Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients

Background Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine. Objective 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. Method 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 x ULN). Final causality was determined in a case-by-case review by five academic experts. Results Serum transaminases increased to > 3 x 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 x 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. 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.