The widespread use of the atypical antipsychotic, clozapine, has been limited due to considerable risks of rare but potentially fatal adverse side effects. Among these adverse effects, cardiac side effects such as myocarditis are under-appreciated despite their association with increased risk of death. Unfortunately, our ability to identify those at greatest risk for clozapine-associated cardiac side effects is poor.
In response to this gap in knowledge, we are conducting the Pharmacogenetics of Clozapine-Induced Myocarditis (PROCLAIM) study. The PROCLAIM study will unite investigators around the world to uncover genomic markers that could be used preemptively by clinicians to identify those patients at highest risk for myocarditis from clozapine therapy and identify the mechanism by which clozapine induces myocardial inflammation and damage.
We invite all clinicians and/or investigators who have cared for and/or studied individuals that have developed myocarditis following clozapine exposure to join the PROCLAIM Study. We are particularly interested in members who can contribute samples and/or genomic data that would enable pooled analyses to be performed. Please contact us if you are interested in becoming a site.
The PROCLAIM study was initiated in 2017 by Dr Chad Bousman and Prof Christos Pantelis at the University of Melbourne. The first nine participants were recruited from the Adult Mental Health Rehabilitation Unit at Sunshine Hospital in Melbourne, Australia. In late 2017, Dr Bousman and the PROCLAIM study relocated to the University of Calgary, maintaining the University of Melbourne as a study site. Currently there are 11 sites covering Australia, Canada, and the US (see below for site details and investigators affiliated with the study).
University of Melbourne Establishment Grant (2017, Bousman)
University of Calgary, Cumming School of Medicine (2017-2019, Bousman)
Study Hypotheses & Aims
1. Patients with clozapine-induced myocarditis will carry distinct genetic variants that will differentiate them from their clozapine-treated counterparts who did not develop myocarditis.
2. Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) of patients with clozapine-induced myocarditis will have a differential response to clozapine exposure compared to iPSC-CMs from patients who did not develop myocarditis.
1. To collect DNA from patients with and without a history of clozapine-induced myocarditis and perform genomic analyses. DNA will be interrogated by next generation sequencing using established methods.
2. To collect blood from patients with and without a history of clozapine-induced myocarditis for the purpose of creating patient- and disease-specific iPSCs. White blood cells will be reprogrammed using established methods to create iPSCs.
3. To establish in vitro models of clozapine-induced myocarditis by differentiating iPSCs into cardiomyocytes. Applying existing protocols, patient iPSCs will be differentiated into iPSC-CMs by the introduction of defined factors.
4. To characterize the structural and functional effects of clozapine on patient-derived cardiomyocytes. iPSC-CMs from cases and controls will be incubated with clozapine. A variety of techniques will be used to characterize the structure and function of these cells.
Chad Bousman, MPH, PhD
University of Calgary
University of Calgary
Steven Greenway, MSC, MD, FRCPC
Quan Long, PhD
Rory Sellmer, BPE, MD, FRCPC
David Crockford, MD, FRCPC, DABPN, FAPA, FCPA
Maja Tarailo-Graovac, BSc, PhD
University of Melbourne
Christos Pantelis, MBBS, MRCPsych, MD, FRANZCP
Naveen Thomas, MBBS
Mahesh Jayaram, MBBS, DPM, MMedSc
Kathlyn Ronaldson, BSc, MSc, DPhil, MPH
John McNeil, MBBS, MSc, PhD, FRACP, FAFPHM
University of New South Wales, Neuroscience Research Australia
Cynthia Shannon Weickert, BA, Mphil, PhD
University of Queensland
Dan Siskind, MD, PhD
Karl Winckel, BPharm
The University of Newcastle
Murray Cairns, PhD
Kevin J Li, MD
Lynn DeLisi, MD
Ronald Gurerra, MD
Jerry Fleming, MPH
University of Toronto, Centre for Addictions & Mental Health
Gary Remington, MD, PhD
William Osler Health System
Shailesh Nadkarni, MBBS, MHSA
Amlan Das, MD
Charles Ohene-Darkoh, MD
University of British Columbia
Robert Stowe, MD, ABPN, FRCPC
University of Alberta
Katerine Aitchison, BM BCh, PhD, MRCPsych