Melatonin, insomnia and the use of melatonergic drugs V Srinivasan 1 , Rahimah Zakaria 2 , Zahiruddin Othman 3 , Amnon Brzezinski 4 1 Sri Sathya Sai Medical Educational and Research Foundation, Prasanthi Nilayam, 40-Kovai Thirunagar, Coimbatore-641014, Tamilnadu, India 2 Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia 3 Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia 4 Department of Obstetrics and Gynecology, The Hebrew University, Hadassah Medical Center, Jerusalem, 91120, Israel Summary Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT 1 and MT 2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon’s use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders. Key Words : Melatonin, ramelteon, insomnia, agomelatine, depressive disorder. Correspondence to be addressed to: Dr. V Srinivasan PhD MAMS, Email: sainivasan@yahoo.com 1. Introduction Melatonin (N-acetyl-5-methoxytryptamine), first identified by Lerner et al. (1958), is the major neurohormone secreted from the pineal gland mainly during dark hours of the night and is released in higher concentrations into the cerebrospinal fluid (Tricoire et al., 2003). The circadian pattern of pineal melatonin secretion is regulated by suprachiasmatic nucleus (SCN) of the hypothalamus. A major portion of the SCN is projected to the subparaventricular zone of the hypothalamus from where fibers proceed to terminate in the areas involved in sleep-wake regulation (Saper et al., 2005b). Sleep regulation involves interaction of two separate mechanisms namely an endogenous biological-clock that drives the circadian-rhythm of sleep-wake cycle (process-C) and a homeostatic process (process-S) that influences sleep- propensity which is determined by the duration of previous sleep episodes (Borbely, 1982). These two processes interact continuously and determine the consolidated bout of sleep at night and consolidated bout of wakefulness during daytime. Melatonin has a role in sleep regulation, since its nocturnal rise leads to “opening of the sleep gate” and augmentation of sleep propensity (Dijk and Cajochen, 1997). Importance of melatonin in both initiation and maintenance of sleep has been demonstrated (Cajochen et al., 2003). In diurnal animals and in human beings the onset of melatonin secretion has been shown to coincide with the timing of increase in nocturnal sleep propensity (Lavie, 1997). Since melatonin has both hypnotic and chronobiotic properties, it has been used for treatment of age-related insomnia and other primary and secondary insomnia (Zhdanova et al., 2001), and prolonged release of melatonin preparations are also effective in treating insomnias (Wilson et al., 2010). Melatonin has also been used successfully for treatment of sleep disturbances due to disruptions of the circadian time keeping system like jet-lag, shift-work disorder or delayed sleep phase syndrome (Arendt et al., 1997; Srinivasan et al., 2010b). The high density of MT 1 and MT 2 melatonin receptors in the hypothalamic SCN confirms that melatonin regulates sleep and the sleep- J Endocrinol Reprod 16 (2012) 1 : 15-24 Review Article 15