dysfunction after lithium therapy. Besides a tachycardia of 132 bpm (most likely due to anxiety), no other somatic abnormalities were found in physical examination on admission. The patient was using lamotrigine (200 mg/day), olanzapine (20 mg/day), and quetiapine (300 mg/day). Notable past medication included lithium, which was stopped 3 years earlier because of renal insufficiency. Since the current pharmacological treatment was insufficiently effective, olanzapine was gradually switched to clozapine. Lamotrigine and quetiapine were continued for its antidepressive effect. Clozapine was initiated on day 1 in a dosage of 12.5 mg twice a day and titrated according to prescribing recommendations. On day 15 she reached a dosage of 300 mg/day.

On day 18 she complained about nausea and vomited once. The pre-existing tachycardia was still present, with a heart rate of 111 bpm. Further physical examination was without abnormalities. She did not suffer from diarrhea, abdominal cramps or pains, loss of appetite, or fever. Differential diagnosis at this point included gastrointestinal infection, constipation, drug-induced nausea, myocardial infarction, and (clozapine-induced) myocarditis. Although gastrointestinal infection is the most likely cause of nausea and vomiting and suspicion for myocardial infarction and (clozapine-induced) myocarditis at this point was low, further diagnostic investigation was initiated to rule out these potentially life-threatening conditions. Non drug-related causes of myocarditis, such as viral infections, were less likely because of the lack of symptoms associated with viral disease and the arise of symptoms shortly after the initiation of clozapine. Besides clozapine, few cases have been described in which lamotrigine or quetiapine was the cause of drug-induced myocarditis [21,22,23,24]. However, our patient was using lamotrigine and quetiapine long before the symptoms occurred (> 1 year), making it far less likely to be the current cause of the myocarditis.

Laboratory results showed leukocytosis, eosinophilia, elevated troponin I, creatine kinase, and monocytes (Table 1). Electrocardiogram (ECG) showed a sinus rhythm of 103 bpm, normal heart axis, slight PTa depression inferior in V5-V6, and no signs of ischemia.

Table 1 Laboratory results

An ultrasound of the heart showed a non-dilated left ventricle with normal systolic function, but abnormal relaxation. The right ventricle had a normal dimension and function. There was a suspicion of minimal compression of the right ventricular outflow tract and little pericardial effusion of the right ventricle was seen.

Considering symptomatology, lab results (elevated heart enzymes and eosinophilia), and radiology findings (pericardial effusion), there was a high clinical suspicion of clozapine-induced myocarditis and clozapine was discontinued abruptly. Cardiac magnetic resonance imaging (MRI) confirmed the diagnosis. It showed edema in the myocardium, which is a sign of (early) myocarditis. There was no delayed enhancement or signs of pericarditis. Little pericardial effusion and a normal systolic function of both ventricles was seen.

After discontinuation of clozapine, the nausea improved. Troponin levels returned to normal and the heart ultrasound showed no abnormalities, except for minimal pericardial effusion of the right ventricle. No further cardiological follow-up was required. The patient was switched to amisulpride, but this did not improve her symptoms. Ultimately, symptoms diminished after electroconvulsive therapy.

Discussion and conclusions

Our patient experienced nausea and vomiting in absence of chest pain or shortness of breath. A systematic search was performed in Pubmed (last updated on 12 June 2020) using the following terms: clozapine, leponex, clozaril, clozapine-induced myocarditis, myocarditis, nausea, and vomiting. The search yielded one result; a case report of a patient who suffered from nausea, and in addition, fever, dyspnea, fatigue, sinus tachycardia, elevated troponin, and C-reactive protein (CRP) levels, and reduced ejection fraction, leading to the diagnosis of clozapine-induced myocarditis [25]. When studying (systematic) reviews, a few cases were found in which nausea and vomiting were prominent symptoms [26,27,28]. However, of these cases, only two presented without any cardiopulmonary symptoms. These cases have not been yielded by our systematic search, because in one, the case is only mentioned as part of the review and in the other, the case is not described in detail but is part of a summary of other cases of clozapine-induced myocarditis. In the case report of Caetano and Ghandi (2008), ‘feeling feverish’ was reported as the only extra presenting symptom [26]. Hägg et al. (2001) described a patient suffering from nausea and vomiting in addition to influenza-like disease, fever, exanthema, tachycardia, confusion, and stroke [28]. Another patient from the same study experienced nausea and vomiting as well, but no other symptoms were described. An unexpected sudden death is reported in this patient. Autopsy confirmed the diagnosis of myocarditis [28]. However, the case is not described in detail. This makes our case report unique, since it is the only case of a patient with nausea and vomiting as the only presenting symptoms of clozapine-induced myocarditis described in detail. Several cases have been described in which patients remained asymptomatic and in some cases only post-mortem analysis led to the diagnosis of myocarditis [5, 13, 29].

When clozapine-induced myocarditis is suspected, further examination is essential for early detection and intervention. In more than half of described cases, one or more of the following clinical findings were reported: fever, tachycardia, elevated CRP levels, eosinophilia, elevated cardiac markers, and elevated troponin levels [13]. Less commonly reported are hypotension, tachypnea, lung crepitation, S3 and/or S4 heart sound, and ECG changes (most reported are ST-segment elevation and T-wave inversions). As these findings are often nonspecific, additional research by echocardiogram and especially cardiac MRI is recommended. Most reported findings include ventricular dilatation and/or dysfunction, pericardial effusion, edema, and late gadolinium enhancement of the myocardium [13, 30].

After diagnosis of clozapine-induced myocarditis the first step is to discontinue the drug immediately and to consult a cardiologist [31]. Treatment with diuretics, angiotensin converting enzyme inhibitors, beta-blockers and steroids might be needed [13]. In general, future rechallenge of clozapine is not recommended due to the high risk of recurrence of cardiac problems [32, 33]. However, due to the lack of an equally effective alternative antipsychotic, sometimes rechallenge is embarked, after carefully weighing the benefits and risks. Shivakumar et al. (2019) proposed a protocol for clozapine rechallenge in which they suggest a strategy of slow titration combined with interruption of titration once any indices increase (monocytes, neutrophils, eosinophils, or CRP) [32].

Further research to identify the risk factors associated with clozapine-induced myocarditis may enable personalized medicine to better estimate which patients will experience serious side effects, and may reduce the delay in starting this most effective drug therapy [34]. Ronaldson et al. (2012) identified clinical and phenotypic risk factors for clozapine-induced myocarditis and found the risk to be increased in the case of rapid dose titration, (odds ratio (OR) 1.26, 95% confidence interval (CI) 1.02–1.55, p = 0.03), concomitant use of sodium valproate (OR 2.59, CI 1.51–4.42, p = 0.001), and ascending age (OR 1.31, CI 1.07–1.60, p = 0.009) [35]. These risk factors accounted for less than 50% of the risk of clozapine-induced myocarditis, and it was hypothesized that genetic factors might be responsible for another substantial portion of the risk. The same research group performed a genome-wide association study and human leucocyte antigen (HLA) analyses and identified four single nucleotide proteins to be associated with increased risk of myocarditis and two HLA alleles [36]. Polygenic risk score based on variation at 96 different genetic sites explained 66% of liability (p = 9.7 × 10^-5) [33]. The combination of both clinical and genetic factors provided the highest increase in proportion of variability accounted for (r2 0.73, p = 9.8 × 10^-9) [34]. Further research with larger sample sizes is needed for validation.

Summarizing, when treating patients with clozapine, it is crucial to be aware of the risks of this drug and to know how to manage them. Clinical presentation of clozapine-induced myocarditis is often nonspecific and nausea and vomiting can be the only symptoms present (as it was in our patient). Early recognition and intervention can prevent further myocardial damage and safe lives. However, the risk of myocarditis should not create a barrier to start with clozapine in patients who can benefit from this highly effective drug treatment. In the future, identification of phenotypic and genotypic risk factors may enable personalized medicine to reduce the risk of developing serious adverse events.

In conclusion, we recommend to seriously consider clozapine-induced myocarditis as a cause of nausea and vomiting in every patient in the first month after initiation of clozapine, because of the relatively high occurrence of myocarditis in the first 30 days of treatment. This recommendation applies regardless of the patient’s age, gender, or history. Further diagnostic work-up with laboratory testing and electrocardiography should always be performed.

Availability of data and materials

Not applicable.





Magnetic Resonance Imaging


C-reactive Protein


Odds Ratio


Confidence Interval


Human Leucocyte Antigen


  1. 1.

    Meltzer HY. Suicide and schizophrenia: clozapine and the InterSePT study. International Clozaril/Leponex suicide prevention trial. J Clin Psychiatry. 1999;60(Suppl 12):47–50.

    CAS  PubMed  Google Scholar 

  2. 2.

    Devarajan S, Kutcher SP, Dursun SM. Clozapine and sudden death. Lancet. 2000;355(9206):841.

    CAS  Article  Google Scholar 

  3. 3.

    Haas SJ, Hill R, Krum H, Liew D, Tonkin A, Demos L, et al. Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993–2003. Drug Saf. 2007;30(1):47–57.

    CAS  Article  Google Scholar 

  4. 4.

    Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841–5.

    CAS  Article  Google Scholar 

  5. 5.

    Curto M, Girardi N, Lionetto L, Ciavarella GM, Ferracuti S, Baldessarini RJ. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68.

    Article  Google Scholar 

  6. 6.

    Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, et al. Update on myocarditis. J Am Coll Cardiol. 2012;59(9):779–92.

    Article  Google Scholar 

  7. 7.

    Buggey J, ElAmm CA. Myocarditis and cardiomyopathy. Curr Opin Cardiol. 2018;33(3):341–6.

    Article  Google Scholar 

  8. 8.

    Patriki D, Gresser E, Manka R, Emmert MY, Lüscher TF, Heidecker B. approximation of the incidence of myocarditis by systematic screening with cardiac magnetic resonance imaging. JACC Heart Fail. 2018;6(7):573–9.

    Article  Google Scholar 

  9. 9.

    Higgins JM, San C, Lagnado G, Chua D, Mihic T. Incidence and management of clozapine-induced myocarditis in a large tertiary hospital. Can J Psychiatry. 2019;64(8):561–7.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Dawson JL, Clark SR, Sluggett JK, Procter NH, Bell JS. Is the higher incidence of clozapine induced myocarditis in Australia due to awareness and monitoring? Letter to the editor. Schizophr Res. 2018;201:426–7.

    Article  Google Scholar 

  11. 11.

    Datta T, Solomon AJ. Clozapine-induced myocarditis. Oxf Med Case Reports. 2018;2018(1):omx080.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Riggs AR, Cooper DM. Clozapine-induced myocarditis. US Pharm. 2018;43(11):HS2–7.

    Google Scholar 

  13. 13.

    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  Google Scholar 

  14. 14.

    Taliercio CP, Olney BA, Lie JT. Myocarditis related to drug hypersensitivity. Mayo Clin Proc. 1985;60(7):463–8.

    CAS  Article  Google Scholar 

  15. 15.

    Pursnani A, Yee H, Slater W, Sarswat N. Hypersensitivity myocarditis associated with azithromycin exposure. Ann Intern Med. 2009;150(3):225–6.

    Article  Google Scholar 

  16. 16.

    Ben m’rad M, Leclerc-Mercier S, Blanche P, Franck N, Rozenberg F, Fulla Y, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore). 2009;88(3):131–40.

    Article  Google Scholar 

  17. 17.

    Fenoglio JJ Jr, McAllister HA Jr, Mullick FG. Drug related myocarditis. I. Hypersensitivity myocarditis. Hum Pathol. 1981;12(10):900–7.

    Article  Google Scholar 

  18. 18.

    Wang JF, Min JY, Hamptom TG, Amende I, Yan X, Malek S, et al. clozapine-induced myocarditis: role of catecholamines in a murine model. Eur J Pharmacol. 2008;592(1–3):123–7.

    CAS  Article  Google Scholar 

  19. 19.

    Elman I, Goldstein DS, Eisenhofer G, Malhotra AK, Adler CM, Pickar D, et al. Mechanism of peripheral noradrenergic stimulation by clozapine. Neuropsychopharmacology. 1999;20(1):29–34.

    CAS  Article  Google Scholar 

  20. 20.

    Haack MJ, Bak ML, Beurskens R, Maes M, Stolk LML, Delespaul PAEG. Toxic rise of clozapine plasma concentrations in relation to inflammation. Eur Neuropsychopharmacol. 2003;13(5):381–5.

    CAS  Article  Google Scholar 

  21. 21.

    Bayhan T, Sahin M, Yıldırım I, Karagöz T. Lamotrigine related myocarditis: case report. Turk Kardiyol Dern Ars. 2012;40(4):358–60.

    Article  Google Scholar 

  22. 22.

    Wassef N, Khan N, Munir S. Quetiapine-induced myocarditis presenting as acute STEMI. BMJ Case Rep. 2015;2015:bcr2014207151.

    Article  Google Scholar 

  23. 23.

    Bhogal S, Ladia V, Paul TK. Quetiapine-associated Myopericarditis. Am J Ther. 2018;25(5):e578–9.

    Article  Google Scholar 

  24. 24.

    Hagiwara H, Fukushima A, Iwano H, Anzai T. Refractory cardiac myocarditis associated with drug rash with eosinophilia and systemic symptoms syndrome due to anti-bipolar disorder drugs: a case report. Eur Heart J Case Rep. 2018;2(4):yty100.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    De La Fuente J, Hicks SB, Anavekar NS. 40-year-old man with fatigue, dyspnea, and nausea. Mayo Clin Proc. 2019;94(1):e1–6.

    Article  Google Scholar 

  26. 26.

    Caetano D, Gandhi C. Clozapine-induced myocarditis. Aust N Z J Psychiatry. 2008;42(5):434–5.

    PubMed  Google Scholar 

  27. 27.

    Belloni E, De Cobelli F, Esposito A, Mellone R, Gentinetta F, Meloni C, et al. Myocarditis associated with clozapine studied by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2007;9(3):591–3.

    Article  Google Scholar 

  28. 28.

    Hägg S, Spigset O, Bate A, Soderström TG. Myocarditis related to clozapine treatment. J Clin Psychopharmacol. 2001;21(4):382–8.

    Article  Google Scholar 

  29. 29.

    Ronaldson KJ, Fitzgerald PB, McNeil JJ. Clozapine-induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatr Scand. 2015;132(4):231–40.

    CAS  Article  Google Scholar 

  30. 30.

    Hatton JL, Bhat PK, Gandhi S. Clozapine-induced myocarditis: recognizing a potentially fatal adverse reaction. Tex Heart Int J. 2015;42(2):155–7.

    Article  Google Scholar 

  31. 31.

    Knoph KN, Morgan RJ 3rd, Palmer BA, Schak KM, Owen AC, Leloux MR, et al. Clozapine-induced cardiomyopathy and myocarditis monitoring: a systematic review. Schizophr Res. 2018;199:17–30.

    Article  Google Scholar 

  32. 32.

    Shivakumar G, Thomas N, Sollychin M, Takács A, Kolamunna S, Melgar P, Connally F, Neil C, Bousman C, Jayaram M, Pantelis C. Protocol fo Clozapine Rechallenge in a Case of Clozapine-Induced Myocarditis. Can J Psychiatry. 2020;65(7):448–453. Epub 2019 Dec 9.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012;134(2–3):180–6.

    Article  Google Scholar 

  34. 34.

    Shah P, Iwata Y, Plitman E, Brown EE, Caravaggio F, Kim J, et al. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: a systematic review. Psychiatry Res. 2018 Oct;268:114–22.

    CAS  Article  Google Scholar 

  35. 35.

    Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeil JJ. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res. 2012;141(2–3):173–8.

    Article  Google Scholar 

  36. 36.

    Lacaze P, Ronaldson KJ, Zhang EJ, Alfirevic A, Shah H, Newman L, et al. Genetic associations with clozapine-induced myocarditis in patients with schizophrenia. Transl Psychiatrty. 2020;10:37.

    CAS  Article  Google Scholar 

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MZH and FH were involved in the consultation and long-term follow-up of the patient. MZH and FH were involved in the writing of the manuscript. JJL revised the manuscript and contributed to the completion of the manuscript. The authors read and approved the final manuscript.

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Correspondence to M. Z. van der Horst.

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van der Horst, M.Z., van Houwelingen, F. & Luykx, J.J. Isolated nausea and vomiting as the cardinal presenting symptoms of clozapine-induced myocarditis: a case report. BMC Psychiatry 20, 568 (2020).

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  • Clozapine
  • Myocarditis
  • Clozapine-induced myocarditis
  • Schizophrenia
  • Case report