Agomelatine (AGM) was approved for the treatment of major depressive disorder (MDD) in adults by the
European Medicines Agency (EMA) in February 2009. It is an analogue of melatonin and features a unique
pharmacodynamic profile with agonism on both types of melatonergic receptors (MT1/MT2) and antagonism at
serotonergic 5-HT2C receptors. There is, however, an ongoing debate regarding the efficacy and safety of this novel
antidepressant agent, originally evoked by claims of a significant publication bias underlying the assessment of AGM
being an effective antidepressant. Indeed, two recent comprehensive metaanalyses of published and unpublished clinical
trials found evidence for a relevant publication bias. However, due to its statistically significant advantage over placebo
based on the results of these metaanalyses AGM must be referred to as an effective antidepressant agent in the acute phase
of MDD. However, the effect sizes of AGM in the treatment of MDD were evaluated as being small in comparison to
other antidepressant agents. In addition, there is insufficient evidence for the efficacy of AGM in relapse prevention of
MDD. Apart from efficacy issues, AGM appears to have the potential to exhibit severe hepatotoxicity (the EMA has
identified AGM-associated “hepatotoxic reactions” as a new safety concern in September 2013) that is currently poorly
understood. Considering these aspects, it seems inappropriate to evaluate AGM as an antidepressant agent of first choice.
Nevertheless, its unique mechanism of action with particular sleep modulating effects may represent a specific treatment
strategy for patients with particular characteristics; further studies with thorough characterization of patients are needed to
test this hypothesis.
Keywords: Adverse drug reaction, antidepressant, hepatopathy, liver enzymes, melatonin, pharmacovigilance, S20098.
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