Psychopharmacology 3e Web Box 18.3 - Clinical Applications: Agomelatine

Sleep disruptions and multiple circadian dysfunctions are central features of clinical depression. Additionally, polymorphisms of genes of the biological clock in the suprachiasmatic nucleus of the hypothalamus represent a genetic predisposition to circadian irregularities in some depressed patients. One classic approach to resynchronizing endogenous rhythms and the sleep–wake cycle is administration of melatonin. Melatonin, a pineal gland hormone regulated by light exposure, induces sleep and regulates circadian function by acting at MT1 and MT2 melatonin receptors. Although melatonin has been shown to be effective in treating circadian sleep disorders such as those associated with jet lag and shift work, primary sleep disorders are not effectively improved because melatonin has a very short half-life in the blood circulation. In contrast, novel long-acting melatonin agonists such as agomelatine reset circadian rhythms by binding to both MT1 and MT2 receptors in the suprachiasmatic nucleus of the hypothalamus. Additionally, agomelatine blocks 5-HT2 receptors with high affinity in several brain areas including the cerebral cortex, hippocampus, and amygdala. In addition to resynchronizing rhythms in various animal models that have disrupted circadian rhythms, agomelatine also has antidepressant-like activity in several animal models of depression. Paralleling the animal studies, multiple double-blind, placebo-controlled trials with depressed patients showed that agomelatine was effective in significantly reducing symptoms of moderate to severe major depressive disorder while normalizing sleep patterns. It is quite possible that the antidepressant effect is at least partially due to the resynchronization of the circadian rhythms of depressed patients. Data from several meta-analyses found that agomelatine was superior to placebo statistically, making it an effective antidepressant. Although it was not as effective as the comparitor antidepressants, its onset of effectiveness was much more rapid. Agomelatine may be more effective in patients with particular pathological features such as disrupted sleep cycle or insomnia. Unfortunately there was not enough evidence to evaluate its ability to prevent relapse (Gahr, 2014). Furthermore, agomelatine demonstrated only mild adverse effects, not different from placebo, and it was tolerated better than established antidepressant drugs. Side effects included headache, symptoms of the common cold, fatigue, and gastrointestinal complaints. Unlike many current antidepressants, it does not impair sexual function, and discontinuation leads to no rebound withdrawal syndrome. Effects of overdose are relatively mild. One potential problem is a transient increase in liver enzymes in about 1% of the patients. However, two European studies reported more severe hepatotoxic reactions that were reversible after several weeks. For that reason periodic liver function tests are required. Its distinct pharmacological profile and mechanism of action would make it a valuable treatment option particularly for treatment-resistant patients and those who cannot tolerate the conventional drugs. Long-term safety must still be evaluated, including effects on liver function and potential drug interactions.

A brief review is provided by Sansone and Sansone (2011).



Gahr, M. (2014). Agomelatine in the treatment of major depressive disorder: An assessment of benefits and risks. Curr. Neuropharmacol., 12, 287–398.

Sansone, R. A., and Sansone, L. A. (2011). Agomelatine: A novel antidepressant. Innov. Clin. Neurosci., 8, 10–14.