Does melatonin treatment change emotional processing? Implications for understanding the antidepressant mechanism of agomelatine.

The antidepressant, agomelatine, has a novel pharmacological profile, with agonist properties at M1 and M2 receptors and antagonist properties at 5HT2C receptors. Whether the antidepressant effects of this treatment are mediated by the drug's effects at the M1 and M2 receptors or the 5HT2C receptor or a synergy between these actions remains unclear. In the present study, a healthy volunteer model of emotional processing, which discriminates between effective and non-effective antidepressant compounds, was used to assess the contribution of melatonin agonism to the efficacy of agomelatine. Fifty-eight healthy volunteers were randomised to receive 7 days of once daily treatment with either 1 mg melatonin, 3 mg melatonin or placebo. Seven days treatment with 3 mg melatonin resulted in earlier bedtimes consistent with a phase advance in circadian rhythm. Some marginal effects of melatonin were observed on emotional processing; however, these were neither consistent with nor comparable to those seen following conventional antidepressant treatment or with agomelatine itself. These data suggest that the antidepressant action of agomelatine cannot be accounted for solely by its action at the M1 and M2 receptors.