Cases That Test Your Skills

A young man’s affair of the heart

Current Psychiatry. 2007 September;6(9):87-92

References

1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-96.

2. Meltzer HY, Alphs L, Green AI, et al. International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;60:82-91.

3. Stahl SM. Antipsychotic polypharmacy, part 1: therapeutic option or dirty little secret? J Clin Psychiatry 1999;60:425-6.

4. Clozaril monograph. Novartis Phamaceuticals Corp.; April 12, 2006. Available at http://www.novartis.ca/downloads/en/products/clozaril_scrip_e.pdf. Accessed August 13, 2007.

5. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333:269.-

6. Physicians’ desk reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.

7. Merrill DB, Dec GW, Goff DC. Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol 2005;25:32-41.

8. Jenie LE. Cardiovascular toxicity with clozapine therapy. Riverview Hospital Pharmacy Newsletter 2002;22:1-3.

9. Devarajan S, Kutcher SP, Dursun SM. Clozapine and sudden death. Lancet 2000;355:841.-

10. Vaddadi KS, Soosai E, Vaddadi G. Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol 2003;55:307-9.

11. Williams DP, O’Donnell CJ, Maggs JL, et al. Bioactivation of clozapine by murine cardiac tissue in vivo and in vitro. Chem Res Toxicol 2003;16:1359-64.

12. Fineschi V, Neri M, Riezzo I, Turillazzi E. Sudden cardiac death due to hypersensitivity myocarditis during clozapine treatment. Int J Legal Med 2004;118:307-9.

13. Kendell KR, Day JD, Hruban RH, et al. Intimate association of eosinophils to collagen bundles in eosinophilic myocarditis and ranitidine induced hypersensitivity myocarditis. Arch Pathol Lab Med 1995;119:1154-60.

14. Pollmacher T, Schuld A, Kraus T, et al. On the clinical relevance of clozapine-triggered release of cytokines and soluble cytokine-receptors [in German]. Fortschr Neurol Psychiatr 2001;69(suppl 2):S65-S74.

15. Killian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-5.

16. Committee on Safety of Medicines Myocarditis with antipsychotics: recent cases with clozapine (Clozaril). Curr Probl Pharmacovigilance 1993;19:9.-

17. Degner D, Bleich S, Grohmann R, et al. Myocarditis associated with clozapine treatment. Aust NZ J Psychiatry 2000;34:880.-

18. La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States (letter). N Engl J Med 2001;345:224-5.

19. Reinders J, Parsonage W, Lange D, et al. Clozapinerelated myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service. Aust NZ J Psychiatry 2004;38:915-22.

20. Haas SJ, Hill R, Krum H, 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;30:47-57.

21. Wehmeier PM, Heiser P, Remschmidt H. Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine. J Clin Pharm Ther 2005;30:91-6.

22. Merrill DB, Ahmari SE, Bradford JM, Lieberman JA. Myocarditis during clozapine treatment. Am J Psychiatry 2006;163:204-8. Erratum in Am J Psychiatry 2006;163:556.-

23. Coulter DM, Bate A, Meyboom RH, et al. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. BMJ 2001;322:1207-9.

24. Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002;166:1185-6.

25. Kay SE, Doery J, Sholl D. Clozapine associated pericarditis and elevated troponin I. Aust NZ J Psychiatry 2002;36:143-4.

26. Berk M, Fitzsimons J, Lambert T, et al. Monitoring the safe use of clozapine: a consensus view from Victoria, Australia. CNS Drugs 2007;21:117-27.

27. American Psychiatric Association Work Group on Schizophrenia, Lehman AF, chair. Practice guideline for the treatment of patients with schizophrenia, 2nd ed, 2004. Available at: http://www.psych.org/psych_pract/treatg/pg/SchizPG-Complete-Feb04.pdf. Accessed August 15, 2007.

The authors’ observations

Mr. Z’s sudden-onset physical symptoms suggest myocarditis, a rare but potentially fatal side effect of clozapine whose specific cause is unclear (Box 1).^5-14 Myocarditis has been reported in 0.02% to 0.18% of patients exposed to clozapine,^15-18 with incidence as high as 1.3% per 235 patients.¹⁹

Affected patients typically have been taking clozapine at therapeutic dosages (100 to 450 mg/d).⁷ Clozapine use is most prevalent among men ages 20 to 40, who tend to have more severe schizophrenia and lower cardiac risk than other populations. Correspondingly, clozapine-induced myocarditis is most prevalent in younger men,²⁰ although what specifically causes this susceptibility is unknown.

Nonspecific symptoms such as dyspnea, tachycardia, chest pain, or fever can signal myocarditis (Table)^7,21 and can surface within 4 to 8 weeks of starting clozapine.²² Haas et al²⁰ reported other symptoms—such as leukocytosis—in young (median age 30), predominantly male patients with clozapine-induced myocarditis. Symptoms that typically occur during clozapine titration—such as fever and tachycardia—can mask “subclinical” myocarditis.²²

Mr. Z’s nonspecific symptoms could signal clozapine-induced agranulocytosis or a viral syndrome, or could be delusional. The patient’s acute, sudden symptom onset strongly suggests a cardiac cause. Also, his delusions subsided, and normal blood readings helped us rule out agranulocytosis.

Coulter et al²³ associated myocarditis and cardiomyopathy, a noninflammatory heart muscle disease, with several antipsychotics—including clozapine, chlorpromazine, fluphenazine, haloperidol, and risperidone—as well as lithium. More research is needed to confirm this association.

Clinical Point

Nonspecific symptoms during clozapine therapy could be delusional or signal agranulocytosis or a more serious problem

Emergency medical intervention is critical because mortality rates for myocarditis induced by clozapine have been estimated at 50%.²⁰ Myocarditis could progress to dilated cardiomyopathy,²⁴ with similarly high mortality rates across 5 years.⁷

Order a cardiology consult and workup including:

serum electrolytes
complete blood count
ECG²¹
tests for myocardial damage including creatine kinase with MB fractionation (CK-MB) and testing for serum troponin I,²⁵ lactic dehydrogenase, and aspartate transaminase (SGOT)²¹
assessment for immune activation and peripheral eosinophilia.²⁵

Findings on ECG are wide-ranging and might include sinus tachycardia, atrial or ventricular arrhythmias, left ventricular hypertrophy, nonspecific ST segment and T-wave abnormalities, and intraventricular conduction defects. Assess cardiac function with echocardiography to monitor for dilated cardiomyopathy. Stop clozapine immediately if findings suggest myocarditis.¹⁹

Table

Symptoms that could signal myocarditis in patients taking clozapine

Chest pain Confusion/mental status changes Dyspnea Edema Fatigue/weakness Fever Prolonged tachycardia
Source: Reference 7

TESTING: ‘Is this necessary?’

We contact the ER physician to request the above-mentioned tests, but he questions the need for such extensive and costly testing in a psychiatric patient with nonspecific symptoms.

After several phone conversations to review our recommendations, the emergency physician suggests sending Mr. Z home on a watch-and-wait protocol. We politely but firmly emphasize that Mr. Z needs a full cardiac workup, after which the physician consents to the tests (Box 2).

FINDINGS: suspicious readings

Mr. Z’s cardiac imaging results suggest a cardiopathy:

echocardiogram shows mild ventricular enlargement with a decreased ejection fraction of 45% (normal reading, 55% to 60%)
ECG shows normal sinus rhythm with low-voltage diffuse T-wave flattening throughout all leads without ST elevation
creatine phosphokinase (CPK) and CKMB are within normal ranges
troponin I is 0.33 ng/mL, a high-normal reading.

Mr. Z had no past cardiac abnormality, but an aunt had died in her 30s of viral myocarditis.

Based on these readings, the cardiology service admits Mr. Z with a presumptive diagnosis of clozapine-induced cardiomyopathy. The attending cardiologist stops clozapine and starts the angiotensin-converting enzyme inhibitor enalapril, 2.5 mg bid, for ventricular remodeling. Medical workup includes cytologic testing to rule out immunologic or viral disease.

Five days later, Mr. Z’s cardiac symptoms have resolved. The cardiology unit discharges him on enalapril, 2.5 mg bid, and schedules a cardiac ultrasound for 2 weeks after discharge to confirm progress.

The authors’ observations

Maintain high clinical suspicion while using clozapine. Similar to other patients with a clozapine-induced cardiopathy,¹⁶ Mr. Z showed rapid symptomatic changes after a benign initial course and experienced fairly vague symptoms that raised limited clinical concern at first.

Before starting clozapine therapy, screen all patients for pre-existing cardiac disease, which contraindicates this medication. Alert patients and caregivers to the risks and symptoms that require close monitoring early in treatment.

Many researchers suggest monitoring for myocarditis during the first month of therapy and ordering ECG at baseline and 2 and 4 weeks after starting clozapine.^21,22 Berk et al²⁶ suggest more aggressive monitoring, including:

baseline ECG
transthoracic echocardiogram
baseline troponin/CK-MB
ECG and troponin/CK-MB at 7 and 14 days
echocardiogram at 6 and 12 months and then annually.

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