Emerging Targets for the Pharmacological Treatment of Depression: Focus on Melatonergic System

Abstract

Depression is a disabling condition 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. In the last years, besides the classical research involving serotonin, norepineprine and dopamine, non-monoaminergic mechanisms have been explored in the attempt to discover new antidepressants. One such innovative approach focused on melatonergic system, as melatonin is involved in synchronizing circadian rhythms, which are known to be altered in depression. This narrative 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 of depression. In 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 MT1 and MT2 agonism with 5-HT(2C) 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.

Metabolomics analysis reveals insights into biochemical mechanisms of mental stress-induced left ventricular dysfunction

“…It is well documented that various compounds in the CNS (e.g. tryptophan products, such as kynurenic acid (Soltis and DiMicco 1992; Miura et al 2008; Oxenkrug 2013), serotonin (McCall and Clement 1994; Ramage and Villalón 2008; Miura et al 2008; Oxenkrug 2013), N -acetyl-sero-tonin (Oxenkrug 1999; Oxenkrug and Ratner 2012), and melatonin (Simko and Paulis 2007; Catena-Dell'Osso et al 2012) play roles in modulating physiological and psychological responses during stress. Synthesis of these compounds, which is essential for maintaining healthy neurotransmission, is dependent on the transport of precursor amino acids across the blood brain barrier.…”

Possibility of early withdrawal of benzodiazepine hypnotics by combination with ramelteon for the treatment of insomnia: A pilot study

“…12 Therefore, as the method for gradual reduction of BZ hypnotics, reducing about a quarter of daily dose in every 2 to 4 weeks is recommended. 13 Most subjects in this study took BZ hypnotics more than one year, and the speed of reduction was faster than recommendation. Because of the small number of subjects and no evaluation of the effect of concomitant psychotropic drugs, it is difficult to clarify that RMT has potential to prevent withdrawal symptoms.…”

“…Generally, if the duration of administration of BZ hypnotics exceeds six months to one year, withdrawal symptoms appear in about 80% of patients . Therefore, as the method for gradual reduction of BZ hypnotics, reducing about a quarter of daily dose in every 2 to 4 weeks is recommended . Most subjects in this study took BZ hypnotics more than one year, and the speed of reduction was faster than recommendation.…”

Antipsychotic-like effect of agomelatine in a rodent model

“…Melatonin treatment may have some beneficial effects in the treatment of mental disturbances (2) due to its anti-inflammatory (3) antinociceptive (4), anxiolytic (5), chemical detoxification properties (6) and its protective effects against oxidative stress (7,8). Agomelatine, a naphthalene bioisostere of melatonin, which is a potent Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 28, Number 2, June 2015 MT1 and MT2 agonist and 5-HT(2C) receptor antagonist, has also been found effective in the treatment of depressive and anxiety symptoms associated with major depression (9).…”