Antidepressant - agomelatine

Melatonin is the body's timekeeper. The endogenous neurohormone regulates the circadian rhythms in humans and other mammals. The pineal gland produces melatonin at night, and it acts at the melatonin receptors, which are predominantly found in the hypothalamus. Melatonin can be used to reset the biological clock that is normally regulated by the natural light and dark cycle. However, because it has a short half-life and poor selectivity at the melatonin receptor sites in the hypothalamus, its use in the treatment of circadian rhythm disorders is limited.

As a result, a number of melatonin analogues have been investigated in an attempt to make its administration more effective, and agomelatine is being developed by Servier.¹ Agomelatine is structurally similar to melatonin, but the indole nucleus has been replaced by a naphthalene moiety, which increases its metabolic stability.

Agomelatine is now being investigated as an antidepressant agent, because disruption of the circadian rhythm patterns has been implicated in the pathophysiology of depression, with the disorganisation of the body's internal rhythms claimed to be characteristic of mood variation. While the SSRI class of medicines is a huge leap forward from the older tricyclic antidepressants, there are still side-effects. There is also some doubt as to whether they are effective in severe cases of depression. As agomelatine acts in a completely different way, it could provide an alternative treatment option.

In a double blind, randomised, dose finding study, 28 in-patients were given 5 or 100mg of agomelatine for 2856 days.² Both groups saw antidepressive effect, though those given the lower dose showed more benefits.

Its efficacy has been compared to paroxetine in a randomised, double blind, placebo controlled trial in 711 patients, most of whom had major depressive disorder, and the remainder bipolar disorder.³ Patients were given 1, 5 or 25mg agomelatine/day or 20mg paroxetine/day for eight weeks. All the patients were given placebo for one week before the trial started, and those who responded to this were excluded from the analysis. The trial showed that the 25mg dose was as effective as paroxetine in improving the symptoms of depression. Agomelatine was better tolerated than paroxetine, and gave similar remission rates.⁴