Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT 2C antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine (both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration of agomelatine and melatonin was completely inhibited by an acute injection of the MT 1 /MT 2 antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT 2C antagonist properties.

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Agomelatine is a novel antidepressant acting as a melatonergic receptor agonist and serotonergic (5-HT 2C ) receptor antagonist. In adult rats, chronic agomelatine treatment enhanced cell proliferation and neurogenesis in the ventral hippocampus (VH), a region pertinent to mood disorders. This study compared the effects of agomelatine on cell proliferation, maturation, and survival and investigated the cellular mechanisms underlying these effects. Agomelatine increased the ratio of mature vs immature neurons and enhanced neurite outgrowth of granular cells, suggesting an acceleration of maturation. The influence of agomelatine on maturation and survival was accompanied by a selective increase in the levels of BDNF (brain-derived neurotrophic factor) vs those of VEGF (vascular endothelial factor) and IGF-1 (insulin-like growth factor 1), which were not affected. Agomelatine also activated several cellular signals (extracellular signal-regulated kinase1/2, protein kinase B, and glycogen synthase kinase 3b) known to be modulated by antidepressants and implicated in the control of proliferation/survival. Furthermore, as agomelatine possesses both melatonergic agonist and serotonergic (5-HT 2C ) antagonist properties, we determined whether melatonin and 5-HT 2C receptor antagonists similarly influence cell proliferation and survival. Only the 5-HT 2C receptor antagonists, SB243,213 or S32006, but not melatonin, mimicked the effects of agomelatine on cell proliferation in VH. The promoting effect of agomelatine on survival was not reproduced by the 5-HT 2C receptor antagonists or melatonin alone. However, it was blocked by a melatonin antagonist, S22153. These results show that agomelatine treatment facilitates all stages of neurogenesis and suggest that a joint effect of melatonin agonism and 5HT 2C antagonism may be involved in promotion by agomelatine of survival in the hippocampus.