1. Clozapine and its Cardiac Adverse
Effects: Myocarditis and
Cardiomyopathy
ADONIS SFERA, MD
INCIDENCE OF CLOZAPINE INDUCED CARDIOMYOPATHY
TRENDS IN CLOZAPINE PRESCRIBING
CARDIOVASCULAR ADVERSE EFFECTS OF CLOZAPINE
TIPS FOR CLINICIANS

2. Clozapine a Complex Drug

3. Who Gets Clozapine?
 Patients who have had a suboptimal response to
adequate trials with two first line antipsychotics
(haloperidol, loxapine, perphenazine, quetiapine,
risperidone).
 An adequate trial to determine clozapine’s
effectiveness is 3-6 months.
Recommendations for Antipsychotic Selection in Schizophrenia and Schizoaffective Disorders, June 2012, Medical Advisory Panel.

4. Cardiomyopathy and Myocarditis Associated
With The Use of Clozapine in US
 Between the US approval of clozapine in September
of 1989 and December 2, 1999, the FDA received
reports of 28 cases of myocarditis, including 18
deaths, and 41 cases of cardiomyopathy.
N Engl J Med 2001;345:224-225, July 19, 2001 DOI:10.1056/NEJM2001071934550317

5. Incidence of Myocarditis or Cardiomyopathy in Clozapine
Treated Patients
 Clozapine is associated with a low risk (0.015%-0.188%)
of potentially fatal myocarditis or cardiomyopathy
 Merrill DB, Dec GW, Goff DCJ Clin Psychopharmacol. 2005 Feb;25(1):32-41. Adverse cardiac effects associated with clozapine .

6. Trends in Clozapine Prescribing
 The percentage of schizophrenia patients receiving
clozapine rose from 9.0% in 1996 to 10.1% in 2007
(p<0.001).
 In the same period, the percentage of patients having
clozapine treatment augmented with another
antipsychotic increased from 43.1% to 64.2%,
p<0.001.

7. Psychiatrists More Hesitant to Prescribe
Clozapine
 Although, the percentage of schizophrenia patients receiving clozapine
increased from 1996 to 2007, the time from diagnosis of schizophrenia
until first prescription of clozapine increased.

8. Etiology of Clozapine Induced Myocarditis
 Inflammation: Noting that clozapine increases
inflammatory cytokines, some authors believe TNF-alpha and
other inflammatory cytokines contribute to myocarditis.
 Allergy: The common presence of peripheral eosinophilia on
autopsy—including diffuse eosinophilic infiltrates in
myocardial and perivascular areas—might suggest a
hypereosinophilic syndrome mediated by clozapine.
 Toxicity: direct toxic effect on cardiac myocytes related to
impaired clozapine metabolism in some patients

9. Histopathological Features of Clozapine Induced
Myocarditis
Myocytolysis and necrosis with florid infiltrate, consisting of lymphocytes,
neutrophils, and prominent eosinophils (red granular cytoplasm with bilobed
nucleus).

10. Cardiovascular Adverse Effects of Clozapine
 Tachycardia – caused by anticholinergic activity
 Orthostatic Hypotension – alpha adrenergic
blockade
 Myocarditis
 Cardiomyopathy
 Pericarditis

11. TIPS FOR CLINICIANS
 At present there is no proven method for either predicting or preventing
the development of myocarditis (a new protocol might be introduced).
 Patients who have persistent tachycardia at rest, especially during the
first two months of treatment, should be closely observed for other signs or
symptoms of myocarditis or cardiomyopathy. These include palpitations,
arrhythmias, symptoms mimicking myocardial infarction, chest pain and
other unexplained symptoms of heart failure.
 Patients in whom myocarditis or cardiomyopathy is suspected should stop
clozapine and undergo urgent diagnostic evaluation by a cardiologist.
 Patients with clozapine-induced myocarditis or cardiomyopathy must not
be re-exposed to clozapine.

12. More Tips
 Flu-like symptoms: unexplained fever, fatigue, lethargy
 Chest discomfort (often vague, or angina pectoris), palpitations
 Respiratory symptoms: tachypnea, dyspnea, orthopnea, paroxysmal nocturnal
dyspnea
 Abnormal vital signs: hypotension, narrowed pulse pressure, persistent resting
tachycardia
 Cardiovascular signs: raised jugular venous pressure, presence of a third or fourth
heart sound, pericardial friction rub, muffled first heart sound, mitral or tricuspid
regurgitation, peripheral edema
 Respiratory signs: crackles on auscultation
 ECG changes: sinus tachycardia, atrial or ventricular arrhythmias, left ventricular
hypertrophy, diffuse nonspecific ST-segment and T-wave abnormalities, low voltage
and intraventricular conduction defects
 CXR changes: possible cardiac enlargement, pulmonary venous congestion,
pulmonary edema
 Blood work changes: hypereosinophilia
 Many of these signs and symptoms are nonspecific, but if any occur in a clozapine-
treated patient, especially if the onset is sudden or unexpected, suspicions should be
raised followed by prompt cardiologic assessment.

13. A New Monitoring Protocol For Clozapine-
Induced Myocarditis
 A study published in Australia in 2011 showed the following:
-in 90% of patients troponin was increased at least twice
-5 cases had C-reactive protein more than 100 mg/l
Proposed Protocol:
Baseline troponin I/T
C reactive protein on days 7, 14, 21 and 28
Echocardiography (baseline).
Mild elevation in troponin or C-reactive protein, persistent tachycardia or signs or symptoms consistent
with infective illness should be followed by daily troponin and C-reactive protein values until features
resolve.
Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is
over 100 mg/l.
Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of
100%.
The sensitivity for asymptomatic disease is unknown.
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 NZ J
Psychiatry; 2011 Jun;45(6)458-65 Epub 2011 Apr 27.

14. Transthoracic echocardiograms demonstrating
enlargement of the left ventricle
(A) Short axis parasternal view showing dilation of both the left ventricle and atrium. (B) Long axis
parasternal view demonstrating enlargement of the cardiac chambers. Abbreviations: LA, left atrium; LV,
left ventricle, RA, right atrium; RV, right ventricle.
Makhoul B et al. (2008) Dilated cardiomyopathy: an unusual complication of clozapine therapy
Nat Clin Pract Cardiovasc Med doi:10.1038/ncpcardio1292

15. Future Screening
 The level of B-type natriuretic peptide, a hormone
secreted in response to ventricular wall stress, may
be useful for evaluating patients with clozapine-
induced cardiac dysfunction and may in the future be
useful for screening asymptomatic patients.