An original pharmacoepidemiological–pharmacodynamic method: application to antipsychotic‐induced movement disorders

• Published in: British journal of clinical pharmacology Vol. 83; no. 3; pp. 612 - 622
• Main Authors: Nguyen, Thi Thu Ha, Pariente, Antoine, Montastruc, Jean‐Louis, Lapeyre‐Mestre, Maryse, Rousseau, Vanessa, Rascol, Olivier, Bégaud, Bernard, Montastruc, François
• Format: Journal Article
• Language: English
• Published: England Wiley 01.03.2017; John Wiley and Sons Inc
• Subjects: Adverse Drug Reaction Reporting Systems - statistics & numerical data; Antipsychotic Agents - adverse effects; antipsychotic drugs; Dopamine D2 Receptor Antagonists - adverse effects; drug mechanisms; Dyskinesia, Drug-Induced - epidemiology; Human health and pathology; Humans; Life Sciences; Methods in Clinical Pharmacology; movement disorders; Muscarinic Antagonists - adverse effects; pharmacoepidemiology; Pharmacoepidemiology - methods; Pharmacovigilance; Psychiatrics and mental health; Santé publique et épidémiologie; Serotonin 5-HT2 Receptor Antagonists - adverse effects; VigiBase; World Health Organization; drug mechanisms; VigiBase; movement disorders; antipsychotic drugs; pharmacoepidemiology
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13145

Aims Pharmacovigilance databases are usually used to detect new potential signals that are relevant for drug safety. They are seldom used for explanatory purposes, e.g. to understand the mechanisms of adverse drug reactions (ADRs). The aim of the present study was to combine pharmacovigilance and pharmacodynamic data to investigate the association between dopamine D2, serotonin 5HT2A, and muscarinic M1 receptor occupancy and the risks of antipsychotic drug (AP)‐induced movement disorders. Methods First, we performed a case–noncase analysis using spontaneous reports from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database, VigiBase®. We thus measured the risk of reporting movement disorders compared with all other ADRs [expressed as a reporting odds ratio (ROR)] for APs. Second, we performed a linear regression analysis to explore the association between the estimated risk of reporting for individual drugs and their receptor occupancy properties, for D2, 5HT2A and M1 receptors. Results Compared with second‐generation APs, first‐generation APs were found to be significantly more associated with the reporting of movement disorders in general but also with dystonia, Parkinsonism, akathisia and tardive dyskinesia, irrespective of gender. A significant inverse correlation was found between the ROR for movement disorders and the receptor occupancy of 5HT2A [P < 0.001; R2 = 0.51; slope = −0.014; 95% confidence interval (CI) (−0.029, 0.001)], M1 (P < 0.001; R2 = 0.56; slope = −0.014; 95% CI (−0.028, 0.001) but not D2 dopamine (P = 0.54; R2 = 0.02; slope = −0.003; 95% CI (−0.007, 0.001) receptors. Conclusions Using the example of AP‐induced movement disorders, the present study underlines the value of the pharmacoepidemiological–pharmacodynamic method to explore ADR mechanisms in humans and real‐life settings.