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Hepatotoxicity Related to Agomelatine and Other New Antidepressants: A Case/Noncase Approach With Information From the Portuguese, French, Spanish, and Italian Pharmacovigilance Systems

Montastruc, François MD*; Scotto, Stefania MD, PhD; Vaz, Ines Ribeiro PharmD, MSc‡§; Guerra, Leonor Nogueira PharmD, MSc; Escudero, Antonio MSc; Sáinz, María PharmD, PhD; Falomir, Teresa PharmD#; Bagheri, Haleh MD, PhD*; Herdeiro, Maria Teresa PharmD, PhD‡§; Venegoni, Mauro MD, PhD; Montastruc, Jean Louis MD, PhD*; Carvajal, Alfonso MD, PhD

Journal of Clinical Psychopharmacology: June 2014 - Volume 34 - Issue 3 - p 327–330
doi: 10.1097/JCP.0000000000000094
Original Contributions

Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4–9.7)], France (ROR, 2.4 [95% CI, 1.5–3.7]), and Italy (ROR, 5.1 [95% CI, 1.7–14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.

From the *Laboratoire de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Unité de Pharmacoépidémiologie de l’UMR INSERM 1027, Faculté de Médecine, CHU de Toulouse, Toulouse, France; †Centro Regionale di Farmacovigilanza, Regione Lombardia, Milano, Italy; ‡Northern Pharmacovigilance Centre, Faculty of Medicine, and §Centre for Research in Health Technologies and Information Systems, University of Porto, Porto; ∥Directorate of Risk Management of Medicines National Authority of Medicines and Health Product-INFARMED, IP, Lisboa, Portugal; ¶Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain; and #Centro Regional de Farmacovigilancia de las Illes Balears, Illes Balears, Spain.

Received April 10, 2013; accepted after revision September 6, 2013.

Reprints: Alfonso Carvajal, MD, PhD, Ramón y Cajal, 7, Facultad de Medicina, Universidad de Valladolid, 47005 Valladolid, Spain (e-mail:

© 2014 by Lippincott Williams & Wilkins.