Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK

Carlos De Las Cuevas; Emilio J Sanz; Jason A Gross; Christoph U Correll; Hélène Verdoux; John Lally; Renato de Filippis; Peter F J Schulte; Espen Molden; Manuel Arrojo-Romero; Adrian D Bostrom; Georgios Schoretsanitis; Emilio Fernandez-Egea; Jose de Leon

doi:10.1016/j.schres.2023.11.010

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK

Schizophr Res. 2023 Dec 7:S0920-9964(23)00422-X. doi: 10.1016/j.schres.2023.11.010. Online ahead of print.

Authors

Affiliations

¹ Department of Internal Medicine, Dermatology and Psychiatry, School of Medicine, University of La Laguna, Canary Islands, Spain; Instituto Universitario de Neurociencia (IUNE), Universidad de La Laguna, San Cristóbal de La Laguna, Spain. Electronic address: ccuevas@ull.edu.es.
² Department of Physical Medicine and Pharmacology, School of Medicine, Universidad de La Laguna, Canary Islands, Spain; Hospital Universitario de Canarias, Tenerife, Spain.
³ HLS Therapeutics, Toronto, Canada. Electronic address: j.gross@hlstherapeutics.com.
⁴ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany; The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA. Electronic address: CCorrell@northwell.edu.
⁵ Université Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, Bordeaux, France. Electronic address: helene.verdoux@u-bordeaux.fr.
⁶ Department of Psychiatry, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.; Department of Psychiatry, St Vincent's Hospital Fairview, Dublin, Ireland; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK. Electronic address: john.lally1@ucd.ie.
⁷ Psychiatry Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
⁸ Mental Health Services Noord-Holland-Noord, Alkmaar, the Netherlands; Dutch Clozapine Collaboration Group, Castricum, the Netherlands. Electronic address: R.Schulte@ggz-nhn.nl.
⁹ Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; Department of Pharmacy, University of Oslo, Oslo, Norway. Electronic address: espen.molden@farmasi.uio.no.
¹⁰ Department of Psychiatry, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. Electronic address: manuel.arrojo.romero@sergas.es.
¹¹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences/Psychiatry, Umeå University, Umeå, Sweden. Electronic address: adrian.desai.bostrom@ki.se.
¹² The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA; Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland.
¹³ Department of Psychiatry, University of Cambridge, Cambridge, UK,; Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Fulbourn, Cambridge, UK. Electronic address: ef280@cam.ac.uk.
¹⁴ Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA; Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain. Electronic address: jdeleon@uky.edu.

PMID: 38065799
DOI: 10.1016/j.schres.2023.11.010

Abstract

Background: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs).

Objective: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality.

Methods: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions.

Results: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number.

Conclusions: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

Keywords: Clozapine/administration and dosage; Clozapine/adverse effects; Clozapine/therapeutic use; Drug labeling; Europe; Schizophrenia.