Association between myocarditis and antipsychotics other than clozapine: a systematic literature review and a pharmacovigilance study using VigiBase

ABSTRACT

Introduction

Pharmacovigilance studies have definitely established that clozapine can cause myocarditis. Two published reviews suggested that on rare occasions other antipsychotics may induce myocarditis.

Areas covered

This review explored myocarditis associated with antipsychotics other than clozapine by conducting a systematic search of the literature and critically analyzing the current data in VigiBase compared to the data on clozapine-associated myocarditis. VigiBase is the World Health Organization’s global pharmacovigilance database that uses a statistical signal for associations with a logarithmic measure of disproportionality called the information component (IC).

Expert opinion

For quetiapine, VigiBase provided 106 reports of myocarditis and a significant statistical signal (IC = 1.8; IC₀₂₅ = 1.5) which was confounded by 48% (51/106) with clozapine co-prescription. Combining the literature and VigiBase cases provided five probable myocarditis cases during quetiapine monotherapy (4 after overdose or rapid titration). For olanzapine, VigiBase provided 107 reports of myocarditis and a significant statistical signal (IC = 2.1; IC₀₂₅ = 1.8) probably explained by 77% (82/107) using clozapine co-prescription. Combining the literature and VigiBase cases provided one probable myocarditis case during olanzapine monotherapy. Combining the literature and VigiBase provided another three probable cases during therapy with other antipsychotics during overdose or titration with a high dose.

KEYWORDS:

• Antipsychotic agents/administration and dosage
• antipsychotic agents/adverse effects
• antipsychotic agents/poisoning
• antipsychotic agents/toxicity
• mortality/drug effects
• myocarditis/chemically induced
• myocarditis/etiology
• olanzapine/adverse effects
• quetiapine/adverse effects
• quetiapine/poisoning

Article highlights

• Pharmacovigilance through the publication of case reports and, more importantly, reviews of the databases from the national drug agencies have demonstrated that clozapine causes myocarditis.

• Two published reviews suggested that on rare occasions other antipsychotics may induce myocarditis.

• Quetiapine: by combining published and VigiBase cases, we identified five probable myocarditis cases associated with antipsychotic monotherapy on quetiapine (four were after overdose or rapid titration). After controlling for confounders in VigiBase, quetiapine co-prescription was associated with increased odds ratios (ORs) for severity and lethality of myocarditis in clozapine patients. Thus, we recommend that clinicians be aware that on rare occasions quetiapine may contribute to myocarditis.

• Olanzapine: combining the literature and VigiBase, we identified only one probable myocarditis case associated with olanzapine. In summary, there is almost no proof that olanzapine is associated with myocarditis.

• Other antipsychotics: by combining published and VigiBase cases, we identified three probable myocarditis cases occurring during an overdose or a high-dose titration of other antipsychotics after excluding clozapine, quetiapine, and olanzapine.

Acknowledgments

The authors are indebted to the national centers that make up the World Health Organization (WHO) Program for International Drug Monitoring and contribute reports to VigiBase. The information comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. However, the opinions and conclusions of this study are not necessarily those of the various centers nor of the WHO. The authors acknowledge Lorraine Maw, from the University of Kentucky Mental Health Research Center at Eastern State Hospital, who helped in editing the article.

Declaration of interest

J de Leon has previously received researcher-initiated grants from Eli Lilly, Roche Molecular Systems, Inc and, in a collaboration with Genomas, Inc., from the NIH Small Business Innovation Research program. He has previously served on the advisory boards of Bristol-Myers Squibb and AstraZeneca. He has previously received support from Roche Molecular Systems for an educational presentation. His lectures have been supported by; Sandoz, Lundbeck, Pfizer, Eli Lilly, Janssen, Bristol-Myers Squibb and Roche Molecular Systems, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.