Schizophrenia Research 199 (2018) 17–30

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Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Clozapine-induced cardiomyopathy and myocarditis monitoring: A

systematic review
Kristen N. Knoph a, Robert J. Morgan III b, Brian A. Palmer b, Kathryn M. Schak b, Amanda C. Owen a,
Megan R. Leloux a, Mayur Patel a, Jonathan G. Leung a,⁎
a
Pharmacy Services, Mayo Clinic, Rochester, MN, United States
b
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States

a r t i c l e i n f o a b s t r a c t

Article history: The use of clozapine requires monitoring the absolute neutrophil count because of the risk of agranulocytosis, but
Received 23 August 2017 other potentially fatal adverse events associated with clozapine (specifically, myocarditis and cardiomyopathy)
Received in revised form 27 February 2018 do not have mandatory procedures. We performed a systematic review of English-language articles to synthesize
Accepted 4 March 2018
an evidence-based approach for myocarditis and cardiomyopathy monitoring. Articles published from January
Available online 13 March 2018
1988 through February 2017 were identified through a search of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Da-
Keywords:
tabase of Systematic Reviews, Web of Science, Scopus, and Google Scholar. Selected articles were required to re-
Antipsychotic late to myocarditis or cardiomyopathy in humans from exposure to clozapine. A total of 144 articles were
Cardiomyopathy included. Recommendations varied widely. Some authors recommended baseline laboratory monitoring, with
Clozapine or without follow-up testing, for C-reactive protein, creatine kinase MB, and troponin. Electrocardiography was
Myocarditis commonly recommended, and echocardiography was less commonly recommended. The expense of monitoring
Safety was a consideration. A unanimous recommendation was to stop the use of clozapine and seek a cardiovascular
Schizophrenia consultation if myocarditis or cardiomyopathy is suspected. Although there is general agreement on which
tests to perform for confirming myocarditis and cardiomyopathy, preemptive screening for these clozapine-in-
duced conditions is controversial, and cost and barriers for the use of clozapine are concerns. For asymptomatic
patients receiving clozapine, testing could include baseline electrocardiography, echocardiography as part of a
cardiac consultation if patients have cardiac disease or risk factors, and monitoring of C-reactive protein and tro-
ponin as indicated.
© 2018 Elsevier B.V. All rights reserved.

1. Introduction mortality rate estimates for myocarditis and cardiomyopathy (10%–

Clozapine is associated with the risk of potentially fatal agranulocy-
tosis and its use requires monitoring the absolute neutrophil count
(ANC) through the US Food and Drug Administration (FDA) Risk Evalu-
ation and Mitigation Strategy (REMS) program. ANC monitoring im-
proves the hematologic safety of clozapine, but other potentially fatal
adverse events associated with clozapine do not have mandatory proce-
dures. Specifically, clozapine is associated with myocarditis and cardio-
myopathy with an estimated absolute risk of 0.01% to 0.19% (Citrome et
al., 2016). This is lower than the risk of agranulocytosis (1.3%), but
Abbreviations: ANC, absolute neutrophil count; CK-MB, creatine kinase MB; CRP, C-
reactive protein; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; FDA, US
Food and Drug Administration; NT-proBNP, N-terminal pro-brain natriuretic peptide;
REMS, Risk Evaluation and Mitigation Strategy.
⁎ Corresponding author at: Pharmacy Services, Mayo Clinic, 200 First St SW, Rochester,
MN 55905, United States.
E-mail address: Leung.jonathan@mayo.edu (J.G. Leung).
46%) are clinically significant (Citrome et al., 2016). In the United States,
the clozapine package insert (2017) mentions common laboratory and
radiologic findings in myocarditis and cardiomyopathy, but it lacks spe-
cific monitoring recommendations.
Compared to patients in other areas of the world, Australian patients
have a higher incidence of myocarditis and cardiomyopathy (Haas et al.,
2007; Kilian et al., 1999), which has led to multiple investigations on the
topic in that region. For example, Ronaldson et al. (2011a) proposed a
myocarditis screening protocol for all patients beginning treatment
with clozapine. This protocol, which includes a baseline echocardio-
gram, has been criticized for not being cost-effective and, if made man-
datory, for possibly introducing a barrier to initiating clozapine therapy
in areas with limited resources (Freudenreich, 2015; Murch et al.,
2013b). Despite the protocol proposed by Ronaldson and colleagues,
consensus is still lacking in the medical literature on the most appropri-
ate monitoring for patients in the absence of clinical suspicion for myo-
carditis or cardiomyopathy. We conducted a systematic review to

https://doi.org/10.1016/j.schres.2018.03.006
0920-9964/© 2018 Elsevier B.V. All rights reserved.

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18 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30
collate all available information and synthesize an evidence-based ap-
proach for the preemptive monitoring of clozapine-induced myocarditis
and cardiomyopathy.
2. Methods
2.1. Literature search
A search of English-language articles published from January
1988 through February 2017 was designed in Ovid MEDLINE,
Ovid Embase, Ovid Cochrane Database of Systematic Reviews,
Web of Science, and Scopus. The strategy included the following
keywords: (“Clozapine”[MAJR] OR clozapine[TIAB]) AND
(“Cardiomyopathies”[MAJR] OR myocarditis[TIAB] OR cardiomyopath*
[TIAB] OR pericarditis [TIAB]) AND (“diagnosis”[Subheading] OR
“Diagnosis”[Mesh] OR “Drug Monitoring”[Mesh] OR monitor* or detect*
or diagnos* or screen* or examin* or inspect* or identif*). As a final search
for relevant articles, references of gathered publications were reviewed
and a Google Scholar search was conducted using search terms “clozapine
and myocarditis” and “clozapine and cardiomyopathy.”
2.2. Screening
Articles were included if they related to myocarditis or cardiomyop-
athy from exposure or reexposure to clozapine. Articles were excluded
if they were duplicates, discussed animal models, or were overdose re-
ports or conference abstracts. The full texts of articles were reviewed by
3 authors (K.N.K., A.C.O., and J.G.L.) who determined inclusion and
reviewed and summarized the articles.
3. Results
The search produced 153 articles after removing duplicates, with an
additional 30 articles found by searching references and Google Scholar.
After screening, 39 articles were eliminated. A total of 144 publications
related to clozapine-associated myocarditis and cardiomyopathy were
included (Fig. 1).
Fig. 1. Flow diagram of included studies.
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3.1. Review articles
In the 27 identified review articles (Table 1), consistent recommen-
dations included obtaining a thorough medical history, family history,
and social history and performing a complete physical examination be-
fore prescribing clozapine. Cardiology consultation was recommended
for any relevant findings from the history or physical examination
(Citrome et al., 2016; Marder et al., 2004; Merrill et al., 2005; Raja and
Raja, 2014; Wooltorton, 2002), including arrhythmias, chest pain, coro-
nary artery disease, heart failure, myocardial infarction, alcohol abuse,
syncope, uncontrolled hypertension, and family history of dilated car-
diomyopathy. A need to detect nonspecific signs and symptoms of phys-
ical illness was widely emphasized as these may represent the early
manifestations of cardiac adverse events (Ronaldson et al., 2015a;
Wehmeier et al., 2005). Authors' recommendations varied in support
of routine laboratory monitoring, if any, and clinical monitoring alone
(Citrome et al., 2016; Cohen et al., 2012; Layland et al., 2009).
Eosinophilia was considered nonspecific or delayed and thus less
helpful for the detection of early myocarditis (Roge et al., 2012). Other
recommendations for baseline laboratory monitoring included
obtaining baseline and weekly levels of C-reactive protein (CRP), crea-
tine kinase MB (CK-MB), and troponin (singly or in combination) within
the first 3 to 4 weeks of therapy. N-terminal pro-brain natriuretic pep-
tide (NT-proBNP) was discussed as having a role in detecting early car-
diac dysfunction, but more data are needed to support its use (Alawami
et al., 2014; Curto et al., 2016; Rostagno et al., 2011a). Erythrocyte sed-
imentation rate (ESR), which may be elevated in acute myocarditis, was
less commonly recommended, and its role in routine monitoring is un-
clear. The articles did not suggest that serum clozapine levels are useful
in predicting myocarditis (Remington et al., 2013). Low selenium levels
may be associated with cardiomyopathy (Berk et al., 2007). One author
cautioned that because myocarditis has a rapid onset, laboratory moni-
toring protocols may provide a false sense of security, highlighting the
ongoing need for concurrent clinical monitoring (Berk et al., 2007).
Electrocardiography (ECG) was commonly recommended at base-
line and at various routine intervals early in therapy to assess the QT in-
terval rather than to specifically assess for myocarditis (Abidi and

Table 1
Review articles.
Source, year
Alawami et al., 2014
Abidi and Bhaskara, 2003
Bishara and Taylor, 2014
Buckley and Sanders, 2000
Manu et al., 2012
Marder et al., 2004
Meltzer, 2012
Merrill et al., 2005
Nielsen et al., 2013
Wehmeier et al., 2005
Wooltorton, 2002
Phansalkar and Osser, 2009
Remington et al., 2013
Remington et al., 2016
Ronaldson et al., 2015a
Rostagno et al., 2011b
Raja and Raja, 2014
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K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30 19
Clinical recommendations and comments
Review focused on cardiomyopathy: Presentation is variable, patients may be asymptomatic, persistent tachycardia requires closer monitoring
for s/sx of heart failure
Treatment: Stop clozapine and initiate cardiac medication; EF b25% at diagnosis is poor prognostic indication; some improve with clozapine
cessation; rechallenge is not recommended except when benefits outweigh risks
Monitoring:
Baseline ECG and CXR with follow-up ECG at 1 month or stable dosing to monitor QTc but not cardiomyopathy
Frequent physical examination after initiation is needed in the first 4 years of therapy
More data are needed to support the use of baseline or routine echo in asymptomatic patients or the use of NT-proBNP for the early detection of
cardiomyopathy
Myocarditis risk noted
General recommendations when starting any SGA: baseline and regular ECG and evaluation of cardiovascular status
Recommended that multidisciplinary experts collaborate
Authors highlighted Australian monitoring parameters for myocarditis monitoring (see Ronaldson et al., 2011a)
Prompt cardiovascular consultation if s/sx of cardiac toxicity are present
Broadly reviewed cardiovascular adverse events with antipsychotic drugs with minimal discussion on myocarditis or cardiomyopathy associated
with clozapine
Review covered clozapine rechallenges: 1 patient with pericarditis and 4 with myocarditis; 1 rechallenge after myocarditis was unsuccessful
Three rechallenged patients: frequent troponin and CRP monitoring with serial echo (for up to 1 year for 1 patient)
Recommended that providers prescribing clozapine be aware of the s/sx of myocarditis
WBCs and troponins should be assessed if myocarditis is suspected
Clozapine should be stopped immediately with medical follow-up after identification of myocarditis
Authors stated, “No specific monitoring recommendations”
Monitoring not specifically addressed
Noted numerous publications suggesting guidance for cardiac monitoring with clozapine and suggested their own:
Baseline: physical examination, complete history, minimization of other QTc-prolonging medications, minimization of benzodiazepines, ECG,
echo (if preexisting structural cardiovascular disease), cardiology consultation (if family history of DCM, history of chest pain, prior MI,
preexisting heart failure, arrhythmias, or syncope)
At 2 and 4 weeks: ECG
At any time: ECG, CK-MB, or troponin I with new symptoms suggestive of cardiovascular disease; cardiology consultation with any changes
Value of eosinophil count and eosinophilic cationic protein is unknown
For confirmation of myocarditis: cardiac MRI (not recommended: endomyocardial biopsy)
No rechallenge after myocarditis
Consider rechallenge or continuation if cardiomyopathy develops (obtain echo every 3 months); consider discontinuation with decrease in LVEF
N15% from baseline or LVEF b45%
Provided grounds for discontinuing clozapine with myocarditis (troponin level twice the upper limit of reference range or ST-segment elevation
—rechallenge not recommended) and cardiomyopathy (confirmation with echo—rechallenge not recommended)
Highlighted patients with no symptoms; suggested that weekly troponin monitoring may be beneficial
With myocarditis or cardiomyopathy, discontinue clozapine without taper
Detection of subclinical cases of myocarditis, cardiomyopathy, or pericarditis is imperative; use clinical, laboratory, and cardiac tests:
palpitations, chest pain, dyspnea, fever, leukocytosis, eosinophilia, troponins, CK, LDH, AST, ECG, echo
Highlighted recommendations for the assessment of myocarditis in the first month of treatment and regular monitoring for cardiomyopathy
Stated that regardless of monitoring strategy, a high degree of awareness should be maintained if patient has cardiac symptoms
Cardiac evaluation before treatment if patient has personal or family history of heart disease
After treatment initiation, maintain high degree of awareness for the following symptoms: flulike symptoms; chest discomfort; respiratory
symptoms, including tachypnea, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and crackles on auscultation; abnormal vital signs,
including hypotension, narrowed pulse pressure, and persistent resting tachycardia; cardiovascular signs, including increased jugular venous
pressure, presence of third or fourth heart sound, pericardial friction rub, muffled first heart sound, mitral or tricuspid regurgitation, and
peripheral edema; ECG changes, including possible cardiac enlargement, pulmonary venous congestion, and pulmonary edema; and
hypereosinophilia
If any are present, recommended prompt cardiologic assessment and prompt, permanent discontinuation of clozapine
Highlighted tachycardia as common and not usually indicative of myocarditis, but ECG is warranted
Clozapine should be discontinued if myocarditis is suspected
Clinicians should monitor cardiac status closely in the first few months, but no specific monitoring recommendations were given
Highlighted heavy alcohol use as an independent risk for cardiomyopathy
Stop clozapine immediately with suspected heart failure
Rechallenge should be done after cardiac consultation and only if benefits outweigh risks
No publication suggests a dose or serum level risk with myocarditis or overall tolerability
Noted published Australian guidelines for myocarditis monitoring, but from internet searches, other centers have adopted their own:
Monitoring with routine clinical assessments, cardiac tests, and laboratory monitoring
Rechallenge is not routine but may be considered
Addressed need for greater use of clozapine and specialized clozapine clinics to enhance initiations and discourage unnecessary discontinuation
Highlighted possible reasons for an underdiagnosis of myocarditis:
Fever and other nonspecific clinical presentations may be overlooked
Myocarditis may be mild and spontaneously resolve
Sudden death not investigated
Symptoms may resemble those of pneumonia or other respiratory illness
Implementation of a routine monitoring system would improve recognition
Within the first 2 months monitoring of troponin and CRP and echo may be useful to diagnose myocarditis
Serial NT-proBNP and echo (“yearly?”) may be useful to detect early cardiac dysfunction
Withdrawal of clozapine is mandatory if cardiac toxicity develops, but rechallenge may be appropriate
Pericarditis occurs within the first month of therapy, and rechallenge often results in recurrence
Before treatment, cardiac evaluation for patients with a personal or family history of heart disease
Diagnosis is guided by clinical evidence; maintain high degree of awareness during first 2 months of clozapine use
Presence of flulike symptoms, tachycardia, chest pain, dyspnea, fever, or eosinophilia is an indication for ECG and measurement of serum
troponin, CK-MB, and CRP
(continued on next page)
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20 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30

Table 1 (continued)

Source, year Clinical recommendations and comments

Layland et al., 2009
Gareri et al., 2008
Hill and Freudenreich, 2013
Citrome et al., 2016
Cohen et al., 2012
Curto et al., 2016
De Berardis et al., 2012
Roge et al., 2012
Koutkias et al., 2017
Berk et al., 2007
Assessment of B-type natriuretic peptide and transthoracic echo may be useful for evaluating patients with clozapine-associated myocarditis and
may be useful in the future for screening asymptomatic patients; contrast-enhanced cardiac MRI may be beneficial, but the role in diagnosis is
uncertain; endomyocardial biopsy is not a practical initial approach
Clinical suspicion should result in the interruption of clozapine treatment, admittance for observation, and cardiologic consultation
Clozapine should be stopped promptly and permanently discontinued; rechallenge is not recommended
Treatment with β-blocking agents, angiotensin-converting enzyme inhibitors, and diuretics leads to resolution
Effectiveness of corticosteroids in clozapine-associated myocarditis is uncertain
Screening for asymptomatic patients: regular assessment of left ventricular function with transthoracic echo (commonly reported at baseline, 6
months, and 12 months), physical examination, and perhaps BNP assessment
Troponin is more useful than CK but has been reported to have low sensitivity (34%) and may not increase in all cases (35% in 1 report)
Suspected toxicity: Full blood count, cardiac biomarkers (troponin and CRP), urgent transthoracic echo
Management: Cessation and supportive care; rechallenge possible
Recommended echo every 6 months to detect myocarditis, especially in elderly people
Recommended comprehensive medical history and baseline ECG before initiation; maintain high degree of awareness early in treatment if s/sx of
cardiac toxicity are present (persistent resting tachycardia, flulike symptoms, chest pain, or dyspnea), and then repeat the ECG, check cardiac
enzyme levels, and consider echo and cardiology consultation
Recommended baseline measurement of eosinophils, CRP, and CK-MB and referral to cardiologist as needed
Common symptoms: dyspnea, palpitations or tachycardia, fever, fatigue, and chest pain
Nonspecific symptoms: sore throat, cough, vomiting, diarrhea, headache, neck pain, dizziness
Suggested weekly (for first 4 weeks) evaluation of peripheral eosinophils, CRP, CK-MB, troponin, and/or WBCs along with possible troponin
monitoring; if laboratory results show elevations, ECG and echocardiogram are indicated
Recommended interruption if symptoms or laboratory tests indicate possible myocarditis or cardiomyopathy; rechallenge is possible (but
generally not recommended) in carefully selected and monitored patients, with appropriate concomitant cardiac therapies
Characterized by tachycardia or hypotension accompanied by other recent-onset symptoms (dizziness, palpitations, dyspnea, or chest pain) or
symptoms of heart failure (arrhythmia, edema, and increased jugular venous pressure)
Further investigations are needed before screening recommendations can be formulated; until then, clinicians should be alert to the possible
development of myocarditis or cardiomyopathy during the first 3 months of treatment and should order appropriate tests if these disorders are
suspected
Discrepancies between Australian and worldwide myocarditis rates may be related to enhanced monitoring in Australia
Laboratory and ECG changes occur early in myocarditis, including CRP, troponin, CK-MB, BNP, NT-proBNP
More data are needed to fully understand the safety of rechallenge after myocarditis; clozapine after cardiomyopathy is not recommended
Commented on numerous recommendations for monitoring with laboratory and radiographic tests and described an overall consensus of clinical
monitoring and repeated assays of cardiac tissue damage in the initial weeks of treatment, but provided no specific recommendations
Risk factors of myocarditis were highlighted: medications (sulfonamides, β-lactams, levothyroxine, ranitidine, lithium, cyclophosphamide,
phenothiazine, sertraline, amitriptyline, imipramine, desipramine, and fluvoxamine), BMI N30 kg/m2, and sustained aerobic exercise
Echo and MRI should be completed with suspected myocarditis; biopsy is not recommended
Ronaldson protocol for monitoring myocarditis is “scientifically sound”
After diagnosis, clozapine should be stopped, and rechallenge should be based on risks and benefits
Fever and eosinophilia are present in many patients but are poor predictors of myocarditis
“Benign fever” may be subclinical myocarditis, and myocarditis should be ruled out with CRP, troponin, and ECG in addition to WBC count with
differential count
Reviewed FAERS, PubMed, and Twitter to establish a continuous learning system for drug safety surveillance by exploiting heterogeneous
publicly available data sources including clozapine-associated cardiomyopathy/myocarditis
Data from FAERS: N = 407; 67% males; mean age, 37; fatal cases, n = 67
No specific comments on monitoring
Authors followed a cardiac screening protocol but noted that myocarditis has a rapid onset, and monitoring may provide a false sense of security:
Baseline: history, vital signs, ECG, echo, troponin and CK-MB, CBC with differential count
At 7 and 14 d: ECG, plasma troponin, CK-MB
At 6 and 12 months: echo (then annually)
Additional: CXR (cardiac dysfunction suspected), inflammatory markers (myocarditis suspected), selenium level (cardiomyopathy suspected)
If myocarditis is clinically suspected: vitals, ECG, WBC and eosinophil count, ESR or CRP, CK-MB, troponin, CXR, echo
When myocarditis is diagnosed, stop clozapine and use corticosteroids if indicated

Abbreviations: AST, aspartate aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; CK, creatine kinase; CK-MB, creatine kinase MB; CRP, C-reactive protein; CXR, chest
radiography; DCM, dilated cardiomyopathy; ECG, electrocardiography; echo, echocardiography; EF, ejection fraction; ESR, erythrocyte sedimentation rate; FAERS, US Food and Drug Ad-
ministration Adverse Event Reporting System; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRI, magnetic resonance imaging; NT-
proBNP, N-terminal pro-brain natriuretic peptide; QTc, corrected QT interval; s/sx, clinical signs and symptoms; SGA, second-generation antipsychotic; WBC, white blood cell count.

Bhaskara, 2003; Berk et al., 2007; Curto et al., 2016; De Berardis et al.,
2012; Hill and Freudenreich, 2013; Merrill et al., 2005). Recommenda-
tions for routine echocardiographic monitoring for myocarditis and
cardiomyopathy were less consistent. Some recommended echocar-
diography at baseline with follow-up echocardiography within
2 months and then yearly or at baseline, 6 months, and annually (Berk
et al., 2007; Gareri et al., 2008; Layland et al., 2009). Others recom-
mended that echocardiography be reserved for patients with a known
cardiac history (eg, myocardial infarction, valvular disease, or cardio-
myopathy) and that more research is needed before recommending
routine echocardiography for asymptomatic patients (Alawami et al.,
2014; Manu et al., 2012; Merrill et al., 2005; Rostagno et al., 2011b).
Chest radiography for baseline monitoring was mentioned in only 1 re-
view (Alawami et al., 2014). Several articles did not discuss specific
monitoring because of the scope of the review (Buckley and Sanders,
2000; Koutkias et al., 2017; Meltzer, 2012).
A unanimous recommendation was to discontinue clozapine and
seek a cardiovascular consultation when myocarditis or cardiomyopa-
thy is suspected (Bishara and Taylor, 2014; Nielsen et al., 2013). How-
ever, to prevent unnecessary disruptions in therapy, the use of
specialized clozapine clinics was encouraged (Remington et al., 2016).
Rechallenge with clozapine is controversial owing to a lack of data and
is recommended only when the benefits of ongoing clozapine therapy
outweigh the risks, a cardiology provider is consulted, and vigilant mon-
itoring is conducted (Citrome et al., 2016; Manu et al., 2012; Meltzer,
2012; Phansalkar and Osser, 2009).
Reviews were limited by their scope, lack of detailed monitoring rec-
ommendations, and lack of available data at the time of publication.

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 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30
Table 2
Research reports.
Source, year Design
Kelly et al., 2009 Retrospective study (1990–2004)
evaluating autopsies after patients had
taken risperidone or clozapine
Kilian et al., 1999 Retrospective study (1993–1999)
assessing a national database of adverse
events, drug company reports, and local
cases
La Grenade et al., 2001 Retrospective study (1989–1999)
reviewing cases reported to the FDA
Haas et al., 2007 Retrospective study (1993–2003)
reviewing cases reported to the Australian cardiomyopathy
Adverse Drug Reactions Unit
Coulter et al., 2001 Retrospective study comparing cases
reported to the WHO database of adverse
reactions (time frame not reported)
Baptista et al., 2016 Prospective, observational study
conducted over approximately 1.5 years
with assessments on 1 or 2 occasions at
different times
Curto et al., 2015 Prospective, 4-week, open-label study
assessing the effect of early clozapine
therapy on LV function (N = 15)
Murch et al., 2013b Retrospective review (2002–2009)
assessing echo monitoring policy (at
baseline, 6 months, 12 months, and
yearly) for patients starting to take
clozapine
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Type of Results
cardiotoxicity
reported
All Cardiovascular disease–related deaths:
cardiac-related clozapine (11%) vs risperidone (7%); P =
deaths .48
Cardiomyopathy-related deaths:
clozapine (5%) vs risperidone (5%)
Myocarditis-related deaths: clozapine
(1.6%) vs risperidone (0%)
BMI: clozapine (31.9 kg/m2) vs
risperidone (25.3 kg/m2); P = .014
Myocarditis, Of 8000 patients who began taking
cardiomyopathy clozapine, 23 had myocarditis or
cardiomyopathy
Myocarditis (n = 15): median onset, 15 d
(range, 3–21 d); variable clinical
presentation; 5 died 14–18 d after starting
clozapine (4 had no reported clinical
symptoms)
Cardiomyopathy (n = 8): median onset,
12 months (range, 2–36 months); 1 died,
and 1 improved after cessation
Myocarditis, Myocarditis (n = 28): median onset, 3
cardiomyopathy weeks (range, 2–7 weeks); 17 confirmed,
18 deaths; survivors were treated for
shorter durations and with a lower dose
(median, 225 mg vs 450 mg)
Cardiomyopathy (n = 41): median onset,
9 months (range, 2 weeks to 7 years); 22
confirmed, 10 deaths; survivors had
similar exposure times and dosage (450
mg vs 400 mg)
Myocarditis, Of 116 reported cases: 77.6% were male;
median age, 30 years; 69% of cases
occurred within 21 d, but 10% occurred
after 1 years; clinical presentation was
highly variable; 12 deaths
Concomitant psychotropic medications
included benzodiazepines (n = 25),
valproate (n = 21), antidepressants (n =
15)
Cardiomyopathy co-occurred in 10
patients (4 within 21 d); without
additional review, authors noted 90
clozapine-related cases reported in the
same database
Myocarditis, Detected a signal for association between
cardiomyopathy clozapine and myocarditis or
cardiomyopathy that was stronger than
with other antipsychotics
Myocarditis Sample included 153 patients treated
with clozapine and 389 patients treated
with other antipsychotics; only 1 patient
had myocarditis
LV dysfunction Slow titration of 25-mg increases weekly
to 100 mg
Findings suggested subclinical LV
impairment without clinical
manifestations; mean heart rate increased
significantly
No significant changes in laboratory
values assessed
Eosinophil count increased
nonsignificantly
Troponin I and BNP were undetectable or
within the reference
CRP increased only slightly
Myocarditis, Clozapine was started in 159 patients
cardiomyopathy (71.3% were male; median age, 32 years)
Baseline echo in 73% of patients; ≥1
follow-up echo in 65%
Myocarditis was identified in 3 patients
and clinically suspected before echo
LVEF decreased from 60% to 40% after 2
years in 1 asymptomatic patient
21
Comments and recommendations
Obesity is a risk factor for heart failure;
use of any antipsychotic leading to weight
gain may independently contribute to the
risk
No specific monitoring recommended
Potentially higher incidence of
myocarditis and cardiomyopathy in
Australian patients
Prospective studies are required to justify
the use of routine laboratory or
radiographic tests
No specific monitoring recommended
Clinicians should have a high degree of
awareness when symptoms are
suggestive of myocarditis or
cardiomyopathy
No specific monitoring recommended
Prospective studies are needed to
establish definitive risks
Stringent monitoring for symptoms with
regular ECGs recommended by drug
companies
Routine monitoring of echo changes and
troponin/cardiac biomarkers, while useful
in many cases, is expensive and
cumbersome
No specific recommendations for
monitoring discussed
Single case of myocarditis started with an
initial dose of 200 mg and resolved after
withdrawal of clozapine
Specific
myocarditis/cardiomyopathy-related
monitoring during the study:
Baseline and weekly: vital signs, CBC with
diff
Baseline and at 4 weeks: ECG, echo
Week 3: CRP, troponin I, BNP
Week 4: clozapine serum level
Biomarkers were not related to early LV
dysfunction; more study is needed to
determine the importance of subclinical
LV dysfunction
Routine echo is not helpful in screening
for clozapine-associated myocarditis and
should be reserved for confirmatory
testing
CRP and troponin monitoring may
augment clinical monitoring in the first
month
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22 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30
Table 2 (continued)
Source, year Design
Murch et al., 2013a Retrospective study (2002–2009)
investigating the use of echo to assess
cardiac function and frequency of
abnormal findings in patients starting to
take clozapine
Serrano et al., 2014 Prospective, observational study
(2007–2011) assessing the frequency of
cardiomyopathy in patients treated with
clozapine or any other antipsychotic
Wehmeier et al., 2004 Retrospective study reviewing charts of
pediatric and young adult patients
prescribed clozapine to identify cases of
clozapine cardiotoxicity
Patients had weekly visits for 18 weeks
and then monthly; CK, LDH, AST, CBC with
diff, vital signs, and physical problems
were assessed; ECGs were periodically
assessed
Youssef et al., 2016 Retrospective study (2000−2011)
determined cases of myocarditis or
cardiomyopathy using predefined case
definitions
Pai and Vella, 2012 Retrospective study (2001−2010) to
investigate a patient database for reasons
for discontinuing clozapine
Reinders et al., 2004 Retrospective study (1999–2002) to
identify cases of myocarditis or
cardiomyopathy with reevaluation by
multidisciplinary panel
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Type of Results Comments and recommendations
cardiotoxicity
reported
Myocarditis, Baseline echo was performed in 89 of 122 With the estimated 0.22% incidence, the
cardiomyopathy patients (73%); 79 (65%) had ≥1 follow-up cost of echo screening at baseline and at 6
echo; only 13 (11%) had echo at the months would be about $160,000 per case
recommended 6-month follow-up after of clozapine-associated cardiomyopathy
starting clozapine (ie, per Australian detected; using another study's estimate
guidelines) of 0.05%, the cost would be about
Of 79 patients with follow-up echo, 6 fit $700,000
predefined study criteria: LVEF b50% and Echo should be mandatory at baseline but
N5% decrease from baseline (only 1 case not at the previously recommended
over 453.84 patient-years was believed to follow-up at 6 months
be secondary to clozapine; estimated Echo at 6 months is not helpful for
incidence, 0.22%) myocarditis screening, and more weight
Myocarditis developed in 3 patients should be placed on clinical monitoring
before follow-up echo and laboratory investigations within the
first month
Cardiomyopathy Patients treated with clozapine (n = 125) Recommended a need for additional
or any other antipsychotic (n = 59) for ≥3 studies to define risk factors and establish
months were identified tests that could result in early recognition
No cases of cardiomyopathy were of cardiomyopathy
diagnosed by a cardiologist who assessed No specific recommendations for
physical symptoms, echo, and ECG monitoring discussed beyond reiteration
Marginally abnormal LVEF (50%–55%) and of previous published recommendations
grade I diastolic dysfunction were similar
between groups
Minor valve abnormalities and small
pericardial effusions were more frequent
in patients not taking clozapine
Myocarditis, Patients (n = 36) were identified and Early detection of subclinical cases is
cardiomyopathy, followed for an average of 7.5 months; important
pericarditis N66% had ≥1 abnormalities in parameters Clinical symptoms, troponin I, CK, LDH,
investigated: eosinophilia (66.7%), AST AST, ECG, and echo would ensure safety
elevation (58.3%), CK elevation (52.7%), (no specific monitoring schedule
fever (41.7%), and ECG abnormalities described)
(25%) Recommended discontinuing use of
No cases of myocarditis, cardiomyopathy, clozapine if a cardiac-related event occurs
or pericarditis
Myocarditis, After assessing patient charts (n = 129), 5 No specific recommendations for
cardiomyopathy cases of myocarditis (3.88%) and 6 cases monitoring discussed
of cardiomyopathy were reported Concomitant SSRI use requires future
Myocarditis: mean onset, 19.4 d (range, study
14–28 d); presentation was variable; SSRI No cases were prescribed valproate
use was identified as increasing the risk Clozapine use was continued in 2 patients
6-fold with cardiomyopathy
Cardiomyopathy: mean onset, 12 months Authors called for a mandatory
(range, 8–66 months); significant monitoring protocol for
reduction in LVEF in all patients (mean, clozapine-induced cardiotoxicity
−17.5%) but 4 improved after cessation
Various Of patients in the database (n = 151), No specific recommendations for
“cardiac complications” accounted for monitoring discussed
14.3% of the clozapine discontinuations
Myocarditis, Cases of myocarditis (n = 8) were The panel agreed that increased
cardiomyopathy concluded to be highly probable (n = 3), monitoring should include baseline echo,
probable (n = 3), or possible (n = 2) inflammatory markers, storage of serum if
No patient had preexisting cardiac needed for future testing, low threshold
conditions for follow-up ECG, and troponin studies,
Mean onset of symptoms: 14.4 d (range, especially during the first 8 weeks
11–18 d) Suggested that if myocarditis does not
ECG findings were abnormal in 8 patients result in severe medical consequences, a
Abnormal echo findings with clinical rechallenge with close monitoring is
symptoms of heart failure were present in reasonable (1 patient had a successful
highly probable cases, low-normal EF in rechallenge); hospitalization, patient
probable cases, and normal EF in possible consent, collaboration with cardiology
cases services, and slower titration would be
All patients had elevations in CRP, ESR, prudent for a rechallenge
eosinophil count, and detectable
troponins
In 1 patient with a possible case, clozapine
was continued after diagnosis
In 1 patient, cardiomyopathy was
diagnosed; this patient died suddenly
while hospitalized after 161 d of clozapine
treatment; baseline ECG, echo, and stress
test were normal
 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30
Table 2 (continued)
Source, year Design
Ronaldson et al., 2010 Retrospective study (1999–2008)
assessing diagnostic characteristics of
clozapine-induced myocarditis
Ronaldson et al., Retrospective study (1994–2009)
2011a comparing patients who had
clozapine-induced myocarditis with
controls taking clozapine for ≥45 d to
develop a monitoring protocol
Ronaldson et al., Retrospective study (1996–2009)
2011b comparing fatal cases of
clozapine-induced myocarditis with
nonfatal cases
Ronaldson et al., Case-control study (1993–2009)
2012b assessing risk factors for myocarditis
Rostagno et al., 2011b Prospective, open-label study
(2006–2007) assessing serum NT-proBNP
and echo for diagnosing subclinical
cardiotoxicity (excluded patients with
comorbidities, BMI N35 kg/m2, or age N 50
years)
Rostagno et al., 2012 Follow-up study of Rostagno et al., 2011a
with repeated NT-proBNP and echo at 3
and 12 months
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Type of Results
cardiotoxicity
reported
Myocarditis Patients (n = 38) who met case definition
for myocarditis were evaluated; onset was
14–22 d after clozapine initiation in 36 of
38 cases
No clinical symptoms of myocarditis were
found in 2 patients (1 died)
Clinical presentation was highly variable;
16 patients did not have chest pain;
troponin I or T was elevated in 31 patients
and ECG showed abnormalities in 29;
elevated eosinophil count, CK-MB, and
ESR were less commonly noted;
eosinophilia that did occur was often
delayed after a diagnosis of myocarditis
Myocarditis Patients (n = 75) with clozapine-induced
myocarditis were included: 9 patients
died; 83% of cases occurred within the
first 21 d of exposure
Authors described a general pattern for
the clinical course: mild increases of HR,
then onset of nonspecific symptoms at
10–19 d, then moderate increase of HR,
and then up to a 5-d delay in elevated
troponin and CRP, with decreased blood
pressure and chest pain, and nonspecific
ECG changes with LV impairment noted
on echo
No symptoms in 6 patients; 5 patients
with mild cases continued clozapine with
transient signs and symptoms but no
cardiac injury
Troponin N2× ULN; CRP N100 mg/L;
CK-MB N ULN; chest pain; fever N38 °C;
SBP b 100 mmHg occurred less commonly
or did not occur in controls
Myocarditis Fatal cases (n = 10) had a greater
percentage of individuals (60%) with BMI
N30 kg/m2 vs 26% nonfatal cases (n = 66)
(P = .025); patients who died received
clozapine for a longer mean (range)
duration, 20.8 (14–33) d vs 17 (10–26) d
(P = .0057)
There was no difference in mean dose,
percentage of patients prescribed
valproate, age, or sex
Myocarditis Cases (n = 105) were compared to
controls (n = 296) with a multivariate
analysis
Rate of titration (each additional 250 mg
administered in the first 9 d; OR, 1.26)
and use of concomitant valproate (OR,
2.59) each successive decade of life (OR,
1.31) were reported to be significant risk
factors
Cardiomyopathy Included 38 patients (mean age, 34.8
years) with long-term (mean, 66 months)
clozapine therapy (mean dose, 296 mg at
the time of blood sample)
LVEF 50%–55% in 12 patients; LVEF b50%
in 2; LVEF b30% in 1
Only 2 patients had NT-proBNP above
ULN, but AUC indicated that NT-proBNP of
31.9 pg/mL was a good predictor of LV
dysfunction
Cardiomyopathy Included 38 patients (mean age, 34.8
years) with long-term (mean, 66 months)
clozapine therapy (mean dose, 296 mg at
the time of blood sampling)
Baseline: 91.6% sensitivity to exclude LVEF
b55% and NT-proBNP b62 pg/mL
Follow-up: 1 patient with
cardiomyopathy at baseline was
excluded; in 33% of patients with LVEF
N56%, LVEF decreased to b55% at 1 years;
23
Comments and recommendations
Eosinophil count should not be used for
diagnosis of myocarditis
CRP may be an early indicator of
developing myocarditis; a CRP N50 mg/L
or fever should result in closer
monitoring, including daily ECG and
troponins
Improved diagnosis with troponin, CRP,
and ECG at baseline and at 7, 14, 21, and
28 d
Clozapine should be discontinued with
elevated troponin or new ECG
abnormality
Authors recommended a specific
monitoring guidelines:
Echo: baseline
CRP, troponin: baseline and days 7, 14, 21,
and 28
Vital signs: at least every 48 h for the first
28 d
Continue clozapine with daily troponin,
CRP, and clinical monitoring if signs or
symptoms of unidentified illness, or HR
N119 bpm or increases N30 bpm, or CRP
50–100 mg/L, or troponin ≤2 ULN
Stop clozapine (and seek cardiology
consultation/follow-up echo) if troponin
N2 ULN or CRP N100 mg/L
Eosinophil count is unreliable; sensitivity
of ECG for myocarditis is low
Recommended routine monitoring that is
not conditional on clinical symptoms but
is intensified with physical illness in the
first 4 weeks of clozapine exposure
Although myocarditis did not develop in
some patients who were concomitantly
prescribed valproate or underwent a more
rapid titration, it was recommended to
slowly titrate clozapine and avoid
valproate during initiation
Larger studies are needed to confirm
results from this study, but NT-proBNP
N31.9 pg/mL might be an indication for
echo monitoring and allow for early
intervention such as β-blockers or ACEI
Variation of the conclusion from 2011
study; NT-proBNP N62 pg/mL might be an
indication for echo monitoring and allow
for early intervention, such as β-blockers
or ACEI
(continued on next page)
24 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30

Table 2 (continued)

Source, year Design Type of Results Comments and recommendations

cardiotoxicity
reported

patients with LVEF b55% had a greater

Tirupati, 2006 Retrospective study (2001–2004)
assessing for cardiac complications
resulting in discontinuation of clozapine
Winckel et al., 2015 Retrospective study (2005–2013)
reviewing reported cases of myocarditis
Chow et al., 2014 Prospective, open-label study assessing
patients treated with clozapine for N1
year, any other antipsychotic for N1 y, or
controls without schizophrenia and not
receiving antipsychotics
Montastruc et al., French Pharmacovigilance Database study Cardiomyopathy
2010 (1990–2007) looking at reported cases of
drug-induced cardiomyopathy
Kidd et al., 2013 Retrospective review (2000–2008)
exploring the long-term cardiac
complications of clozapine
Vaddadi et al., 2003 Prospective comparison of selenium
levels in patients treated with clozapine
and patients with schizophrenia not
treated with clozapine, patients with
mood disorder, and healthy controls
Kropp et al., 2005 Prospective, open-label study assessing
NT-proBNP levels after initiation of a new
antipsychotic
Hill and Retrospective study assessing a New
Harrison-Woolrych, Zealand monitoring database
2008 (2000–2007)
Khan et al., 2017 Prospective follow-up study (2009–2015)
assessing discontinuation of clozapine,
NT-proBNP compared to those with LVEF
N 56% (P = .0036)
Not specified Of 143 patients starting to take clozapine,
7 stopped it because of cardiac
complications
Myocarditis and cardiomyopathy were
confirmed in 4 of these patients; all cases
occurred within the first 7 weeks of
clozapine initiation; all patients were
male, and 3 were younger than 25 years
Myocarditis In review of medical records for 20
patients, 13 did not meet the authors'
definition for myocarditis; 17 had
increased troponin, but other diagnostic
parameters were not reported or not
conducted
ECG abnormalities only were reported for
12 patients, fever for 12, and HR N 100
bpm for 11
URI in 5 patients was a confounder
Cardiomyopathy Patients taking clozapine (n = 100) had
lower LVEF (58.3%) compared to patients
not taking clozapine (62.2%) and patients
without schizophrenia (64.8%) (P b .001)
LVEF b50% in 9 patients (9%) in the
clozapine group and in 0 patients in other
groups (P = .19)
Neutrophil count and HDL were
independently associated with the degree
of LV dysfunction, but other biochemical
markers were not
Of 258,729 ADR reports, 47 cases of
cardiomyopathy were reported; of those,
866 were related to clozapine with 4
clozapine-associated cardiomyopathy
cases; reporting OR 18.9 (95% CI,
6.9–52.2) (P b .01)
Various Included 25 patients (mean age, 39 years)
who were taking clozapine for an average
of 6.5 years (range, 1–13.5 years)
All patients had ≥1 echo and ECG annually
Cardiomyopathy developed in 3 patients
6, 7, and 9 years after beginning to take
clozapine; 2 patients died suddenly with
no cause determined at 14 months and
11.5 years of clozapine use
Not specified Selenium levels in patients treated with
clozapine (n = 54) were significantly
lower than in patients with schizophrenia
not treated with clozapine (n = 41),
patients with mood disorder (n = 36),
and healthy controls (n = 56)
Not specified NT-proBNP levels varied with age, sex,
and drug administered; 1 group, which
contained patients taking quetiapine,
olanzapine, or clozapine, was the only
group with increased NT-proBNP levels
from day 0 to day 7
Myocarditis Reported on 25 patients (84% male; mean
age, 35.5 years); 2 died
Dosage was documented for 20 patients
(mean, 256 mg)
Time to onset was documented for 24
patients (mean, 1 months) (onset
occurred at N1 year for 3 patients and at
N9 years for 1 patient)
Cardiomyopathy occurred in 3 patients
Myocarditis (and All patients were followed with a
SCD) standardized monitoring protocol
Monitoring for cardiac complications may
require mandatory screening, especially
within the first 2–3 months
Review of cases found inconsistent and
likely suboptimal monitoring
When myocarditis is suspected, an
accurate diagnosis is crucial to avoid
inappropriate discontinuation of
clozapine
Clinical evaluation of ECG and echo are
routinely conducted at baseline, 3
months, 1 year, 2 years, 4 years, and 10
years after starting clozapine; if
dysfunction or declining function, the
approach should be individualized
NT-proBNP, troponin T, and CRP were not
independent predictors of LV function
using a multivariate analysis
Demonstrated a signal that clozapine may
contribute to the development of
cardiomyopathy and should be more
formally studied
There is a need for agreement on
monitoring protocols; authors advocated
for cardiac investigations every 6 months
but annually at a minimum
Deficiency of selenium is implicated in the
pathophysiology of cardiomyopathy and
myocarditis
Further study is required to determine the
use of monitoring selenium levels or
providing selenium supplementation to
reduce the risk of clozapine-associated
cardiac toxicity
Larger studies are needed to assess
whether NT-proBNP levels can be used to
identify high-risk patients for
cardiovascular adverse events related to
antipsychotics; NT-proBNP may be a more
accurate maker of early cardiac
dysfunction than BNP
No specific recommendations
Baseline measurements: weight, blood
pressure, glycemic control, ECG, echo, and

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 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30 25

Table 2 (continued)

Source, year Design Type of Results Comments and recommendations

cardiotoxicity
reported

all-cause mortality, incidence of sudden
death, incidence of myocarditis, and time
to myocarditis
Prisco et al., 2016 Prospective, open-label assessment of
BNP monitoring in clozapine patients
Hagg et al., 2001 Retrospective study assessing adverse
reactions submitted to the Swedish
Adverse Drug Reactions Advisory
Committee (1983–1999)
(baseline and regular ECG, echo, CBC, and troponin
clozapine serum levels) Patients taking clozapine require regular
Definition of myocarditis: increased assessment of LV function
troponin level and LV dysfunction on Safety of rechallenge as a treatment
echo; of 503 patients followed (mean, 9 option remains unknown
years), myocarditis developed in 14 (3%)
in a mean (SD) of 15 (7) d
All patients with myocarditis
discontinued use of clozapine
One retrial (after 4 years of LVEF
recovery) was conducted, but myocarditis
recurred within 7 d and required ICU
management
SMI, DM, epilepsy, and smoking were
predictors of sudden death (n = 10; 2%);
2 autopsies reported findings of
myocarditis
Cardiac Patients (n = 2) with schizophrenia Baseline measurement of NT-proBNP
dysfunction, began taking clozapine but stopped concentrations early in clozapine
pericarditis because of presentation and/or findings exposure is promising for detecting
First patient was asymptomatic but with cardiovascular side effects, especially
CRP 16.9 mg/dL, NT-proBNP 1004 pg/mL, when the patient is asymptomatic
and troponin 0.14 ng/mL, and an echo was
suggestive of cardiac tamponade
Second patient had tachycardia,
subjective chest pain, progressive
shortness of breath, and dyspnea with
CRP 10.5 mg/dL and NT-proBNP 164.1
pg/mL
Cardiac toxicity Identified 8 patients with myocarditis Early detection of myocarditis and
(mean age, 33 years; 75% male; mean discontinuation of clozapine are prudent,
dose, 291 mg; range of onset, 3 d to 20 and corticosteroids should be considered
months)
Of the 8, 3 died
Presentation was variable, but many
involved fever and tachycardia; 2 patients
had severe symptoms of HF and were also
treated with corticosteroids
Resolution, when it occurred, was at days
4–14

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ADR, adverse drug reaction; AST, aspartate aminotransferase; AUC, area under the curve; BMI, body mass index; BNP, brain
natriuretic peptide; bpm, beats per minute; CBC, complete blood cell count; CK, creatine kinase; CK-MB, creatine kinase MB; CRP, C-reactive protein; diff, differential count; DM, diabetes
mellitus; ECG, electrocardiography; echo, echocardiography; EF, ejection fraction; ESR, erythrocyte sedimentation rate; FDA, US Food and Drug Administration; HDL, high-density lipopro-
tein; HF, heart failure; HR, heart rate; ICU, intensive care unit; LDH, low-density lipoprotein; LV, left ventricular; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain
natriuretic peptide; OR, odds ratio; SBP, systolic blood pressure; SCD, sudden cardiac death; SMI, silent myocardial ischemia; SSRI, selective serotonin reuptake inhibitor; ULN, upper limit
of normal; URI, upper respiratory infection; WHO, World Health Organization.

3.2. Original research reports
Thirty-one original research studies were identified (Table 2). Many
were a retrospective review of an adverse event database (Coulter et al.,
2001; Haas et al., 2007; Hagg et al., 2001; Hill and Harrison-Woolrych,
2008; Kelly et al., 2009; Kilian et al., 1999; La Grenade et al., 2001;
Montastruc et al., 2010). Those studies highlighted the need for routine
monitoring but rarely presented compelling data for recommending a
specific monitoring strategy. One study noted that the routine monitor-
ing of echocardiographic changes and cardiac biomarkers, while often
useful, is expensive and cumbersome (Haas et al., 2007). Only 1 study
specifically examined the costs associated with cardiac monitoring:
The estimated cost to detect 1 case of cardiomyopathy (reported inci-
dence, 0.05%–0.22%) would be $160,000 to $700,000 (Murch et al.,
2013a). More consistently, authors recognized the lack of routine car-
diac screening and recommended baseline echocardiography but did
not specify the frequency of follow-up testing (Curto et al., 2015; Kidd
et al., 2013; Reinders et al., 2004; Tirupati, 2006; Wehmeier et al.,
2004; Winckel et al., 2015). Follow-up echocardiography at 2 to
6 months is not helpful for detecting myocarditis because it is outside
the usual window of occurrence, and clinical monitoring should be
emphasized instead (Murch et al., 2013a; Murch et al., 2013b). One
study noted the considerable cost and low yield of a protocol that rec-
ommended echocardiography at baseline and 6 months (Murch et al.,
2013b). Baseline echocardiography (with or without follow-up) was re-
ported in other studies as well (Khan et al., 2017).
Of the cardiac biomarkers, troponins I and T were more commonly
recommended over CK-MB. Assessment of elevated CRP was the other
most commonly reported baseline screening recommendation.
Ronaldson et al. (2010) suggested that a CRP N50 mg/L or the presence
of fever should prompt close monitoring of the ECG and troponin levels
to detect myocarditis. Their final recommendation was to monitor CRP,
troponins, and ECG at baseline and at weeks 1, 2, 3, and 4 to improve de-
tection. Additionally, in that study of patients with myocarditis, CK-MB
and ESR were less commonly elevated, and eosinophilia was delayed or
absent. A subsequent study by Ronaldson et al. (2011a) led to the devel-
opment of a formalized monitoring protocol that is now commonly
cited. In that study, the authors confirmed that eosinophilia was unreli-
able and the sensitivity of the ECG for myocarditis was low. Their proto-
col recommends baseline echocardiography and weekly monitoring of
CRP and troponin. Clozapine is discontinued if the troponin level is
more than twice the upper limit of the reference range or the CRP

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26 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30

level exceeds 100 mg/L. The combination of these laboratory tests had
an estimated sensitivity of 100% for symptomatic clozapine-induced
myocarditis. The level of NT-proBNP has been measured in screening
for cardiovascular side effects in asymptomatic patients and as an indi-
cation for echocardiography (Kropp et al., 2005; Prisco et al., 2016;
Rostagno et al., 2011a; Rostagno et al., 2012). However, while mild left
ventricular dysfunction is common in patients prescribed clozapine,
NT-proBNP and other biomarkers (eg, CRP and troponin) were not asso-
ciated with left ventricular function and should not replace echocardi-
ography (Chow et al., 2014; Curto et al., 2015).
Several studies also attempted to describe risk factors for clozapine-
induced myocarditis or cardiomyopathy. Reported risk factors for myo-
carditis include rapid titration, initiating clozapine at a high dose, older
age, and exposure to concomitant valproate or selective serotonin reup-
take inhibitors (Baptista et al., 2016; Ronaldson et al., 2012b; Youssef et
al., 2016). Age, sex, concomitant valproate use, and dose did not affect
mortality after the development of myocarditis (Ronaldson et al.,
2011b; Serrano et al., 2014). Independent risk factors for cardiomyopa-
thy that might influence monitoring include selenium deficiency, obe-
sity, and heavy alcohol use (Kelly et al., 2009; Vaddadi et al., 2003).
Available research reports were limited by the fact that less than
one-third were prospective studies, and those were of limited sample
size. They generally lacked external validity given the frequent exclu-
sion of those with cardiac risk factors, hypertension, diabetes mellitus,
substance use, and obesity. Few studies focused on the impact of mon-
itoring parameters, or were able to make specific recommendations
based on study findings. Long-term outcomes related to monitoring
were not studied. While retrospective studies were larger, the recom-
mendation for baseline echocardiography was limited by recognition
of a need for higher quality studies.
3.3. Commentary and other reports
Eight letters were included (Table 3). All publications but 1 were
commentaries about prior articles on extensive monitoring for cloza-
pine-associated myocarditis or cardiomyopathy (Committee on Safety
in Medicines, 1993; de Leon et al., 2015; Degner et al., 2000;
Devarajan et al., 2000; Ellis and Cameron, 2012; Freudenreich, 2015;
Ronaldson et al., 2015b; Warner et al., 2000). One author suggested
using eosinophil cationic protein to identify eosinophilic reactions
when the eosinophil count is normal (Devarajan et al., 2000). To explain
the increased risk in Australian regions, several authors suggested a ge-
netic predisposition or influences from ozone concentrations (de Leon
et al., 2015; Devarajan et al., 2000; Warner et al., 2000). Other authors
presented cost concerns associated with required monitoring that may
prohibit the use of clozapine (Ellis and Cameron, 2012; Freudenreich,
2015).
While commentaries and letters generally do not have a major im-
pact on practice, they are useful forums for clinicians to share hypothe-
ses, viewpoints, and practical points related to clozapine-induced
myocarditis and cardiomyopathy. As more hospitals and health systems
increase awareness of these cardiac adverse events, clinical practice

Table 3
Commentary and other reports.

Source, year Referent Clinical recommendations

publication, year

Devarajan et al., 2000
Warner et al., 2000
de Leon et al., 2015
Freudenreich, 2015
Ellis and Cameron, 2012
Ronaldson et al., 2015b
Degner et al., 2000
Committee on Safety
in Medicines, 1993
Kilian et al., 1999
Kilian et al., 1999
Ronaldson et al., 2015a
Ronaldson et al., 2015a
Ronaldson et al., 2011a
Ronaldson et al., 2012b
Kilian et al., 1999
NA
Authors commented on possible mechanism of clozapine-associated myocarditis (poor metabolism, M2
muscarinic receptor antagonism enhancing myocardial toxicity, rapid titration, and high ozone concentration in
Australia)
Suggested using eosinophil cationic protein to identify eosinophilic reactions when eosinophil count is normal
and using corticosteroids and discontinuing clozapine if results are abnormal
Authors commented on the unusually high incidence of myocarditis in an Australian population as indicating a
possible genetic susceptibility or environmental exposures
Authors suggested that the high incidence of myocarditis should not be extrapolated to the rest of the world given
the small number of cases in the Australian data, and they presented data from numerous studies supporting the
statement that worldwide alarm is not warranted
Recommended slow titration to enhance safety
Author commented on the concern about “unrealistic and unsupported” screening recommendations that may
deter from clozapine use in areas with limited resources
Monitoring recommendations in addition to clinical monitoring and vital signs:
CRP or ESR and troponin or CK for weekly monitoring
ECG (to compare to baseline) and cardiac enzymes if myocarditis is suspected
Awareness that eosinophilia may indicate subclinical myocarditis
Assess serum clozapine levels
Titrate clozapine by 25 mg every 3–4 d for outpatients
Minimize use of other psychotropic medication
Patient and family education
Baseline echo is not necessary and would be a financial burden
Agreed to vital signs, troponin, and CRP at baseline and weekly for 4 weeks. to facilitate early diagnosis of
myocarditis
Ronaldson et al., 2012a replied that baseline echo improves the reliability of diagnosing myocarditis, reduces
unnecessary discontinuation of clozapine (if preexisting LV dysfunction existed), and helps to more readily detect
cardiac disease warranting treatment
Analysis from a previous case-control study:
In 90% of patients, eosinophil count does not exceed ULN at onset of myocarditis but peaks 7–8 d after clozapine
withdrawal
Troponin values varied widely, but in 30% of patients, troponin was N1 μg/L; all values rapidly normalized after
clozapine discontinuation
CRP generally increases 3 d before troponin value increases and well before eosinophil count increase
Recommended ECG weekly in the first 4 weeks of clozapine therapy or with dose increases or unexplained fever
Brief report mentioned 3 fatal cases of clozapine-associated myocarditis
Highlighted that confirmatory testing of myocarditis cannot always be completed, and clozapine should be
stopped when there is clinical suspicion

Abbreviations: CK, creatine kinase; CRP, C-reactive protein; ECG, electrocardiography; echo, echocardiography; ESR, erythrocyte sedimentation rate; LV, left ventricular; NA, not applica-
ble; ULN, upper limit of normal.

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 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30 27

may shift as protocols are implemented based on expert consensus and
literature review.
3.4. Case reports and case series
Seventy-eight publications of cases or case series were identified,
representing 96 patients having clozapine-induced myocarditis (n =
78) or cardiomyopathy (n = 18) (Supplementary Table). Preemptive
monitoring was not common despite many authors concluding that car-
diovascular monitoring is crucial in the first 4 weeks to detect myocar-
ditis and that monitoring for cardiomyopathy should be ongoing. The
protocol developed by Ronaldson et al. (2011a) was frequently men-
tioned, but overall there was no clear consensus for adopting these rec-
ommendations. When specific monitoring was endorsed, it included a
baseline clinical examination and review of the patient's medical and
family history. Baseline ECG was often recommended, but the interval
for follow-up testing was inconsistent. The most commonly recom-
mended laboratory tests were for troponins I or T and CRP to be checked
weekly for the first 2 to 4 weeks. If troponin monitoring is not available,
CK-MB was recommended as an alternative test. Eosinophil count and
ESR were considered less reliable. Chest radiography was reported to
be unremarkable in many myocarditis cases. Conflicting recommenda-
tions for the use of echocardiography for monitoring myocarditis and
cardiomyopathy ranged from using it only in patients with clinical
symptoms to using it at baseline, then monthly for 6 months, and
then yearly.
Several cases of clozapine-induced myocarditis describe initial titra-
tion rates that were faster than the usually recommended 12.5- to 25-
mg daily increases (Cook et al., 2015; Fineschi et al., 2004). Additionally,
in 2 cases patients had been prescribed clozapine for 10 years and were
then rapidly reexposed to high doses with subsequent onset of myocar-
ditis (Baptista et al., 2015; Smith et al., 2014). It is therefore plausible
that slow initial titration and retitration may mitigate the risk of
myocarditis.
In case reports and case series, rechallenge was generally not recom-
mended but could be addressed on an individual basis. When
rechallenging a patient after a diagnosis of myocarditis or cardiomyop-
athy, the clear consensus was for more vigilant preemptive monitoring
with laboratory tests, ECG, and echocardiography. Slower titration is
also warranted. Of 14patients rechallenged after myocarditis, 6 had re-
currence. Of 2 patients rechallenged after cardiomyopathy, 1 required
discontinuation owing to dyspnea and pulmonary congestion.
While case reports and series have limitations, they represent the
bulk of published work on clozapine-induced myocarditis and cardio-
myopathy. They also capture the heterogeneity of the illness, which is
a good reminder to clinicians to consider myocarditis or cardiomyopa-
thy even when only mild symptoms are present. Clinicians should con-
tinue to report cases of clozapine-induced cardiomyopathy and
cardiomyopathy with enhanced attention to rate of titration, concomi-
tant medications, radiographic findings for cardiomyopathies, and
whether a monitoring plan was used.
4. Discussion
This systematic review collated the literature published on cloza-
pine-associated myocarditis and cardiomyopathy and assessed the evi-
dence supporting preemptive monitoring. In total, 27 review articles, 31
research reports, 8 letters, and 78 case reports and case series were
reviewed. An increasing number of publications have raised awareness
of clozapine-induced myocarditis and cardiomyopathy. However, there
are no specific recommendations for myocarditis and cardiomyopathy
monitoring in FDA-approved clozapine drug labels or the REMS pro-
gram. Thus, clinicians must develop a systematic way of detecting
signs and symptoms of myocarditis and cardiomyopathy while com-
pleting required adverse-event monitoring (Table 4). A comprehensive
review of all clozapine-related monitoring parameters is beyond the
scope of this article but has been addressed in recent reviews
(Citrome et al., 2016; Remington et al., 2016).
Myocarditis is not well defined clinically. Its heterogeneous nature
makes any potential manifesting signs and symptoms important to rec-
ognize (Citrome et al., 2016; Layland et al., 2009). Common symptoms
reported with myocarditis include dyspnea, palpitations, tachycardia,
fever, fatigue, and chest pain. Even nonspecific physical symptoms
such as malaise, diarrhea, headache, and neck pain should heighten sus-
picion of an emerging clozapine-induced myocarditis (Citrome et al.,
2016). Recognition of these symptoms is especially important within
the first 21 days after initiation of clozapine when the risk is greatest, al-
though myocarditis may develop at any point during treatment. A com-
prehensive guide to management of myocarditis is outside the scope of
this article, but clinicians should take into account the severity of symp-
toms, the patient setting (ie, inpatient vs outpatient), and access to
medical services to guide treatment plans when myocarditis is
suspected. Any suspicion should result in holding clozapine, obtaining
a primary care/cardiology consultation, and/or referral to the emer-
gency department.
Cardiomyopathy may be a consequence of myocarditis, and thus the
2 drug-induced illnesses are related. Even many years later, cardiomy-
opathy can develop in patients after a full recovery from myocarditis.
However, it is unknown whether asymptomatic myocarditis affects
the risk of cardiomyopathy (Sagar et al., 2012). In general, literature

Table 4
Myocarditis and cardiomyopathy monitoring for patients receiving clozapine.

Feature Myocarditis Cardiomyopathy

Usual onset Acute: greatest risk in first 2 months with peak occurrence during Insidious: commonly detected after at least 6 months of therapy
third week of therapy
Can occur anytime
Presenting signs Heterogeneous and nonspecific: malaise, sweating, tachycardia, Signs and symptoms of heart failure: shortness of breath, cough,
and symptoms chest pain, palpitations peripheral edema, chest pain, persistent tachycardia
Routine monitoring Frequent assessment of clinical presentation Frequent assessment of clinical presentation
parameters Vital signs, especially new tachycardia or increases in heart rate N Vital signs
10–20 beats per minute Cardiology consultation warranted for known cardiac disease,
CRP and troponin with any possible sign/symptom of myocarditis, structural abnormalities, or other cardiac risk factors
especially in the first 8 weeks after initiation
Consider CRP and troponin monitoring in asymptomatic patients
during first 8 weeks of therapy
Laboratory or radiographic Eosinophil count may be elevated but is nonspecific No specific/routine laboratory measures recommended
abnormalities Troponins plus CRP elevations are highly specific and sensitive in Echocardiography with LV dysfunction, dilation, or hypertrophy
symptomatic patients
Nonspecific electrocardiographic changes
Echocardiography with LV dysfunction or hypertrophy
Cardiac MRI for confirmation

Abbreviations: CRP, C-reactive protein; LV, left ventricular; MRI, magnetic resonance imaging.

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28 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30
reports suggest that cardiomyopathy develops much later after cloza-
pine initiation (ie, 8 months) than does myocarditis. Given the more in-
sidious onset of cardiomyopathy, it is plausible that many early signs
and symptoms go unreported or undetected. Importantly, asymptom-
atic clozapine-induced cardiomyopathy has been reported (Layland et
al., 2009). Signs and symptoms indicative of cardiomyopathy include fa-
tigue, shortness of breath, chest discomfort, persistent tachycardia, or
peripheral edema. Overall, clozapine-induced cardiomyopathy is not
well characterized in the literature. The most common type of cloza-
pine-induced cardiomyopathy (when reported) is a dilated cardiomy-
opathy, while many reports simply describe a reduced ejection
fraction. Similar to monitoring for myocarditis, vigilant clinical monitor-
ing for cardiomyopathy is crucial to avoiding potentially fatal outcomes.
This review showed that while the tests for confirming myocarditis
and cardiomyopathy are generally agreed upon, preemptive screening
for these drug-induced conditions is controversial. Unlike the standard-
ized process for monitoring ANC values, standardized monitoring in the
United States to reduce these potentially fatal cardiac adverse effects
does not exist, and some authors expressed concern that implementa-
tion of such a program may increase barriers to use of clozapine. This
is an important consideration given that clozapine may be underused
and not prescribed because of practice guidelines (Kane, 2012; Stroup
et al., 2014; Warnez and Alessi-Severini, 2014). The cost of monitoring
for asymptomatic patients was another concern (Murch et al., 2013a).
Whereas weekly tests for troponin and CRP during the first 4 weeks of
therapy might cost several hundred dollars, a required baseline echo-
cardiography could increase the cost to several thousand dollars. The lo-
gistics of obtaining echocardiography during an inpatient
hospitalization as well as availability in the outpatient setting would
also add barriers to clozapine initiation.
The association between myocarditis and clozapine first gained at-
tention in 1999 after Kilian et al. (1999) reported 15 cases of myocardi-
tis and 8 cases of cardiomyopathy in an Australian population. In
response, the manufacturer suggested vigilant cardiac monitoring but
did not extend this recommendation internationally. Those recommen-
dations included ECG; troponin or CK-MB at baseline, day 7, and day 14;
and an echocardiogram at 6 months (Ronaldson et al., 2011a).
Ronaldson et al. (2011a) conducted a study that focused on the early
clinical, radiologic, and laboratory findings during myocarditis, which
resulted in the creation of a monitoring protocol that has been cited
over 75 times. The protocol stresses the high risk of myocarditis within
the first 3 weeks of clozapine use and recommends echocardiography at
baseline in addition to weekly troponin and CRP monitoring for
4 weeks. Clozapine is discontinued only when CRP is N100 mg/L or
when troponin I or T is 2 times the upper limit of the reference range.
Follow-up echocardiography is conducted when myocarditis is
suspected. In symptomatic patients, the protocol had a reported sensi-
tivity of 100% to detect myocarditis when both CRP and troponin levels
were elevated. Highlighted in that study were 6 asymptomatic patients
(8%), 3 of whom died, which is arguably a reason for routine screening
for all patients beginning to take clozapine.
Published support for monitoring for clozapine-induced cardiomy-
opathy is even more scant than recommendations for monitoring for
myocarditis. Those recommendations range from performing echocar-
diography only when a patient is symptomatic to performing it as fre-
quently as yearly even in the absence of symptoms. NT-proBNP has
been studied as an early marker for cardiac toxicity and may be useful
in detecting early cardiomyopathy, but there are no clear evidence-
based recommendations for this practice.
Several reviews have compared echocardiography monitoring for
clozapine-induced myocarditis and cardiomyopathy with monitoring
before, during, and after exposure to anthracycline chemotherapeutics
owing to their known cardiac toxicity, including cardiomyopathy. How-
ever, a recent review of anthracycline monitoring noted that despite the
known toxicity, echocardiography monitoring has yielded limited out-
comes data, and contradictory guidelines exist (Levis et al., 2017).
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Additionally, the authors highlighted unintended consequences of
intensive cardiac surveillance. These include anxiety related to testing
and resultant treatment of subclinical issues without evidence for re-
ductions in heart failure or cardiac death. These concerns and unin-
tended consequences likely also apply to routine cardiac screening
for clozapine therapy. However, the authors suggested that the pres-
ence of a preexisting cardiac history would warrant base echocardiog-
raphy before anthracycline treatment. These preexisting factors
include cardiac disease, advanced age, long-standing or poorly con-
trolled hypertension, hyperlipidemia, poorly controlled diabetes
mellitus, obesity, or current smoking. These factors would encompass
a large percentage of clozapine-eligible patients. With the market
share of clozapine in the United States dropping from 11% in 1999 to
b4% in 2008, any potential practice changes posing a barrier to cloza-
pine utilization should be critically evaluated instead of universally
implemented (Kelly et al., 2018).
From this literature review, the following information can be ex-
tracted: 1) The risk of myocarditis is greatest within the first 3 weeks
after clozapine initiation. 2) ESR and chest radiography may not be ben-
eficial in routine screening for myocarditis. 3) Eosinophilia often occurs
after signs and symptoms of myocarditis develop. 4) Baseline ECG to as-
sess for a corrected QT interval is recommended before starting any an-
tipsychotic medication. A follow-up ECG after medication titration may
be warranted, but repeating ECGs at routine intervals specifically for
myocarditis monitoring is unnecessary. 5) CRP and troponin monitoring
is beneficial for symptomatic patients, but the utility of routine screen-
ing in asymptomatic patients is unknown. Cases of asymptomatic
myocarditis and cardiomyopathy have been reported. 6) Baseline echo-
cardiography is controversial, but it has been advocated to establish
baseline cardiac dysfunction and to be used for comparison if myocardi-
tis or cardiomyopathy concerns arise later.
From this information, screening for myocarditis and cardiomyopa-
thy in asymptomatic patients receiving clozapine could include the
following:
• Perform baseline ECG.
• Perform echocardiography, as a part of a cardiology consultation, to
establish baseline cardiac function in patients with known cardiac dis-
ease, structural abnormalities, or other cardiac risk factors.
• Observe a low threshold for initiating CRP and troponin monitoring,
especially during the initial 4 weeks of clozapine therapy if any signs
or symptoms suggestive of myocarditis develop, including asymp-
tomatic tachycardia or heart rate increases of 10 to 20 beats
per minute. Positive findings warrant a cardiology consultation. Neg-
ative results with symptoms suggestive of possible myocarditis sup-
port weekly CRP and troponin monitoring during the symptomatic
period. Internal medicine/cardiology consultation should be consid-
ered for persistent symptoms.
The published articles suggest the following for determining when a
rechallenge may be considered after a patient has myocarditis or cardio-
myopathy associated with clozapine:
• The decisions should involve collaboration between the psychiatrist,
cardiologist, and patient/caregiver when benefits outweigh risks. Re-
sidual morbidity from the initial cardiac insult must be considered,
as well as recognizing that patients with schizophrenia often have co-
morbidities that may affect the outcomes of a rechallenge.
• According to limited case reports, rechallenge may be successful.
• Rechallenged patients should be closely monitored for recurrence
with a stricter monitoring plan than what is proposed for most pa-
tients beginning to use clozapine. For example, monitoring strategies
during a clozapine rechallenge have included CRP and troponin mon-
itoring twice weekly (a strategy similar to that used for monitoring
ANC during a rechallenge after severe neutropenia).
 K.N. Knoph et al. / Schizophrenia Research 199 (2018) 17–30
• Retitration of clozapine should occur more gradually than the usual
recommended rate of 25 mg daily.
• Echocardiography is warranted during a rechallenge.
This review had several limitations. First, although clozapine is also
associated with other cardiovascular conditions, such as pericarditis
and polyserositis, this review focused on only myocarditis and cardio-
myopathy. Second, few publications were related to preemptive myo-
carditis screening, and they often cited the same protocol published
by Ronaldson and colleagues (Ronaldson et al., 2011a). Third, the inci-
dence of myocarditis and cardiomyopathy in Australia appears to be
greater than elsewhere in the world. Thus, research is needed at centers
outside Australia to assess whether increased monitoring leads to early
detection or reduced severity of myocarditis in both symptomatic and
asymptomatic patients.
5. Conclusions
Clinicians must continue reporting and researching cardiovascular
adverse events associated with clozapine therapy. Some published find-
ings may be interpreted by individual providers or institutions for the
purpose of implementing myocarditis and cardiomyopathy monitoring,
but monitoring efforts should account for available resources and not
create a new barrier to improving use of clozapine. Such protocols
should be created with the awareness that evidence-based, cost-effec-
tive monitoring for asymptomatic patients does not exist. Required
monitoring (eg, through an FDA REMS program) is premature until
such an evidenced-based, cost-effective protocol can be determined.
Overall, despite the controversy surrounding myocarditis and cardio-
myopathy monitoring for patients receiving clozapine, the use of labo-
ratory or radiologic tests should not preclude a thorough patient
history or vigilant clinical assessment.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.schres.2018.03.006.
Role of the funding source
This study received no funding.
Contributors
Kristen N. Knoph, PharmD, RPh: primary author contributor.
Jonathan G. Leung, PharmD, RPh: secondary author contributor.
Robert J. Morgan III, MD, PhD: content expert and review.
Kathryn M. Schak, MD: content expert and review.
Amanda C. Owen, PharmD, RPh: synthesis of reviewed data tables.
Megan R. Leloux, PharmD, RPh: synthesis of reviewed data tables.
Mayur Patel, PharmD, RPh: review of manuscript and contribution to content of
Discussion.
Brian A. Palmer, MD, MPH: content expert and review.
Conflict of interest
All authors declare that they have no conflicts of interest.
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