Diagnostic algorithm for clozapine-induced myocarditis: A systematic review

Table 1 Summarizes studies and guidelines for screening and diagnosing clozapine-induced myocarditis

Ref.	Study type	Sample size	Monitoring protocol	Biomarkers used	Imaging techniques	Outcomes reported	NOS scores	Certainty of evidence	Strengths	Limitations
Berk et al[45], 2007	Guidelines	N/A	Baseline: Clinical evaluation, EKG, plasma troponin, CK-MB, TEE-days 7 and 14: Clinical evaluation, EKG, plasma troponin, CK-MB-6 months and annually: TEE	Troponin, CK-MB (routine); WBC, eosinophil count, ESR, CRP (suspected cases)	Echo (routine)	No outcome reported for guidelines	6/9	Low: Expert-driven with no supporting data	First suggested protocol	Based on expert opinion and clinical consensus, with no data supporting the guidelines
Ronaldson et al[5], 2010	Study	75	Baseline: Echo, troponin I or T, CRP-weekly for 4 weeks: Troponin I or T, CRP	Troponin and CRP	Echo (baseline), EKG (suspected cases)	Reduced mortality and early detection	7/9	Moderate: Strong evidence but a moderate sample	Strong evidence, comprehensive	Moderate sample size, limited follow-up, limited imaging role, and lack of guidelines for overlapping conditions
Murch et al[52], 2013	Study	122	Baseline Echo and repeated Echo at 3 and 6 months	CBC and CRP	Echo	73% had the Echo before starting clozapine 65% had one follow-up echo	4/9	Low: Small study with high bias risk	Examine the role and benefit of echo in patients with myocarditis	Limited utility, high cost of using echo for screening, and lack of guidelines for overlapping conditions
			Symptomatic patients had CBC, CRP			3 patients screened positive, 2/3 had findings in the echo suggesting myocarditis
Youssef et al[55], 2016	Retrospective study	129	No protocol. They had criteria for myocarditis based on symptoms and one of the following (elevated troponin, EKG changes, or echo changes)	Troponin	Echo and EKG were inconsistently assessed	3.88% met the diagnosis of myocarditis	6/9	Moderate: Large sample but retrospective	Large sample	Inconsistent use of imaging and lack of exclusion of overlapping conditions
McNutt et al[53], 2021	Study	38	Baseline and weekly for 4 weeks: Troponin I or T, CRP	Troponin, CRP	Cardiology involved 2 cases had echo/CMR 2 other patients only had elevated CRP	50% of patients who screened positive were confirmed to have myocarditis	4/9	Low: Small study, inconsistent imaging	Cardiologist for suspected cases	Small study, inconsistent use of images, and lack of guidelines for overlapping conditions
Anıl Yağcıoğlu et al[46], 2019	Study	38	Baseline and weekly for 4 weeks: Clinical evaluation, troponin, CRP, ESR, eosinophil count	Troponin, CRP, ESR, and eosinophil count	Echo (suspected cases), CMR (1 patient)	11.3% suspected myocarditis, 1.4% confirmed	6/9	Low: Small study	Echo for suspected cases	Small study, no clear management consensus
Nachmani Major et al[48], 2020	Retrospective study	24	Routine: Clinical symptoms, WBC, troponin, CRP, BNP- Suspected cases: Clinical assessment, EKG, echo, MRI	Troponin, CRP, WBC, BNP	EKG, echo, MRI (suspected cases)	8.6% suspected myocarditis, 1.4% confirmed with imaging	5/9	Low: Small retrospective study	Moderate sample size	Retrospective study and lacks guidelines for overlapping conditions
Kanniah et al[51], 2020	Guidelines	N/A	Baseline and weekly for 4 weeks: Vital signs, CRP, ESR, CPK, troponin-after 4 weeks: Eosinophil count monitoring	CRP, ESR, CPK, troponin, eosinophil count	EKG (symptom-driven)	No outcome reported for guidelines	5/9	Low: Screening-focused, expert-driven	Focused on screening	There are no work-up recommendations for suspected cases or guidelines for overlapping conditions
Sandarsh et al[47], 2021	Study	100	Baseline and weekly for 4 weeks: Clinical symptoms, CRP, eosinophil count, CPK	CRP, eosinophil count, CPK, troponin I	EKG, echo (2/6 positive cases)	5.3% suspected myocarditis after initial exposure, 3.5% after restarting	6/9	Moderate: Larger study	Larger study	Screening-focused, no further workup guidance
Segev et al[54], 2021	Retrospective study	228	Undetermined	CRP and troponin	Echo/MRI for suspected cases	Myocarditis was ruled out in 78.7%, confirmed in 9.8%, and undetermined in 11.5%	6/9	Moderate: Large study with cardiology input	A large study involved cardiology for further workup	Retrospective study, studied other antipsychotics other than clozapine, no workup for overlapping conditions
de Leon et al[56], 2022	Guidelines	N/A	Baseline and weekly for 4 weeks: CBC, CRP; troponin optional in resource-rich settings	WBC, CRP, troponin (optional)	None specified	No outcome reported for guidelines	NA	Low: International guidelines, no outcomes	International guidelines	Focused on screening with no workup for presumptive cases or workup to exclude overlapping conditions
NSW Health[50], 2022	Guidelines	N/A	Baseline: Clinical symptoms, CRP, CPK, troponin, EKG, echo-weekly for 6 weeks: Troponin, CRP - every 6 months: EKG - every 12 months: Echo	CRP, CPK, troponin	EKG (routine), echo(routine), MRI (suspected cases)	No outcome reported for guidelines	NA	Low: Expert-driven, no outcomes	Clear workup for suspected cases	No outcome data
Tirupati et al[6], 2024	Retrospective study	327	Baseline and weekly for 6 weeks: Troponin I or T, CRP	Troponin, CRP	EKG, echo (most positive cases)	9.8% incidence of clozapine-induced myocarditis	7/9	Moderate: Large study, comprehensive	Large study, comprehensive follow-up	Retrospective, no exclusion of overlapping conditions
Griffin et al[49], 2021	Expert opinion and case series	NA	Baseline and weekly for 8 weeks: Troponin, CRP, BNP/NP-pro BNP and EKG	CRP, BNP/pro-BNP	Consult cardiology for suspected cases. TEE, CMR, and LVEF should be assessed in 6 months, and based on the results, clozapine can be reinstated	No outcome reported for guidelines	7/9	Low: Expert opinion, no outcomes	Expert opinion. Includes more workup for presumptive cases	The suggested protocol does not have data to support it and does not include a workup for overlapping presentations

NOS: Newcastle-Ottawa Scale scores; N/A: Not applicable; NA: Not available; EKG: Electrocardiogram; TEE: Transesophageal echocardiography; CK-MB: Creatinine kinase; WBC: White blood count; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; CBC: Complete blood count; CMR: Cardiac magnetic resonance; BNP: B-type natriuretic peptide; MRI: Magnetic resonance imaging; CPK: Creatinine phosphokinase; LVEF: Left ventricular ejection fraction.

Table 2 Summarizes studies on clozapine rechallenges after presumptive diagnosis of myocarditis

Ref.	Study type	Sample size	Rechallenge success rate	Fatal failure	Diagnostic certainty	Confirmatory test used	Key findings	Limitations
Richardson et al[57], 2021	Systematic review	88 cases from 88 case reports/case series	64.7%	2.9%	Low (4.5% biopsy-confirmed)	Biopsy (4.5%) No CMR	High failure rate, rare fatalities	Based on the case report, we rely on biomarkers for diagnosis, with no exclusion of overlapping conditions
McMahon et al[58], 2024	Systematic review	45 cases	68.9%	0%	Moderate (EKG/TEE in < 33%)	EKG, TEE (< 33%)	No fatalities, 1/3 failed	Based on case reports
						No CMR		Most of the studies diagnosed myocarditis based on biomarkers alone
								With no workup overlapping conditions
Noël et al[59], 2019	Case series	3 cases	33.3%	0%	High (EKG/TEE evidence)	EKG, TEE	Success is only in mild cases	Case series

CMR: Cardiac magnetic resonance; EKG: Electrocardiogram; TEE: Traneosophageal echocardiography.

Table 3 Highlights the overlap between symptoms of clozapine-associated pneumonia and myocarditis

Symptom	CIM frequency (%)	CIP frequency (%)
Fever	40-70[14]	71-75[39]
Difficulty breathing	27-70[14]	67-75[39]
Dizziness with postural changes	50[14]	35[39]
Rapid heartbeat	46-50[14]	53[40]
Chest pain	32-40[14]	39-49[39]
Fatigue	20[14]	90[39]
Lower limbs swelling	20[14]	Uncommon

CIM: Clozapine-induced myocarditis; CIP: Clozapine-induced pneumonia.

Table 4 Summary of the significance of various tests for both clozapine-induced myocarditis and clozapine-induced pneumonia

Test	CIM sensitivity/specificity	CIP sensitivity/specificity	Dynamic monitoring	Comments
EKG changes	Non-specific and seen in 78% of patients[21]	Non-specific[40]	NA	Feasible in all settings
				Non-specific changes (e.g., ST changes, T-wave inversion) in CIM; normal in 22% of cases
				Limited use in CIP
cTnl	34%/89%	Elevated by 52%[43]	Cornerstone for CIM screening; elevated in CIP	Feasible in all settings
				Repeating testing is critical for trends (> 20% rise suggests escalation)
CRP	52%/81%[22]	Elevated in 75%[44]	Yes (24-48 hours) in CIM Repeat testing (e.g., > 50 mg/L) informs interim management	Feasible in all settings
Echo changes	Nonspecific and seen in 30-60%[23]	Likely normal	Yes (48 hours-5 days)	Feasible in most settings
				Detects wall motion defects in CIM, normal in CIP. Serial testing is key in resource-limited settings (echo-only pathway)
Chest X-ray	NA	51% sensitivity	NA	Feasible in most settings
				Misses CIP in approximately 50% of cases; used in resource-limited settings. Normal X-ray requires clinical correlation
Chest CT	NA	90.7%	NA	Gold standard for CIP; critical for excluding CIP in CIM workup
				Limited to well-resourced settings due to cost (300 dollars-1000 dollars)
Endomyocardial biopsy	60%/80%[28]	NA	NA	Gold standard for CIM; invasive, rarely used. Feasible only in specialized centers with severe cases
Cardiac MRI	88%/91%[32]	NA	NA	Non-invasive, highly sensitive for CIM
				Limited by cost (1000 dollars-3000 dollars) and access (2-4-week wait)
				Preferred in well-resourced settings

Dynamic monitoring: Indicates whether serial testing (e.g., 24-48 hours for biomarkers, 48 hours to 5 days for echocardiography) enhances diagnostic precision, as per the interim management strategy in Figure 2. Resource availability: Chest X-ray, electrocardiogram, echocardiography, and biomarkers are feasible in resource-limited settings; however, chest computed tomography and cardiac magnetic resonance imaging are typically limited to well-resourced settings. Differentiation: Clozapine-induced pneumonia exclusion via chest computed tomography (or X-ray in resource-limited settings) is critical before clozapine-induced myocarditis (CIM) confirmation. Echocardiography and cardiac magnetic resonance imaging are key for CIM, with serial testing improving reliability in resource-limited settings. Sensitivity and specificity data for CIM are primarily derived from viral myocarditis studies[4,30]. CIM-specific data are limited and require validation. cTnl: Cardiac tropinin; CRP: C-Reactive protien; CT: Computed tomography; MRI: Magnetic resonance imaging; CIM: Clozapine-induced myocarditis; CIP: Clozapine-induced pneumonia; NA: Not available.