Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

Abstract

Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

“…Pre-clinical and clinical data support the notion that the selective MT1/MT2 agonist ramelteon, which has a substantially longer half-life than melatonin, might be considered as a drug of choice for the treatment of circadian rhythm sleep disorders (Salva and Hartley, 2012).…”

“…A bidirectional link between circadian rhythm and these disorders has been suggested (Salva and Hartley, 2012;Yalyn et al, 2006;Yousaf et al, 2010). Agents that synchronize circadian fluctuations are considered to possess chronobiotic activity (Pévet et al, 2002).…”

“…Despite its chronobiotic activity as a pure MT1 and MT2 receptor agonist, ramelteon is unlikely to affect depressive symptoms in MDD (Salva and Hartley, 2012 (Arendt and Rajaratnam, 2008;Eser et al, 2007). Preclinical data has revealed that exogenous melatonin is active in routinely used screening tests for antidepressant actions, such as the forced swim test (FST) (Bourin et al, 2004;Brotto et al, 2000;Ergün et al, 2008;Micale et al, 2006;Overstreet et al, 1998;Raghavendra et al, 2000;Shaji et al, 1998;Ramírez-Rodríguez et al, 2014;Zahra et al, 2012;) and the tail suspension test (TST) (Prakhie et al, 1998;Mantovani et al, 2003;Binfarè et al, 2010;Oxenkrug et al, 2010) (Table 2).…”

“…Melatonin receptor expression is under the control of light, and secretion of endogenous ligand follows a circadian rhythm (Salva and Hartley, 2012). While melatonin synthesis is regulated by the SCN clock, the hormone directly affects the activity of the SCN through activation of melatonin receptors (Pèvet et al, 2002).…”

Contributions of animal models to the study of mood disorders

“…Their main function is to regulate biological processes with circadian periodicity. [162][163][164] Circadian rhythm abnormalities have been associated with BD, but its potential role in the pathophysiology of BD is still poorly understood. 164 Studies have found that life events that disrupt the social rhythm are associated with the onset of manic episodes in BD patients.…”