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Received: 17 September 2021    Accepted: 18 December 2021

DOI: 10.1111/acps.13398

S Y S T E M AT I C R E V I E W

Risk factors for clozapine-­induced myocarditis and

cardiomyopathy: A systematic review and meta-­analysis

Mark Vickers1,2,3  | Vinay Ramineni1,2  | Eva Malacova4  | Lars Eriksson5  |

Kirsten McMahon1,2  | Vikas Moudgil1,2  | James Scott1,4   | Dan Siskind2,6,7

1
Metro North Mental Health Service,
Royal Brisbane and Women’s Hospital, Abstract
Brisbane, Queensland, Australia Objective: Clozapine is the most effective medication for treatment-­refractory
2
Faculty of Medicine, University of schizophrenia, but it is associated with severe cardiac adverse events includ-
Queensland, Brisbane, Queensland,
Australia
ing myocarditis and cardiomyopathy. To aid treatment decision-­making for
3
Faculty of Health, Queensland clinicians, patients and their carers, we conducted a systematic review and meta-­
University of Technology, Brisbane, analysis to identify potential risk factors for clozapine-­induced myocarditis and
Queensland, Australia
cardiomyopathy.
4
QIMR Berghofer Medical Research
Methods: A systematic search was conducted of PubMed, Embase, CINAHL,
Institute, Brisbane, Queensland,
Australia Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and
5
Herston Health Sciences Library, cardiomyopathy among people on clozapine and potential risk factors. We cal-
University of Queensland, Brisbane, culated pooled effect sizes on risk factors using a random-­effects meta-­analytic
Queensland, Australia
6
model. Risk of publication bias was assessed using the Newcastle-­Ottawa scale.
Queensland Centre for Mental Health
Research, Brisbane, Queensland, Results: Seven studies met the inclusion criteria, of which six studies had quan-
Australia titative data included in the meta-­analysis. The odds of clozapine-­induced myo-
7
Metro South Addiction and Mental carditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled
Health Service, Brisbane, Queensland,
Australia
OR 3.58, 95% CI 1.81–­7.06), but were not significantly greater with the use of que-
tiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review
Correspondence identified conflicting results reported for increasing age and higher clozapine
Vinay Ramineni, Metro North Mental
Health Service, Royal Brisbane and dose as risk factors for myocarditis. No other factors, including genetic risk, sex,
Women’s Hospital, Brisbane, QLD 4006, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were
Australia.
associated with greater odds of myocarditis. No risk factors for cardiomyopathy
Email: vinay.ramineni@uqconnect.
edu.au were identified in the literature.
Conclusion: Concurrent use of sodium valproate increases the odds of clozapine-­
induced myocarditis. Thus, clinicians should consider the temporary cessation of
sodium valproate during the initial titration phase of clozapine.

KEYWORDS
cardiomyopathies, clozapine, myocarditis, risk factors

Mark Vickers and Vinay Ramineni shared first authorship.

© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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442    wileyonlinelibrary.com/journal/acps
 Acta Psychiatr Scand. 2022;145:442–455.
VICKERS et al.
1  |  I N T RO DU CT ION
Clozapine is the most effective medication for reducing
the positive symptoms of treatment-­refractory schizo-
phrenia and hospitalisations.1-­3 Despite its efficacy,
clozapine initiation is often delayed because of a poten-
tial side-­effect profile, which includes agranulocytosis,
sedation, hypotension, constipation, myocarditis and
cardiomyopathy.2,4-­7 Typically, myocarditis is acute and
occurs within 30  days of clozapine initiation, while car-
diomyopathies are more chronic in nature and occur
months to years later.4,7,8 Reported rates of myocarditis
are higher in Australia and New Zealand, at 2% compared
with 0.3% in the rest of the world, while cardiomyopathy
rates are 1.4% in Australia and New Zealand compared
with 0.2% elsewhere.7 This is likely related to a detection
bias because of increased monitoring for cardiac adverse
events in Australia and New Zealand.7
Clozapine-­induced myocarditis is a potentially life-­
threatening condition and reported mortality rates range
from 10% to 30%.9 While the mechanism for clozapine-­
induced myocarditis is not fully understood, it appears that
an immunoglobulin E-­mediated hypersensitivity reaction
is the predominating driver.10 Animal models demon-
strate disruption to multiple physiological processes, in-
cluding upregulation of pro-­inflammatory and cholinergic
agents, increased myocardial apoptosis, oxidative stress
and the concurrent downregulation of endogenous anti-
oxidants.10-­12 Although endomyocardial biopsy is the gold
standard diagnostic approach, this is rarely performed in
practice because of its arguably low sensitivity, technical
difficulty and the risk of adverse events such as arrhyth-
mias and bleeding.13 Rather, clozapine-­induced myocardi-
tis is typically diagnosed on a combination of clinical and
laboratory signals, including tachycardia, heart failure
signs, echocardiographic evidence, electrocardiographic
changes and elevated C-­reactive protein and troponin.14
Most centres rely on criteria and monitoring protocols de-
rived from the work of Ronaldson et al.14,15 A systematic
review of clozapine-­induced myocarditis explored clinical
signs and investigations, but did not look specifically at
risk factors.16 In recent years, several factors have been
suggested in the literature, which may increase the risk
of clozapine-­induced myocarditis, including concomitant
medications such as sodium valproate, rapid dose titration
of clozapine, prior cardiac comorbidities and genetic pre-
disposition; however, these have not been systematically
reviewed to date.17-­19
There is no consensus and a paucity of data on the
pathogenesis of clozapine-­induced cardiomyopathy.8,20
Suggested mechanisms have included accumulated
alpha-­adrenergic blocking effects, direct toxicity simi-
lar to anthracycline-­induced cardiomyopathy, comorbid
     |  443
Summations
• Concurrent use of sodium valproate with clo-
zapine likely increases the odds of clozapine-­
induced myocarditis.
Limitations
• There is only a small amount of available prior
research considering risk factors for clozapine-­
induced myocarditis and cardiomyopathy.
• Because of the heterogeneity of assessed risk
factors, data for only a small number of risk fac-
tors could be combined in the meta-­analysis.
Therefore, our meta-­analysis should be viewed
with caution.
exposure to illicit drugs or alcohol, environmental factors
impacting cholinergic receptor dysfunction and genetic
risk associated with variations in regulation of clozapine
metabolism via cytochrome P450 (CYP) enzymes.8,21-­24 A
systematic review of clozapine-­induced cardiomyopathy
reported that clinical signs include shortness of breath and
palpitations, but did not explore risk factors.8 We could
identify no prior systematic review of the research which
identified risk factors for clozapine-­induced cardiomyop-
athy. Risk factors are well established in the general pop-
ulation and include coronary artery disease, tachycardia,
diabetes mellitus, age, hypertension, smoking and higher
body mass index (BMI).25 These factors may be present as
comorbidities in patients on clozapine.
1.1  |  Aims of the study
There is no prior systematic review or meta-­analysis on the
risk factors for clozapine-­induced myocarditis and cardio-
myopathy. A better understanding of the current literature
on this topic would allow clinicians to improve patient se-
lection, clozapine monitoring algorithms and treatment
regimens. Hence, this systematic review and meta-­analysis
aimed to synthesise the current evidence on this topic and
stratify risk factors by their clinical importance.
2  |  METHODS
This review and meta-­analysis were conducted in accord-
ance with the Preferred Reporting Items for Systematic
Reviews and Meta-­Analysis (PRISMA) guidelines.26 A
protocol was registered with the National Institute for
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444       VICKERS et al.
Health Research International Prospective Register of
Systematic Reviews ‘PROSPERO’ on the 15 May 2021
(CRD42021254709). There was no requirement for ethi-
cal approval, as data were already freely available in the
public domain.
2.1  |  Search strategy and
exclusion criteria
A systematic search was conducted using PubMed,
Embase, CINAHL, Web of Science, the Cochrane Central
Register of Controlled Trials (CENTRAL) and PsycInfo
from database inception up to 26 May 2021. The full
search strategy is provided as Appendix S1. Duplicates
were excluded from the search results prior to review
by two researchers (MV and VR) who independently as-
sessed search results for inclusion in a three-­step process
that screened by title, abstract and full-­text. Any discrep-
ancies were resolved by consultation with a third reviewer
(DS). We included all languages. Articles were consid-
ered eligible for inclusion if the following criteria were
met: (1) the study included patients who were treated
with clozapine, (2) the study included patients who were
treated with clozapine and developed myocarditis or car-
diomyopathy secondary to clozapine commencement, (3)
the study reported on risk factors for clozapine-­induced
myocarditis and/or cardiomyopathy and (4) the study
design provided quantitative data on patients who did
and did not develop clozapine-­induced myocarditis and/
or cardiomyopathy. There were no criteria for minimum
sample size.
2.2  |  Data collection and definitions
A data extraction sheet was developed and refined dur-
ing the full-­text review stage. Data were independently
extracted by two authors (MV and VR) and then reviewed
for discrepancies. Data were categorized as follows: (1)
potentially modifiable risk factors, (2) non-­modifiable risk
factors, (3) general study characteristics and (4) author
recommendations.
Potentially modifiable risk factors included concur-
rent medications, clozapine dosing regimens, BMI and
concurrent substance use. Non-­modifiable risk factors
included age, gender, ethnicity, genetic risk factors and
comorbidities. General study characteristics included
study type, country of origin, study length, follow-­up pe-
riod, patient cohort, definition and assessment modali-
ties of myocarditis, definition and assessment modalities
of cardiomyopathy, statistical methods used and study
limitations. Author recommendations included only
those recommendations made which related to the man-
agement of risk factors.
We compared the diagnoses of clozapine-­induced
myocarditis and cardiomyopathy provided in the included
manuscript against the definitions described by Ronaldson
et al. and Youssef et al. respectively.15,27 Ronaldson defined
clozapine-­induced myocarditis as the development at least
one of the following: (1) chest pain, (2) flu-­like symptoms,
(3) persistent tachycardia (heart rate >100 beats per min-
ute) or (4) signs of heart failure (third heart sound, basal
crepitations, peripheral oedema) with at least one of ei-
ther: (1) elevated troponin I (>2 × upper limit of normal),
(2) echocardiographic evidence of systolic dysfunction
or (3) evolutionary electrocardiograph changes involving
T-­wave inversion or >1  mm ST-­segment deviation in at
least two contiguous leads.15 Youssef et al. extended the
work of Ronaldson et al. and defined clozapine-­induced
cardiomyopathy as new onset systolic dysfunction on any
echocardiogram in the follow-­up period, characterised as
left ventricular ejection fraction <50% and at least a 10%
reduction in left ventricular ejection fraction from base-
line or most recent echocardiogram.27
2.3  |  Heterogeneity and publication bias
Two authors (MV and VR) independently reviewed
included articles for risk of bias. Case–­control stud-
ies were assessed using the Newcastle–­Ottawa Quality
Assessment Scale.28 For these articles, risk of bias was
considered across four domains: (1) study selection, (2)
cohort comparability, (3) exposure and (4) sample size.
Where discrepancies occurred, a third author (DS) was
consulted.
2.4  |  Statistical analysis
We combined raw data on risk factors among cases and
controls from individual studies to calculate the pooled
effect size using a random-­effects model with a Mantel–­
Haenszel method. We conducted a meta-­analysis on any
comparable data that were presented in two or more
studies. Heterogeneity between studies was assessed
using the I2 statistic with values of 25%, 50% and 75% cor-
responding to low, moderate and high levels of heteroge-
neity respectively. Funnel plots were used to assess risk
of publication bias. All analyses were performed with
Revman v5.29
VICKERS et al.
3  |  R E S U LTS
3.1  |  Characteristics of included articles
We identified 2423 unique articles of which 2369 were
excluded at title and abstract level. At full-­text review,
54 articles were assessed and seven4,17-­19,27,30,31 met
the inclusion criteria and were included in the final
systematic review and meta-­analysis. A PRISMA dia-
gram demonstrating reasons for exclusion is shown in
Figure 1. Characteristics of included articles are detailed
in Table  1. A list of all articles excluded at the full-­text
review stage and reasons for exclusion is provided as
Table S2.
F I G U R E 1   PRISMA flow chart of study inclusion/exclusion
     |  445
Across the seven included studies, there were a total
of 192 cases of myocarditis and six cases of cardiomyop-
athy. Cases of myocarditis were compared with a total
of 1214 controls. All seven of the included articles were
case-­control in design. Six of the studies were retrospec-
tive in design.4,17-­19,27,31 Five studies were carried out in
Australia,17,18,27,30,31 while one was conducted in New
Zealand4 and one in Turkey.19 The duration of studies
ranged from 2 to 16 years, with a mean of 7 years and stan-
dard deviation (SD) of 4.8 years. One study did not define
its inclusion dates.18 Year of publication ranged from 2012
to 2021. Definitions of myocarditis were in line with the
work of Ronaldson et al. 2010 in six of the studies,4,17-­19,27,31
while the other study defined myocarditis as an increase
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446       VICKERS et al.

T A B L E 1   Characteristics and risk factors of included articles

Study
(name/ Location of Time Frame Cases of Number of Deaths from
year) Study type study (years) Cohort myocarditis controls myocarditis

Bellissima Retrospective New Zealand 2011–­2012 (2), Patients initiated 9 65 0

et al. Case–­Control Enriched or re-­initiated
20214 data included on clozapine
cases from between
2014–­2017 2011–­2012

Khan et al. Prospective Australia 2009–­2015 (4) Patients receiving 14 489 0

201730 Case–­Control clozapine
between
2009–­2015

Lacaze et al. Retrospective Australia Not Reported Not described 42 67 Not Reported
202018 Case–­Control
VICKERS et al.
Cases of
cardiomyopathy Length of followup Risk factors assessed
2 90 days Age, Cumulative dose (mg),
Sex, Ethnicity (Maori),
Concomitant medication:
Other antipsychotics;
Benzodiazepine;
Antidepressant; SSRI; Sodium
valproate. Cardiovascular
risk factors: BMI; Smoking;
Type−2 DM; Hypertension;
Abnormal lipids.
NA Mean follow-­up of Age, Sex, Duration of disease
9 ± 6 years (years), Duration of
clozapine, Average clozapine
level, Smoking, Diabetes,
Hypertension, BMI, Epilepsy,
Coronary artery disease,
Weight gain, Neutropenia,
Baseline LVEF, QRS duration,
QTc interval, Heart rate,
Troponin
NA 45 days Age, Sex, Ethnicity, Smoking,
Alcohol abuse, Illicit drug
use, Valproate use, BMI,
Cumulative clozapine dose,
Genetic analyses: Genome-­
wide SNP association; Rare
variants/gene-­level analysis;
Targeted short-­read HLA
typing; long-­read HLA typing/
phasing
     |  447
Cardiomyopathy
Myocarditis criteria criteria
(1) Flu-­like symptoms, and New onset of
(2) At least one symptom global systolic
and/or sign of cardiac dysfunction on any
dysfunction: (a) Chest pain, echocardiogram in
(b) New and persistent the follow-­up
tachycardia (heart rate period characterised
>100 bpm or an increase of as: (1) LVEF <50%
30 bpm over baseline), c) or (2) at least a
Signs of heart failure (SOB 10% reduction in
on exertion, orthopnoea, LVEF from baseline
peripheral oedema). Plus, OR most recent
At least one of the following echocardiogram
diagnostic abnormalities: And (1) No evidence
(1) Elevated troponin, of ischaemia on
(2) CRP >100 mg/L, (3) Angiogram or
Echocardiographic evidence CT-­Angiogram,
of systolic dysfunction, (2) No evidence of
(4) Evolutionary ECG regional wall motion
changes involving T-­wave abnormalities on
inversion or >1 mm ST-­ echocardiogram
segment deviation in at and (3) No evidence
least 2 contiguous leads, of viral, infectious
(5) Cardiac MRI findings (HIV), alcoholic,
consistent with myocarditis thyrotoxic or
and No evidence of a other cause of
viral cause (respiratory or cardiomyopathy
enterovirus or a clinical
picture more consistent
with a viral myocarditis)
Myocarditis was diagnosed NA
based on an increase
in troponin I level and
evidence of left ventricular
systolic dysfunction on
serial echocardiography
Reference made to Ronaldson NA
et al. 201015 case definition
(Continues)
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448       VICKERS et al.

T A B L E 1   (Continued)

Study
(name/ Location of Time Frame Cases of Number of Deaths from
year) Study type study (years) Cohort myocarditis controls myocarditis

Nachmani Retrospective Australia 2012–­2015 (4) Patients 8 123 0

et al. Case–­Control commenced
202031 on clozapine
between
2012–­2015

Ronaldson Retrospective Australia 1993–­2009 (16) Patients who 105 296 9

et al. Case–­Control commenced
201217 clozapine
between
1993–­2009

Yağcıoğlu Retrospective Turkey 2011–­2018 (7) Consecutive 9 62 1

et al. Case–­Control hospitalized
201919 patients
commenced
on clozapine
between 2011–­
2018, pre-­ and
post-­cardiac
monitoring
VICKERS et al.      |  449

Cases of Cardiomyopathy
cardiomyopathy Length of followup Risk factors assessed Myocarditis criteria criteria

NA 4 weeks First time taking clozapine, Reference made to Ronaldson NA

Age, Sex, Main psychiatric et al. 201015 case definition
diagnosis, Illicit drug use,
Concomitant valproate use,
Any liver abnormalities,
Clozapine level in week
2 of titration, cumulative
clozapine dose on day 14,
Any comorbidity, Endocrine/
metabolic abnormality:
Hyperlipidemia; Obesity;
Type−2 DM. Mental and
behavioural disorders,
Diseases of circulatory
system, Diseases of
respiratory system, Diseases
of digestive system,
Concomitant medications,
Antipsychotic use, FGA use,
SGA use, Quetiapine, Mean
number of antipsychotics,
Antidepressant use, SSRI
use, SNRI use, TCA use,
Antiepileptic use, Lithium
use, Alimentary tract and
metabolism drug use, Drugs
for constipation, Drugs for
acid related disorders
NA 45 days Age, Sex, BMI, Ethnicity, Reference made to Ronaldson NA
Smoking, Alcohol Use, et al. 201015 case definitions
Illicit drug use, Asthma,
Primary diagnosis, Duration
of psychiatric illness, Other
medication: Amisulpride;
Aripiprazole; Benztropine;
Chlorpromazine;
Flupenthixol; Haloperidol;
Lithium; Olanzapine;
Quetiapine; Risperidone;
Zuclopenthixol. Cumulative
clozapine dose
NA 28 days Age, Duration of illness, Duration Reference made to Ronaldson NA
of hospitalisation, Dose et al. 201114 case definitions
of clozapine at discharge/
cessation, Dose of clozapine
at x time interval, Sex,
Primary psychiatric diagnosis,
Co-­administered drugs:
Antidepressants; FGA; SGA;
Valproic acid; Lithium;
Benzodiazepines

(Continues)
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450       VICKERS et al.
T A B L E 1   (Continued)
Study
(name/ Location of Time Frame
year) Study type study (years)
Youssef Retrospective Australia 2000–­2011 (11)
et al. Case–­Control
201627
Abbreviations: BMI, body mass index; bpm, beats per minute; CRP, C-­reactive protein; CT, computerized tomography; ECG, electrocardiogram; FGA, first
generation antipsychotic; HIV, human immune deficiency virus; LVEF, left ejection fraction volume; MRI, magnetic resonance imaging; SGA, second
generation antipsychotic; SNRI serotonin and norepinephrine reuptake inhibitor; SOB, shortness of breath; SSRI, selective serotonin reuptake inhibitor; TCA,
tricyclic antidepressant.
in troponin I level and evidence of left ventricular systolic
dysfunction on serial echocardiography.30 Studies defined
cases as patients commenced on clozapine who developed
myocarditis or cardiomyopathy and controls as patients
commenced on clozapine who did not develop myocar-
ditis or cardiomyopathy. One study reported nine deaths
attributed to myocarditis, and another study reported one
death because of myocarditis among their cohort.17,19
We identified 52 different potential risk factors,
which were assessed across the included articles. The
most commonly assessed potential risk factors included
age,4,17-­19,27,30,31 gender,4,17-­19,27,30,31 BMI,4,17,18,27,30,31 so-
dium valproate use,4,17-­19,27,31 ethnicity,4,17,18,27 smok-
ing,4,17,18,30 cardiovascular disease,19,27,30,31 cumulative
clozapine dose,4,17,18,31 antidepressant use,4,19,27,31 selec-
tive serotonin reuptake inhibitor (SSRI) use,4,27,31 lithium
use,17,19,31 benzodiazepine use,4,19,27 other antipsychotic
use,4,27,31 second generation antipsychotic use,17,19,31 pri-
mary psychiatric diagnosis,17,19,31 duration of psychiatric
illness,17,19,30 diabetes,4,30,31 illicit drug use,17,18,31 alcohol
use,17,18 hypertension,4,30 abnormal lipid profile,4,31 first
time taking clozapine,17,31 first or second generation an-
tipsychotic use19,31 and quetiapine use.17,31 The frequency
of all potential risk factors assessed by the included stud-
ies is shown in Table S3.
Cases of Number of Deaths from
Cohort myocarditis controls myocarditis
All patients 5 112 Not reported
initiated on
clozapine
between
2000–­2011
3.2  |  Myocarditis
3.2.1  |  Meta-­analysis of potential risk factors
for myocarditis
We were able to conduct a meta-­analysis for concurrent
use of sodium valproate, SSRIs, quetiapine and lithium
as potential risk factors for clozapine-­induced myocar-
ditis. These were the only risk factors with comparable
data across two or more studies. For concurrent sodium
valproate, we combined data on 178 cases of myocardi-
tis and 725 controls across six studies4,17-­19,27,31 to iden-
tify increased odds of clozapine-­induced myocarditis
(pooled OR 3.58, 95% confidence interval (CI) 1.81–­7.06,
p = 0.0002, I2 = 41%) as shown in Figure 2.
We did not find significantly greater odds of myo-
carditis with the use of SSRIs, quetiapine or lithium.
Furthermore, the heterogeneity of included data for
SSRIs, quetiapine and lithium was higher, with I2 = 56%,
84% and 76% respectively. Among concurrent SSRI users,
22 cases of myocarditis and 300 controls were combined
from three studies (pooled OR 1.39, 95% CI 0.19–­10.08,
p  =  0.74).4,27,31 For quetiapine use, we combined data
on 113 cases and 419 controls from two studies (pooled
OR 2.28, 95% CI 0.3–­17.26, p = 0.43).17,31 For concurrent
VICKERS et al.      |  451

Cases of Cardiomyopathy
cardiomyopathy Length of followup Risk factors assessed Myocarditis criteria criteria

6 30 days (myocarditis), Age, Sex, BMI, Average rate of
12 months dose titration in first 30 days,
(cardiomyopathy) Race, Known cardiac disease,
Concomitant meds: Other
antipsychotic, BZD, ADT,
SSRI, Valproate
At least ONE symptom New onset systolic
AND/OR sign of cardiac dysfunction on any
dysfunction: Chest pain; echocardiogram in
Flu-­like symptoms; the follow-­up period
Persistent tachycardia characterised as:
(heart rate >100 beats LVEF <50%
per minute); Signs of AND
heart failure (third heart At least a 10%
sound, basal crepitations, reduction in LVEF
peripheral oedema) from baseline
PLUS At least ONE of OR most recent
the following diagnostic echocardiogram
abnormalities:
Elevated troponin I (>2
ULN); Echocardiographic
evidence of systolic
dysfunction; Evolutionary
ECG changes involving
T-­wave inversion or >1 mm
ST-­segment deviation in at
least 2 contiguous leads

F I G U R E 2   Forest plot for concurrent sodium valproate use as a risk factor for clozapine-­induced myocarditis

lithium use, we combined data on 122 myocarditis cases
and 481 controls across three studies (pooled OR 4.45, 95%
CI 0.52–­38.03, p = 0.17).17,19,31 Forest plots are provided as
Figures S3–­S5.
3.2.2  |  Qualitative review of potential risk
factors for myocarditis
that when assessing dose of clozapine as a continuous var-
iable in increments of 250 mg, there were increased odds
of clozapine-­induced myocarditis identified with higher
doses (OR 1.26, 95% CI 1.02–­1.55, p = 0.03).17 Bellissima
et al.4 assessed cumulative dose until Day 13 and did
not identify increased odds. Likewise, Lacaze et al. and
Nachmani et al. did not identify increased odds associated
with cumulative dose at Days 9 and 14 respectively.18,31

Cumulative clozapine dose Age

Cumulative clozapine dose was assessed as a potential Age was assessed as a potential risk factor by all seven
risk factor by four articles.4,17,18,31 Ronaldson et al. found included articles.4,17-­19,27,30,31 Ronaldson et al.17 found in
 |
452       VICKERS et al.
multivariate analysis that the odds of myocarditis in those
aged greater than or equal to 50  years were more than
doubled that for those aged between 20 and 29 years (OR
2.28, 95% CI 1.08–­4.82, p = 0.03) and also described this
finding as an increase in odds by 31% for each additional
10 years of age (OR 1.31, 95% CI 1.07–­1.60, p = 0.0009).
In contrast to this, Nachmani et al.31 found in univariate
analysis that their myocarditis cases were significantly
younger (p  =  0.03). The remaining five studies found
no significant association between age and clozapine-­
induced myocarditis.4,18,19,27,30
Antidepressant use and SSRIs
Four articles assessed concurrent antidepressant
usage.4,19,27,31 Three articles assessed SSRI use specifi-
cally.4,27,31 Youssef et al.27 analysed their potential predic-
tors including concomitant medications and demographic
data in a multivariable logistic regression to find that
SSRIs were associated with increased odds of myocardi-
tis (OR 6.79, 95% CI 1.06–­43.48, p  =  0.043). In contrast,
Bellissima et al. and Nachmani et al. found no significant
association.4,31
Sex and ethnicity
Sex was assessed as a potential risk factor by all seven
included articles.4,17-­19,27,30,31 However, none of the in-
cluded studies found sex to be a significant risk factor for
clozapine-­induced myocarditis. Ethnicity as a potential
risk factor was considered by four articles.4,17,18,27 Ethnic
groups assessed included Māori4 and European/
Caucasian.17,18,27 No studies found ethnicity to be a sig-
nificant risk factor.
Smoking, alcohol and illicit substance use
Smoking was assessed by four of the included arti-
cles.4,17,18,30 Illicit substance use17,18,31 and alcohol use17,18
were assessed by three and two articles respectively. There
were no increased odds of myocarditis associated with any
of these factors.
Cardiovascular disease, diabetes, hypertension,
abnormal lipid profile and BMI
Cardiovascular disease was assessed as a potential risk
factor by four articles19,27,30,31 and diabetes was assessed by
three articles.4,30,31 Both hypertension4,30,31 and abnormal
lipid profiles4,31 were assessed by two studies each. No arti-
cles reported increased odds in the presence of these or any
other comorbidities. BMI was assessed by six articles and
none identified increased odds of myocarditis.4,17,18,27,30,31
Genetic risk factors
Only one article considered potential genetic risk fac-
tors for clozapine-­induced myocarditis.18  This article by
Lacaze et al.18 discussed four single-­nucleotide polymor-
phisms (SNPs), one of which was located at the GNA15
gene, which has previously been associated with heart
failure. Lacaze et al.18 also identified seven human leuco-
cyte antigens (HLAs) considered to be protective. None of
the genetic risk factors studied by Lacaze et al. were con-
sidered statistically significant.
3.3  |  Cardiomyopathy
Only two of the included articles identified cases of car-
diomyopathy among their cohort.4,27 Youssef et al. identi-
fied six cases, and Bellissima et al. identified two cases.4,27
Youssef et al. found no significant risk factors for cardio-
myopathy, and Bellissima et al. did not include the two
cases of cardiomyopathy in their analysis.4,27 No deaths
because of cardiomyopathy were reported.
3.4  |  Risk of bias
Using the Newcastle–­Ottawa risk of bias assessment tool
for case–­control studies, we found that included studies
scored well in the study selection domain, receiving the
maximum possible score. A study can score a maximum
of one for each of the domain questions. Four studies re-
ceived a lower score in the comparability domain because
of failure to control for any additional factors.19,27,30,31 We
did not consider failure to mention non-­response rate as
a weakness because non-­responders cannot typically be
included in retrospective studies. A table detailing the
modified Newcastle–­Ottawa scoring questions and as-
sessments are provided as Tables S4 and S5, respectively.
4  |  DISC USSION
This study provides the first systematic review of potential
risk factors for clozapine-­induced myocarditis and cardio-
myopathy. Sodium valproate was the only risk factor iden-
tified as significantly increasing odds of myocarditis in our
meta-­analysis, while SSRIs, quetiapine and lithium were
not significantly associated with increased odds. In the
systematic review, no risk factors were significant across
more than one study, with conflicting results reported for
increasing age and higher clozapine dose. Notably, none
of sex, ethnicity, smoking, alcohol, substance abuse or car-
diometabolic disease were associated with greater odds of
myocarditis. There was no information on risk factors for
cardiomyopathy.
Sodium valproate is a known inhibitor of several
metabolic pathways including of the CYP liver enzyme
VICKERS et al.
CYP2C9. Clozapine is predominantly metabolised in the
liver to N-­demethylated metabolites (norclozapine) and to
N-­oxides in reactions catalysed by CYP2D6, CYP1A2 and
CYP3A4.32 There is conflicting evidence on the impact
that sodium valproate has on plasma clozapine levels.33-­37
Both Rajkumar et al. and Diaz et al. identified among 101
and 37 patients, respectively, increased plasma clozap-
ine levels in those also taking sodium valproate.35,36 Yet
among 1184 patients prescribed both agents compared
with 24000 taking clozapine alone, Couchman et al.37
found no difference in plasma clozapine or norclozapine
levels. Interestingly, however, there is no evidence in the
literature to suggest that sodium valproate in the absence
of clozapine leads to higher rates of myocarditis. Our
study found that sodium valproate may be particularly
important in increasing the risk for clozapine-­induced
myocarditis whether by its impact on metabolism or some
other mechanism. There is no contraindication regarding
sodium valproate and clozapine co-­administration though
pharmaceutical company product information recognises
the potential risk of myocarditis and recommends con-
sidering the discontinuation of sodium valproate during
clozapine initiation.38
Cumulative clozapine dose and titration speed may be
important risk factors for myocarditis. Since myocarditis
typically occurs in the first four weeks of clozapine treat-
ment when patients are on dose uptitration, this would
likely confound an ability to correlate increased dose with
risk. In practice, clozapine is titrated slowly to avoid ad-
verse events, and there is case series evidence that rapid
titration increases the risk of myocarditis.14,39 Several
animal studies support a direct link between rapid titra-
tion and high serum clozapine levels with cardiotoxic
effects.32,40,41 In murine models, Abdel-­Wahab et al.41
identified increased oxidative stress, inflammatory cyto-
kines, DNA damage and apoptosis as well as attenuation
of antioxidant activity correlating directly with increased
clozapine dose. In addition, in their recent study, Arzuk
et al.32 further identified mitochondrial CYP enzymes
present in cardiac tissue that activated clozapine metabo-
lites and suggested that this may be the mechanism driv-
ing clozapine-­induced myocarditis. In addition, there are
several other risk factors for myocarditis in the general
population, which may also be relevant to those taking
clozapine such as staphylococcal and streptococcal infec-
tions or exposure to coxsackievirus, parvovirus, certain
medications, toxins and illicit substances.42-­45
We identified conflicting evidence regarding the risk
associated with increasing age. Advancing age is charac-
terised by changes in drug absorption, distribution, me-
tabolism and elimination.46 Ismail et al.47 demonstrated
that for both clozapine and norclozapine advancing age
correlated with higher blood concentrations. Age-­related
     |  453
changes in body composition include a reduction in total
body water and lean muscle mass with a concomitant
increase in relative body fat.46 Clozapine is a lipophilic
agent, and this may partly explain why advancing age
may increase the risk of clozapine-­induced cardiomyop-
athy. Despite this, however, the literature also demon-
strates that clozapine is significantly more effective than
other antipsychotics in reducing psychotic symptoms
among elderly patients with treatment resistant schizo-
phrenia.48 Clozapine remains the drug of choice in this
population, but may require lower doses and more careful
monitoring.49
Though we could identify no evidence on risk factors
for clozapine-­induced cardiomyopathy in the current
literature, it has been previously established among the
general population that acute myocarditis can progress
to dilated cardiomyopathy.50 In addition, risk factors for
cardiomyopathy which are relevant to the general pop-
ulation, such as diabetes, smoking, obesity, alcoholism,
hypertension and hypercholesterolemia, may be particu-
larly important in those prescribed clozapine.51 The link
between early death from cardiovascular disease and a
mental health diagnosis such as schizophrenia or bipolar
is well established and relates to a combination of lifestyle
factors, comorbidities and the metabolic side effects of
many antipsychotic medications.52,53
4.1  |  Strengths and limitations
This study has several limitations. Firstly, there is a dearth
of available prior research considering risk factors for
clozapine-­induced myocarditis and cardiomyopathy and
most of the research was retrospective in nature. We note
that the number of myocarditis cases was small and that
cardiomyopathy cases were extremely rare. Secondly,
because of the heterogeneity of assessed risk factors, we
could only combine data for a small number of risk factors
in our meta-­analysis and could not control for additional
factors in a multivariate model. We also note that most
included studies were conducted in Australia. Because of
potential detection bias in Australia, there is a possibility
that the false-­positive rates of clozapine-­induced myocar-
ditis cases included in this meta-­analysis may be relatively
high.54 Additionally, our results may not be applicable to
other parts of the world. We did not assess the grey lit-
erature in this field and there may be emerging research
that supports or disputes our findings. Although the het-
erogeneity of the meta-­analysis of valproate was low, the
heterogeneity of the other analyses was high, and as such
these results should be treated with caution. Finally, the
diagnoses of myocarditis and cardiomyopathy were clini-
cal diagnoses, and diagnostic criteria were frequently not
 |
454       VICKERS et al.
provided. As such we could not validate these diagnoses of
myocarditis or cardiomyopathy. One strength of our study
was that we identified a low risk of bias among included
articles. Future directions for research could include fur-
ther prospective studies, particularly in countries beyond
Australia where high-­quality healthcare registry data ex-
ists, such as in Scandinavia.
To conclude, concurrent sodium valproate likely in-
creases the odds of clozapine-­induced myocarditis. The
exact mechanisms involved have yet to be fully elucidated.
Other risk factors are likely to be important, particularly
individual variation associated with genetic risk.
CONFLICT OF INTEREST
10. Higgins JM, San C, Lagnado G, Chua D, Mihic T. Incidence and
None of the authors have any conflicts of interest to
declare.
AUTHOR CONTRIBUTIONS
MV drafted the manuscript, conducted the literature re-
view and risk of bias assessments. VR drafted the man-
uscript, conducted the literature review and risk of bias
assessments. EM carried out the statistical analysis. LE
performed the primary literature search. KM reviewed
and drafted the manuscript. VM conceptualised the study.
DS oversaw project management and final revisions of the
manuscript.
PEER REVIEW
The peer review history for this article is available at
https://publo​ns.com/publo​n/10.1111/acps.13398.
DATA AVAILABILITY STATEMENT
All data used in this systematic review and meta-­analysis
are available in the public domain.
ORCID
James Scott  https://orcid.org/0000-0002-0744-0688
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SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of the article at the publisher’s website.
How to cite this article: Vickers M, Ramineni V,
Malacova E, et al. Risk factors for clozapine-­
induced myocarditis and cardiomyopathy: A
systematic review and meta-­analysis. Acta
Psychiatr Scand. 2022;145:442–­455. doi:10.1111/
acps.13398