The interaction between the internal clock and antidepressant efficacy

Sleep disturbances are often associated with depression and mood disorders, and certain manipulations of the sleep-wake cycle are effective as therapeutic interventions in the treatment of depression. Dysregulated circadian rhythms are thereby considered as causal. Circadian rhythms in mammals are mainly regulated by a core biological clock, located in the hypothalamic suprachiasmatic nucleus; its pacemaker activity is regulated by light and nonphotic modulatory pathways, and the driving mechanisms are serotonergic input from the raphe and the hormone melatonin originating from the pineal gland. In line, the concentration of brain serotonin and the levels of 5-HT2C receptors are high and highly expressed there. Agomelatine, a novel antidepressant drug with proven clinical efficacy in major depressive disorder, has a unique mechanism of action; it acts as an agonist at melatonergic MT1 and MT2 receptors and as an antagonist at 5-HT2C receptors. In animals, agomelatine was shown to increase noradrenaline and dopamine (but not serotonin) in the frontal cortex, to resynchronize the sleep-wake cycle in models with disrupted circadian rhythms, and to exhibit a clear antidepressant effect in various animal models of depression. On the basis of the functional relationship between melatonergic and serotonergic signaling in the suprachiasmatic nucleus, and given agomelatine's affinity at melatonergic and 5-HT2C receptors, the therapeutic efficacy of the drug may be due to the potential synergy of its action at these different receptors.