title: Hepatotoxicity associated with agomelatine and other antidepressants: Disproportionality analysis using pooled pharmacovigilance data from the Uppsala Monitoring Centre.
abstract: Since its marketing approval, the attention to the hepatic side-effect profile of the antidepressant agomelatine (AGM) has gradually increased. Several cases of severe hepatotoxic adverse drug reactions (ADR) have been reported and the European Medicines Agency has released a safety warning regarding AGM-associated hepatotoxicity. However, there are insufficient data for an adequate safety assessment of AGM-related hepatotoxicity. Therefore, we performed a quantitative signal detection analysis using pharmacovigilance data from the Uppsala Monitoring Centre from the WHO that records ADR data from worldwide sources; we calculated reporting odds ratios (ROR) as measures for disproportionality within a case/non-case approach for AGM and several other antidepressants. AGM was statistically associated with an increased risk of hepatotoxicity (ROR 6.4 [95%CI 5.7-7.2]) as well as both positive controls: amineptine (ROR 38.4 [95%CI 33.8-43.6]) and nefazodone (ROR 3.2 [95%CI 3.0-3.5]). Following amineptine, AGM was associated with the second highest ROR, followed by tianeptine (ROR 4.4 [95%CI 3.6-5.3]), mianserin (ROR 3.6 [95%CI 3.3-3.9]), and nefazodone. These results support the hypothesis that AGM is associated with relevant hepatotoxicity. However, the used data and applied method do not allow a quantitative evaluation of hepatotoxicity or assessment of substance-specific differences regarding the extent of hepatotoxicity.
authors: Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany.
authors: Maximilian
authors: M
authors: Gahr
authors: Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany.
authors: René
authors: R
authors: Zeiss
authors: Department of Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany.
authors: Dirk
authors: D
authors: Lang
authors: Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany.
authors: Bernhard J
authors: BJ
authors: Connemann
authors: Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany.
authors: Carlos
authors: C
authors: Schönfeldt-Lecuona
mesh_terms: D000081:Acetamides / Q000009:adverse effects*; D016907:Adverse Drug Reaction Reporting Systems; D000928:Antidepressive Agents / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D060735:Pharmacovigilance; D013548:Sweden / Q000453:epidemiology; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; C084711:agomelatine; D009281:Naphthalenes
keywords: adverse drug reaction; drug safety; liver enzymes; signal detection