Mode of action of agomelatine: Synergy between melatonergic and 5-HT_2C receptors

Abstract

Objectives. The association between depression and circadian rhythm disturbances is well established and successful treatment of depressed patients is accompanied by restoration of circadian rhythms. The new antidepressant agomelatine is an agonist of melatonergic MT₁/MT₂ receptors as well as an antagonist of serotonergic 5-HT_2C receptors. Animal studies showed that agomelatine resynchronizes disturbed circadian rhythms and reduces depression-like behaviour. Methods. This review analyzes results from different experimental studies. Results. Recent data on the effects of agomelatine on cellular processes involved in antidepressant mechanisms have shown that the drug is able to increase the expression of brain-derived neurotrophic factor in prefrontal cortex and hippocampus, as well as the expression of activity-regulated cytoskeleton associated protein (Arc) in the prefrontal cortex. In line with this, prolonged treatment with agomelatine increases neurogenesis within the hippocampus, particularly via enhancement of neuronal cell survival. Agomelatine attenuates stress-induced glutamate release in the prefrontal/frontal cortex. Treatment with 5-HT_2C antagonists or melatonin alone failed to reproduce these effects. Conclusions. The unique mode of action of agomelatine may improve the management of major depression by counteracting the pathogenesis of depression at cellular level, thereby relieving the symptoms of depression. These effects are suggested to be due to a synergistic action on MT₁/MT₂ and 5-HT_2C receptors.

Key words::

• Agomelatine
• circadian rhythms
• depression
• melatonergic receptor
• serotonergic receptor

Acknowledgements

None.

Statement of Interest

G. Racagni has scientific collaboration with and is member of scientific board for Eli Lilly, Innova Pharma, and Servier. M. Popoli has received research support and/or has been consultant for Abiogen, GlaxoSmithKline, MerckSharp & Dohme, Servier and Fidia. M.A. Riva has received honoraria or research support from AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma Co. Ltd, Eli Lilly, Innova Pharma, Merck Sharp & Dohme, Servier and Takeda. The other Authors declare no conflict of interest. All authors did not receive any support for this paper from Servier.