Agomelatine

Agomelatine (trade names Valdoxan, Melitor, Thymanax) is an antidepressant developed by the pharmaceutical company Servier. It is marketed for the treatment of major depressive disorder and has been reported to have a reduced level of sexual side effects as well as discontinuation effects compared to some other antidepressants. Agomelatine may also have positive effects on sleep.

Mechanism of action
Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. Binding studies indicate that it has no effect on monoamine uptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.

History
Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union. In March 2005 Servier submitted agomelatine to the European Medicines Agency (EMEA) under the trade names Valdoxan and Thymanax. On 27 July 2006 the Committee for Medical Products for Human Use (CHMP) of the EMEA recommended a refusal of the marketing authorisation of Valdoxan/Thymanax (agomelatine). The major concern was that efficacy had not been sufficiently shown. The CHMP had no special concerns about side effects. In September 2007, Servier submitted a new marketing application for Valdoxan (agomelatine) to the EMEA. On 20 November 2008, Valdoxan was given a positive opinion, with restrictions, by the EMEA, and was subsequently given marketing authorisation in the European Union on 20 February 2009. Release dates in the individual countries of the EU were dependent on marketing arrangements.

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. It is currently undergoing phase III clinical trials in the US. Novartis lists the drug as scheduled for submission to the FDA no earlier than 2012. It is currently sold in Australia under the Valdoxan trade name.

Indications
Agomelatine is indicated for the treatment of major depressive episodes in adults. It is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. Only limited clinical data is available on the use of agomelatine in elderly patients ≥ 65 years old with major depressive episodes. Therefore, caution should be exercised when prescribing it to these patients.

Pharmacodynamics
Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

Six placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in three of the six short-term double-blind placebo-controlled studies. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies. The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients. Agomelatine has no abuse potential as measured in healthy volunteer studies.

No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients. Agomelatine is contraindicated in patients with hepatic impairment. No dosage tapering is needed on treatment discontinuation.

Agomelatine’s onset of efficacy has been reported as early as the first week of treatment.

The antidepressant efficacy of agomelatine 25 mg to 50 mg has been demonstrated in a 6-week, randomized, double-blind, placebo-controlled, parallel-group study in 260 patients with MDD.

Agomelatine appears to cause fewer sexual side effects and discontinuation effects than sertraline and paroxetine. Additionally, possibly because of its action on melatonin receptors, agomelatine appears to improve sleep quality, with no reported daytime drowsiness. Agomelatine has demonstrated anxiolytic properties in rodents. Its efficacy in generalised anxiety disorder has been assessed by Stein et al (2008) who reported it significantly more effective than placebo treatment.

Results of the meta-analysis of three positive, randomized, double-blind, placebo controlled studies in 357 patients treated with agomelatine and 360 patients treated with placebo show that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In patients with a greater baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points.

Controlled studies in humans have shown that agomelatine is as effective as the SSRI antidepressants paroxetine and sertraline in the treatment of major depression. However, some of the first randomised controlled trials (unpublished) had failed to show that agomelatine is more effective than placebo. Based on the results of the pivotal trials, Agomelatine's efficacy in comparison to placebo was considered to be of positive clinical relevance by the European regulator despite diverging views of some minority members. . A review of the research studies conducted to April 2011 concludes that "it should only be considered as an alternative drug for patients who do not respond to or cannot tolerate other antidepressant drugs".

Structure


The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an NH group, agomelatine has an HC=CH group. Thus melatonin contains an indole part, whereas agomelatine has a naphthalene bioisostere instead.