Approved in 1989 for the management of treatment-resistant schizophrenia, Clozapine is a last-line atypical antipsychotic drug used with increasing frequency. In addition to its well-known side effect of agranulocytosis, this drug also carries with it rare but serious adverse cardiovascular risk of myocarditis. We present a patient on Clozapine who was admitted to the cardiology service with chest pain, ST segment elevations and elevated troponin concerning for acute myocardial infarction. Evaluation with imaging revealed decreased left ventricular function, however, no coronary artery disease was present on catheterization; ﬁndings consistent with a diagnosis of myocarditis. Subsequent discontinuation of the patient’s Clozapine and initiation of brief supportive medical therapy resulted in full recovery of systolic left ventricular function. Given the potential cardiovascular mortality risk, it is important for physicians on cardiology services caring for psychiatric patients to be aware of the presentation of symptoms, diagnostic ﬁndings and management of Clozapine induced myocarditis. INTRODUCTION CASE REPORT Clozapine is a last-line atypical antipsychotic agent used to A 40-year-old transgender male to female with history of schizo- treat patients with difﬁcult to treat schizophrenia. It is classic- phrenia initially presenting for suicidal ideation was admitted to ally known for its potential serious side effects of agranulocyto- the inpatient psychiatric unit. She was enrolled in the Clozapine sis, however also carries a boxed warning for an uncommon, risk evaluation and modiﬁcation strategy program and started but important association with adverse cardiovascular effects, on the drug 7 days after admission. The medication was up- namely myocarditis [1, 2]. In recent reviews, the incidence of titrated to 50 mg in the morning and 150 mg at night. On Day 9, myocarditis associated with Clozapine exposure is 3% [3, 4]. We she reported chest pain. An EKG demonstrated new marked ST report a case of a 40-year-old female started on Clozapine with segment elevations in leads I, avL, II, and V4-V6 (see Figs 1 and subsequent development of myocarditis potentially relating to 2). Laboratory results revealed elevated troponin of 12 ng/ml this agent. We focus in this vignette on the clinical management (normal range 0.000–0.034) and creatine kinase MB (CKMB) of in a cardiac service as well as provide a brief literature review to 48 ng/ml (normal range 0.00–2.30). Given the EKG ﬁndings sug- understand the possible pathophysiology of Clozapine induced gestive of acute ST segment elevation myocardial infarction cardiotoxicity. (STEMI), she was transferred to our cardiac service. Received: July 24, 2017. Revised: October 6, 2017. Accepted: October 26, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx080/4794785 by Ed 'DeepDyve' Gillespie user on 16 March 2018 12 T. Datta and A.J. Solomon Figure 1: EKG prior to Clozapine initiation. Figure 2: EKG during chest pain event after Clozapine therapy. On initial evaluation, the patient described substernal chest rate (ESR) of 30 mm/h and C-reactive protein (CRP) of 36 mg/dl. pressure. Her past medical history revealed no cardiovascular An upper respiratory PCR panel was negative for inﬂuenza A/B disease risk factors. She denied having fevers, chills or upper and other viruses. A urine analysis revealed no signs of infec- respiratory symptoms. Her medication list included Clozapine, tion. A chest x-ray was unremarkable. and prior single doses of Hydroxyzine, Haloperidol and The patient was taken immediately to the catheterization Lorazepam. She took no medications at home. Her vital signs lab and no occlusive coronary artery disease was seen. A trans- were stable, cardiac examination was normal. In addition to thoracic echocardiogram revealed ejection fraction of 30–35% elevated troponin and CKMB, labs showed elevated brain natri- with moderate global hypokinesis. Given high suspicion for uretic peptide (BNP) of 3070 pg/ml, erythrocyte sedimentation drug induced myocarditis, Clozapine was stopped. The patient Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx080/4794785 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Clozapine-induced myocarditis 13 Figure 3: Timeline of events. was monitored on telemetry and started on cardiac medical patient with Clozapine after myocarditis is controversial. While management with low doses of Metoprolol (12.5 mg twice a there have been mixed results, there are not enough cases with day) and Lisinopril (2.5 mg daily). rechallenge reported to draw deﬁnitive conclusions. The deci- She remained chest pain free through the remainder of her sion depends upon patient discussion to weigh quality of life course without development of shortness of breath, orthopnea without Clozapine therapy versus risk of myocarditis on rechal- or lower extremity swelling. On hospital Day 20 (4 days after lenge. We did not rechallenge our patient. A major limitation in discontinuation of Clozapine) a repeat transthoracic echocar- our diagnosis was the inability to obtain cardiac magnetic res- diogram showed fully recovered left ventricular function with onance imaging. In the absence of endomyocardial biopsy, this an ejection fraction of 65% and no wall motion abnormalities. modality is important. Lastly, we could not conﬁrm that the Timeline of Events is shown in Fig. 3. Cardiac medications patient was not abusing any other substances no longer avail- were discontinued and ventricular function remained recov- able once admitted, contributing to functional recovery. ered. The patient was transferred back to the psychiatry Management of clozapine myocarditis is supportive and inpatient team in stable condition for further management of empiric . Once the diagnosis is established, if drug induced her schizophrenia. myocarditis is suspected, the inciting agent should be discon- tinued immediately. Administration of diuretics, beta blockers and angiotensin converting enzyme inhibitors have been DISCUSSION shown to support myocardial function during the acute myo- cardial insult . Trending levels of inﬂammatory markers such Development of myocarditis as a result of Clozapine therapy as ESR and CRP have been suggested as ways to document generally occurs within the ﬁrst 2–8 weeks of therapy . At recovery . time of diagnosis, the mean age of patients has been reported Discontinuation of Clozapine leads to cardiac functional as 33.5 years with mean dose of Clozapine 360 mg . Rule out recovery with a direct correlation in degree of compromised of other etiologies of myocarditis/inﬂammatory cardiomyop- systolic function to degree of recovery, however mortality is athy with testing for viral respiratory infection, autoimmune still 12.5–24% [4, 6, 11]. The timeline of onset of cardiac func- diseases and giant cell myocarditis is imperative [7–9]. tional recovery from the time of discontinuation of drug is vari- Laboratory testing to look for myocardial damage with elevated able. Discontinuation of Clozapine should be done with close cardiac enzymes as well as evaluation of electrocardiogram liason with Psychiatry colleagues as relapse of Schizophrenia and chest x-ray are standard measures. In our case, the diffuse may ensue leading to signiﬁcant patient harm. ST segment elevations on electrocardiogram are seen with peri- The mechanism of Clozapine induced myocarditis has not carditis however taking the entire clinical picture into context, been well established. Links with geographical region based on myocarditis remained the leading diagnosis. Supportive evi- ozone concentrations, genetic predisposition, Ig E mediated dence additionally includes elevated BNP and absence of hyper- hypersensitivity and elemental deﬁciencies have been pro- tension or history of valvular disease. Echocardiogram to posed. In a review conducted of 47 cases of Clozapine induced assess ventricular function and provide conﬁrmation of devel- myocarditis, the development of eosinophilia suggesting IgE oping ventricular failure is also helpful . In the presence of mediated hypersensitivity reaction has been documented in reduced systolic function, a cardiac catheterization to conﬁrm ~66% of cases . The highest rates of Clozapine induced car- lack of obstructive or ischemic coronary disease further con- diomyopathy have been reported in New Zealand and Australia ﬁrms a diagnosis of myocarditis. The role of re-challenging a Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx080/4794785 by Ed 'DeepDyve' Gillespie user on 16 March 2018 14 T. Datta and A.J. Solomon possibly due to possibly increased blockade of M2 receptors REFERENCES and cholinergic receptor dysfunction in these areas of higher 1. De Berardis D, Serroni N, Campanella D, Olivieri L, ozone concentrations . Genetic predisposition is thought to Ferri F, Carano A, et al. Update on the adverse effects of clo- be mediated by mutations in pharmacokinetic enzymes zapine: focus on myocarditis. Current drug safety 2012;7: CYP450-1A2 and CY450-1A3 . 55–62. To further consider is inherent alpha-adrenergic blocking 2. Annamraju S, Sheitman B, Saik S, Stephenson A. Early rec- effects of antipsychotics . This is supported by the fact that ognition of clozapine-induced myocarditis. J Clin patients prescribed Clozapine are those exposed to many anti- Psychopharmacol 2007;27:479–83. psychotics before initiation of this last line agent suggesting 3. Ronaldson KJ, Fitzgerald PB, McNeil JJ. Clozapine-induced some degree of cumulative effect. myocarditis, a widely overlooked adverse reaction. Acta The role of sophisticated monitoring systems dedicated to Psychiatr Scand 2015;132:231–40. detecting cardiovascular complications associated with cloza- 4. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis pine has been established. Protocols focus mainly on keeping a and cardiomyopathy associated with clozapine. Lancet 1999; high index of suspicion for early recognition of symptoms . 354:1841–5. Ongoing discussions remain to include cardiac markers in 5. Curto M, Girardi N, Lionetto L, Ciavarella GM, Ferracuti S, weekly blood work along with markers of inﬂammation in Baldessarini RJ. Systematic review of clozapine cardiotoxi- these protocols. city. Curr Psychiatry Rep 2016;18:68. In summary, our case highlights a rare yet potentially fatal 6. Alawami M, Wasywich C, Cicovic A, Kenedi C. A systematic cardiovascular complication potentially relating to Clozapine review of clozapine induced cardiomyopathy. Int J Cardiol use. Recent cohort studies have shown that myocarditis and 2014;176:315–20. sudden cardiac death are uncommon in patients maintained 7. Dennert R, Crijns HJ, Heymans S. Acute viral myocarditis. on clozapine however given the fatal clinical signiﬁcance, pre- Eur Heart J 2008;29:2073–82. ventive measures need to be further studied . Given lethal 8. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno- risk and boxed warning for cardiovascular toxicity, chest dis- Blanes J, Felix SB, et al. Current state of knowledge on aeti- comfort in a patient commencing Clozapine should be investi- ology, diagnosis, management, and therapy of myocarditis: gated for a symptom of myocarditis. a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur ACKNOWLEDGEMENTS Heart J 2013;34:2636–48, 48a-48d. 9. Heymans S, Eriksson U, Lehtonen J, Cooper LT Jr. The quest All residents and medical staff that assisted in the care of this for new approaches in myocarditis and inﬂammatory car- patient during her hospital stay. diomyopathy. J Am Coll Cardiol 2016;68:2348–64. 10. Ronaldson KJ, Taylor AJ, Fitzgerald PB, Topliss DJ, Elsik M, CONFLICT OF INTEREST STATEMENT McNeil JJ. Diagnostic characteristics of clozapine-induced None declared. myocarditis identiﬁed by an analysis of 38 cases and 47 controls. J Clin Psychiatry 2010;71:976–81. 11. La Grenade L, Graham D, Trontell A. Myocarditis and car- FUNDING diomyopathy associated with clozapine use in the United No funding was required. States. N Engl J Med 2001;345:224–5. 12. Yost BL, Gleich GJ, Fryer AD. Ozone-induced hyperrespon- siveness and blockade of M2 muscarinic receptors by ETHICAL APPROVAL eosinophil major basic protein. J Appl Physiol 1999;87: No ethical approval was required. 1272–8. 13. Munshi TA, Volochniouk D, Hassan T, Mazhar N. CONSENT Clozapine-induced myocarditis: Is mandatory monitoring warranted for its early recognition? Case reports in psychiatry We obtained written signed patient consent for the presenta- 2014;2014:513108. tion of this case. 14. Khan AA, Ashraf A, Baker D, Al-Omary MS, Savage L, Ekmejian A, et al. Clozapine and incidence of myocarditis GUARANTOR and sudden death—Long term Australian experience. Int J Tanuka Datta is the guarantor of this manuscript. Cardiol 2017;238:136–9. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx080/4794785 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Oxford Medical Case Reports – Oxford University Press
Published: Jan 1, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera