Emerging targets for the pharmacological tratment of depression: focus on melatonergic system.

Abstract: Depression is a disabling conditìon which adversely affects a person's family, social and work life, and that is associated with a heavy burden to society Although the available antidepressants have shown their effectiveness and have greatly improved the prognosis of the disorder,the current management of depression is far from being satisfactory. ln the last years,besides the classical research involving serotonin, norepineprine and dopamine, non-monoaminergic mechanisms have been explored in the attempt to discovernew antidepressants. One such innovative approach focused on melatonergic system, as melatonin is involved in synchronizing circadian rhythms, which are known to be altered ir depression This nanative review aims to provide a comprehensive overview of different aspects of the melatonergic system, including biochemical and anatomical characteristics, impact on the sleep/wake system, and implications for the treatment ofdepression. ln particular, the observation that melatonin may promote sleep and synchronize the internal clock led to development of high-affinity agonists for melatonin receptors (MT) Agomelatine, a naphthalene bioisostere of melatonin, which combines a potent MTl and MT2 agonism with 5-HT:c receptor antagonism, has been found to be effective in the treatment of depressive and anxiety symptoms associated with major depression, with rapid and beneficial effects on the regulation of sleep continuity and quality. If substantiated by further evidence,the observation that melatonergic system dysfunctions contribute to the development of depression, as well as that the antidepressant action of agomelatine is linked to its binding properties to MT1/MT2 receptors, might open new avenues for the discovery of antidepressive agents. Keywords: Agomelatine, antidepressants, arylalkylamine N-acetylhansferase (AANAT), depression, melatonin, melatonin receptors, ramalteon.