Both the M1 and M2 receptors are known to be involved in regulation of circadian rhythms. Stimulation of M1 has a positive effect on sleep by attenuating the alerting signal produced by the suprachiasmatic nucleus (SCN) in the brain. M2 has a phase-shifting effect on circadian rhythms. Antagonism of the 5HT_2C increases the activity of dopamine and noradrenalin in the frontal cortex, which can have both anxiolytic and antidepressant effects. It also promotes slow wave sleep or deep, restorative sleep.

Preclinical data on agomelatin have demonstrated that disruption of the receptor systems affected by this drug produce depression-like syndromes in animals. Treatment with agomelatin also relieves these depression-like symptoms. Preclinical data also show that the synergistic action on the three receptors together is necessary to produce the effect.

During his presentation on November 16, Dr. Lam presented results various clinical studies of the agomelatin.

In two randomised, placebo-controlled registration trials on agomelatin that involved nearly 500 patients with depression. These trials demonstrated significant improvements in the Hamilton Depression (HAM-D) rating scale, with a change of 2.30 points in one trial and 3.44 points in the other. A meta-analysis of three randomised controlled trials involving over 600 patients also demonstrated a significant change of 2.86 in the HAM-D with agomelatin. A pooled analysis also revealed that the effect of agomelatin becomes stronger in proportion with the severity of the patient's depression.

An 8-week agomelatin trial comparing the agent with paroxetine and placebo demonstrated both agents to have antidepressant action that is significantly superior to placebo. For agomelatin, a response was identified as early as week 2. In a head-to-head trial of agomelatin and venlafaxine, both agents produced similar response rates and effects on HAM-D ratings.

What differentiates agomelatin from other antidepressants, Dr. Lam said, is that it has a positive impact on sleep and that it is extremely well tolerated. The drug has been shown to improve subjective assessments of sleep, ease the task of getting to sleep, and improve sleep quality as early as 1 week after starting treatment.

But this positive effect on sleep is not the only factor mediating agomelatin's antidepressant effect, Dr. Lam said.

"When you look at, for example, the depression items [on the HAM-D] without the sleep items, agomelatin is still an effective antidepressant," said Dr. Lam. "So, it's quite clear that agomelatin has antidepressant effects independent of the sleep component."

Agomelatin's adverse effect profile is virtually identical to placebo, and it appears to have no sexual side effects or effects on weight. "Here we have a medication that by all indications has a very low side-effect burden," said Dr. Lam.

Agomelatin is expected to be available in the United States, Canada, and other countries within the next couple of years.


[Presentation title: Treatment Gaps in Major Depression: New Directions in Therapy." Abstract I01]

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