Systematic Reviews
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Sep 19, 2025; 15(9): 108525
Published online Sep 19, 2025. doi: 10.5498/wjp.v15.i9.108525
Diagnostic algorithm for clozapine-induced myocarditis: A systematic review
Yassir Mahgoub, Rawan Alhau, Yumna Magzoub, Aya Ali, Eptihal Nour, Mustafa E E Saeed, Sameera G M Mohamed, Ahmed O S Hassan, Omaima Ali
Yassir Mahgoub, Rawan Alhau, Department of Psychiatry and Behavioral Health, Penn State College of Medicine, Hershey, PA 17033, United States
Yumna Magzoub, Aya Ali, Department of Psychiatry, University of Khartoum, Faculty of Medicine, Khartoum 11111, Sudan
Eptihal Nour, Department of Psychiatry, Shendi University, Faculty of Medicine, Khartoum 11111, Sudan
Mustafa E E Saeed, Department of Psychiatry, National Ribat University, Faculty of Medicine, Khartoum 11111, Sudan
Sameera G M Mohamed, Department of Psychiatry, University of Bahri, College of Medicine, Khartoum 11111, Sudan
Ahmed O S Hassan, Department of Psychiatry, Cairo University Kasr Alainy Faculty of Medicine, Cairo 11956, Al Qāhirah, Egypt
Omaima Ali, Department of Medicine, Division of Cardiology, Penn State College of Medicine, Hershey, PA 17033, United States
Author contributions: Mahgoub Y, Alhau R, Magzoub Y, Ali A, Nour E, Saeed MEE, Mohamed SGM, Hassan AOS, and Ali O wrote and reviewed the manuscript; Mahgoub Y carried out conceptualization; Ali O conducted supervision; and all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yassir Mahgoub, MD, Associate Professor, Department of Psychiatry and Behavioral Health, Penn State College of Medicine, 500 University Dr, Hershey, PA 17033, United States. ymahgoub@pennstatehealth.psu.edu
Received: April 17, 2025
Revised: May 14, 2025
Accepted: July 15, 2025
Published online: September 19, 2025
Processing time: 131 Days and 13.3 Hours
Abstract
BACKGROUND

Clozapine, the gold standard for resistant schizophrenia, is underused due to risks like clozapine-induced myocarditis (CIM). Non-specific biomarkers and inconsistent imaging, and the significant overlap with clozapine-induced pneumonia (CIP) lead to misdiagnosis and premature discontinuation.

AIM

To develop a diagnostic algorithm for CIM to enhance accuracy, differentiate from CIP, and guide safe clozapine rechallenge.

METHODS

A systematic review of 119 PubMed studies (published between 1990 and April 2025) was conducted in accordance with PRISMA guidelines. The review analyzed CIM diagnosis and rechallenge outcomes, with a focus on biomarkers, imaging, and collaboration with cardiology.

RESULTS

CIM diagnosis relies on troponin and C-reactive protein; electrocardiography and echocardiography are inconsistently applied, and cardiac magnetic resonance imaging (CMR) is underused. Rechallenge was successful in 64.7% to 68.9% of 136 cases, with 2.9% resulting in fatal outcomes. Up to 65% of presumed CIM cases lack confirmation. A proposed protocol integrates chest computed tomography to exclude pneumonia and CMR for CIM confirmation, with echocardiography as an alternative.

CONCLUSION

A protocol involving multidisciplinary collaboration among computed tomography, CMR, and cardiology improves CIM diagnosis. Slow titration prevents CIM; adjust the dose for CIP and discontinue for confirmed CIM.

Keywords: Clozapine; Myocarditis; Pneumonia; Rechallenge; Protocol; Multidisciplinary management

Core Tip: This systematic review proposes a multidisciplinary diagnostic algorithm for clozapine-induced myocarditis to reduce misdiagnosis with clozapine-induced pneumonia. Integrating chest computed tomography to exclude clozapine-induced pneumonia, cardiac magnetic resonance imaging for clozapine-induced myocarditis confirmation, and echocardiography in resource-limited settings, the protocol emphasizes slower clozapine titration and collaboration with cardiology to enhance diagnostic accuracy and ensure the safe use of clozapine in the treatment of treatment-resistant schizophrenia.