Characterization of agomelatine-induced liver enzyme increase : frequency and risk factors dertermined from a pooled analysis of 7 , 605 treated patients

Background. Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicine Agency for agomelatine. Objective. To assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomaatine. Method. A retrospective pooled analysis of changes in transaminase levels in 9,234 patients treated with agomelatine (25mg or 50mg/day; n=7,605) or placebo (n=1,629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3-fold the upper limit of normal (>3ULN). Final causality was determined in a case-by-case review by five academic experts. Results. Serum transaminase increased to >3ULN in 1.3% and 2.5% of patients treated with 25mg and 50mg of agomelatine respectively, compared to 0.5% for placebo. The onset of increased transaminases occurred before 12 weeks in 64% of patients. The median time to recovery (to≤2ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1% 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. Conclusion. 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. Perlemuter G et al. Agomelatine and liver injury 4