Domenico De Berardis1,2, Tiziano Acciavatti1, Giuseppe Di Iorio1, Mariangela Corbo1, Nicola Serroni2, Daniela Campanella2, Fabiola Di Emidio2, Monica Piersanti3, Marilde Cavuto4, Giovanni Martinotti5, Francesco Saverio Moschetta2, Massimo Di Giannantonio11Department of Neurosciences and Imaging, Chair of Psychiatry, University “G. D'Annunzio”, Chieti; 2NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”; 3NHS, Pharmaceutical Service, Hospital “G. Mazzini”, Teramo; 4IASM, L'Aquila; 5Institute of Psychiatry, Catholic University Medical School, Rome, ItalyAbstract: The circadian pacemaker or biological clock, located in the hypothalamic suprachiasmatic nucleus, is the generation site of circadian rhythms. The light/dark cycle is the circadian pacemaker's dominant synchronizing agent, though it is also influenced by neurotransmitters and the phase-shifting effects of various chemical and pharmacological components, of which melatonin (N-acetyl-5-methoxytryptamine) is the most well established. In recent years, melatonin and melatonin analogs have been commercialized in many countries, mainly with hypnotic purposes. A new compound, agomelatine, has been recently synthesized and studied. Among melatonin analogs, this drug possesses unique pharmacological and clinical features; it is an antagonist at 5-HT2B and 5-HT2C receptors and has well established antidepressant and anxiolytic properties. Agomelatine opens new perspectives in the chronobiotic treatment of depression. The purpose of the present review was to elucidate the effects of the melatonergic system on sleep and the implications for the treatment of psychiatric disorders.Keywords: melatonin, agomelatine, circadian rhythms, depression