The Emerging Role of Melatonin Agonists in the Treatment of Major Depression: Focus on Agomelatine

Abstract

Major Depressive Disorder (MDD) is an extremely disabling, chronic and recurrent disease. Moreover, subthreshold depressive symptoms often persist during periods of apparent remission. Such symptoms include sleep disturbances, sexual dysfunction, weight gain, fatigue, disinterest, anxiety, and/or emotional blunting, which do not often respond to available antidepressant treatments. Agomelatine is a melatonergic agonist (at both MT1 and MT2 receptors) and serotonin 2C (5-HT2C) receptor antagonist. Agomelatine should be particularly useful in the treatment of MDD because of its unique pharmacological profile, accounting for its effective antidepressant action with a relative lack of serious adverse effects. Several clinical trials confirmed the antidepressant efficacy of agomelatine in patients with MDD, with significant efficacy even in severe manifestations of disease and on residual subtreshold symptoms. This compound showed a relative early onset of action as well as an excellent safety and tolerability profile linked to a low discontinuation rate in MDD patients. Moreover, some data suggest that agomelatine has not only antidepressant effects but also anxiolytic effects, with a potential benefit both on anxiety symptoms associated with MDD and in the treatment of generalised anxiety disorder. This review will summarise the role of the melatonergic system in MDD and will describe the characteristics of agomelatine, focusing on its efficacy and safety in the treatment of MDD.

Is There a Role for Agomelatine in the Treatment of Anxiety Disorders? A Review of Published Data

“…The main metabolites of agomelatine are 3-hydroxy S20098, 3-hydoxy, 7-methoxy S20098, 7-desmethyl S20098 and dihydrodiol S20098. A major oxidative metabolite in humans is 3-hydroxy-7 desmethyl agomelatine, which has low affinity for MIl, MT2 and 5-HT2c receptors (9). The mean terminal elimination half-life is 2.3 h.…”

“…Agomelatine, is administered once daily at a dose of between 25 and 50 mg/day at bedtime (9). In February 2009, agomelatine was approved by the European Agency of Medicines (EMEA) for the treatment of Major Depression (MD) and is available in several European countries.…”

“…The circadian pacemaker or biological clock, located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus, above the optic chiasma, is the site of generation of circadian rhythms and prepares the organism to anticipate the daily changes in the environment (6). The activation ofmelatonergic MTl receptors directly inhibits firing of neurons in the SCN, thus regulating the amplitude of the circadian rhythmicity, and facilitating sleep promotion, whereas melatonin-mediated activation of MT2 receptors is responsible for inducing phase shifts and, therefore, may be involved in the entrainment of circadian rhythmicity (7)(8)(9).…”

Agomelatine in the Treatment of Anxiety and Depressive Disorders in Patients With Ischemic Heart Disease

“…На сегодняшний день аго-мелатин имеют самую большую клиническую базу из всех синтетических агонистов MT1 и MT2 мелатони-новых рецепторов. В отличие от мелатонина агомела-тин обладает способностью к антагонизму к рецепто-рам серотонина (5-НТ2С) в центральной нервной си-стеме [49,50].…”

Agomelatine, melatonin and depressive disorder

“…Further, the demonstration that agomelatine is capable of entrainment of the 24-h cycle (circadian cycle) provides a point of conjunction [2]. Efficacy of agomelatine as an antidepressant has been established in clinical trials and extensively, critically reviewed in the literature [3][4][5][6][7][8]. Coupled with its efficacy, the relatively benign side effect profile, at least in the doses used in clinical trials (up to 50 mg/day), would suggest that the compound is ideally suited to the treatment of the majority of cases of MDD [1].…”