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ORIGINAL RESEARCH article

Front. Psychiatry
Sec. Psychopharmacology
Volume 15 - 2024 | doi: 10.3389/fpsyt.2024.1479625
This article is part of the Research Topic Safety and Side Effects of Psychotropic Medications, volume III View all 7 articles

Hepatotoxicity of Antipsychotics: An Exploratory Pharmacoepidemiologic and Pharmacodynamic Study Integrating FAERS Data and In Vitro Receptor-Binding Affinities

Provisionally accepted

The final, formatted version of the article will be published soon.

    Introduction: Antipsychotic psychopharmacotherapy is associated with the risk of drug-induced liver injury (DILI). However, understanding specific risk factors remains challenging due to limited data. This study investigates the relationship between receptor binding affinities and occupancies of antipsychotics and their associated hepatotoxic risks. Methods: A disproportionality analysis with calculation of the Reporting Odds Ratio (ROR) and the Information Component (IC) was conducted using data from the FDA Adverse Event Reporting System (FAERS) to identify signals related to the Standardised MedDRA Query "drug-related hepatic disorders", which served as a proxy for drug-induced hepatotoxicity. This was followed by a pharmacoepidemiologic-pharmacodynamic approach to investigate the relationship between the ROR and substance-related receptor binding affinities and occupancy, which was estimated based on in vitro receptor-binding profiles. Results: Significant signals were identified for several antipsychotics, including chlorpromazine, loxapine, olanzapine, and quetiapine, with chlorpromazine and loxapine showing the highest RORs for DILI. Gender-specific analysis revealed a higher frequency of signals in female patients. Statistically significant negative correlations were identified between the ROR for drug-related hepatic disorders and the affinity for serotonin receptor 5-HT1A (r(17) = -0.68, p = 0.0012), while a positive correlation was observed for cholinergic receptors (r(17) = 0.46, p = 0.048).. No significant correlations were found related to other receptors or drug properties. Conclusion: Our findings suggest that the serotonin and probably the cholinergic system may play a role in the development of DILI related to antipsychotic medications. The identification of antipsychotics with a higher association with DILI, such as chlorpromazine, underscores the need for hat gelöscht: Hepatotoxicity of Antipsychotics: An

    Keywords: Antipsychotic Agents, Chemical and drug induced liver injury, Receptors Serotonin, Pharmacovigilance, receptor binding

    Received: 12 Aug 2024; Accepted: 23 Sep 2024.

    Copyright: © 2024 Zeiss, Schönfeldt-Lecuona, Connemann, Hafner and Gahr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Rene Zeiss, University of Ulm, Ulm, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.