title: Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients.
abstract: Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine.
  
  
  
  The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine.
  
  
  
  A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50 mg/day; n = 7605) or placebo (n = 1629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3 × ULN). Final causality was determined in a case-by-case review by five academic experts.
  
  
  
  Serum transaminases increased to >3 × ULN in 1.3 and 2.5 % of patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for placebo. The onset of increased transaminases occurred before 12 weeks in 64 % of patients. The median time to recovery (to ≤2 × ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1 % of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo.
  
  
  
  Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored.
authors.affiliation: Univ. Paris-Sud, Univ. Paris-Saclay, CHU Bicêtre, 94270, Kremlin-Bicêtre, France. gabriel.perlemuter@aphp.fr.|AP-HP, Hôpital Antoine-Béclère, Service d'Hépato-Gastroentérologie et Nutrition, DHU Hepatinov, 157 rue de la Porte de Trivaux, 92140, Clamart, France. gabriel.perlemuter@aphp.fr.|INSERM U996, IPSIT, Labex Lermit, Clamart, France. gabriel.perlemuter@aphp.fr.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Perlemuter
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, UMR 7211, Paris, France.|Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 75005, Paris, France.|INSERM, UMR_S 959, 75013, Paris, France.|CNRS, FRE3632, 75005, Paris, France.|Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Cacoub
authors.affiliation: DHU UNITY, Service d'Hépatologie, AP-HP, Hôpital Beaujon, Clichy, France.|CRI, UMR1149, Université Paris Diderot, Paris, France.|INSERM U1149, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valla
authors.affiliation: Liver Disease Unit and INSERM U991, CHU Pontchaillou, Rennes, France.|University of Rennes 1, CHU de Rennes, Rennes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guyader
authors.affiliation: Institut de Recherches Internationales Servier, 92415, Suresnes, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Saba
authors.affiliation: Institut de Recherches Internationales Servier, 92415, Suresnes, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Batailler
authors.affiliation: UCL Institute of Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Moore
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D000637:Transaminases / Q000378:metabolism*; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D000637:Transaminases; C084711:agomelatine; D009281:Naphthalenes