Agomelatine

Agomelatine

Systematic (IUPAC) name
N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
Clinical data
AHFS/Drugs.com	International Drug Names
Licence data	EMA:Link
Pregnancy cat.	?
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	<5% [1]
Metabolism	hepatic (90%CYP1A2;10%CYP2C9)
Half-life	< 2 h
Identifiers
CAS number	138112-76-2 Y
ATC code	N06AX22
PubChem	CID 82148
IUPHAR ligand	198
ChemSpider	74141 Y
UNII	137R1N49AD Y
KEGG	D02578 Y
ChEMBL	CHEMBL10878 Y
Chemical data
Formula	C15H17NO2
Mol. mass	243.301
SMILES	eMolecules & PubChem
InChI InChI=1S/C15H17NO2/c1-11(17)16-9-8-13-5-3-4-12-6-7-14(18-2)10-15(12)13/h3-7,10H,8-9H2,1-2H3,(H,16,17) Y Key:YJYPHIXNFHFHND-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

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-HT_2C 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.^[2]

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.^[3] 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.^[3] In September 2007, Servier submitted a new marketing application for Valdoxan (agomelatine) to the EMEA.^[4] On 20 November 2008, Valdoxan was given a positive opinion, with restrictions,^[5] by the EMEA,^[4] and was subsequently given marketing authorisation in the European Union on 20 February 2009.^[6] 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.^[7] It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012.^[8] However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.^[9]

It is currently sold in Australia under the Valdoxan trade name.

Indications

Agomelatine is indicated for the treatment of major depressive episodes in adults.^[2] 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.^[2] 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.^[2]

Pharmacodynamics

Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome^[10] 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.^[2]

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.^[2] Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies.^[2] The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study.^[2]

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.^[2]

Agomelatine has no abuse potential as measured in healthy volunteer studies.^[2]

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.^[2] Agomelatine is contraindicated in patients with hepatic impairment.^[2] No dosage tapering is needed on treatment discontinuation.^[2]

Agomelatine’s onset of efficacy has been reported as early as the first week of treatment.^[11]

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.^[12]

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.^[13] Agomelatine has demonstrated anxiolytic properties in rodents.^[14] Its efficacy in generalised anxiety disorder has been assessed by Stein et al (2008) who reported it significantly more effective than placebo treatment.^[15]

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.^[16]

Controlled studies in humans have shown that agomelatine is as effective as the SSRI antidepressants paroxetine and sertraline in the treatment of major depression^[17]. However, some of the first randomised controlled trials (unpublished) had failed to show that agomelatine is more effective than placebo ^[18]. Based on the results of the pivotal trials, Agomelatine's efficacy in comparison to placebo was considered to be of marginal clinical relevance by the European regulator. A minority of the CHMP members voted against the approval.^[4]. 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" ^[19].

Structure

Melatonin (top) vs. agomelatine (bottom)

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.^[20]

See also

Discovery and development of melatonin receptor agonists

References

1. ^ www.emea.europa.eu/
2. ^ ^{a b c d e f g h i j k l m} "Summary of Product Characteristics" (PDF). European Medicine Agency. 2003. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000915/WC500046227.pdf. Retrieved 2010-09-22. 
3. ^ ^{a b} "Questions and Answers on Recommendation for Refusal of Marketing Authorisation". European Medicines Agency. 18 November 2006. http://www.emea.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-656-657-RQ&A-en.pdf. Retrieved 6 July 2009. 
4. ^ ^{a b c} "CHMP Assessment Report for Valdoxan". European Medicines Agency. 20 November 2008. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000915/WC500046226.pdf. Retrieved 6 July 2009. 
5. ^ Transaminases elavations and interactions with potent CYP 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin]
6. ^ "VALDOXAN (AGOMELATINE), A NOVEL ANTIDEPRESSANT, RECEIVES EUROPEAN MARKETING AUTHORISATION". Servier UK. 25 February 2009. http://www.pharmiweb.com/PressReleases/pressrel.asp?ROW_ID=5770. Retrieved 6 July 2009. 
7. ^ Bentham, Clara (2006-03-29). "Servier and Novartis sign licensing agreement for agomelatine, a novel treatment for depression". Servier UK. http://www.servier.co.uk/news/news-details.asp?StoryID=76. Retrieved 2009-05-15. 
8. ^ "Clinical trials for agomelatine". ClinicalTrials.gov. National Institutes of Health. http://clinicaltrials.gov/ct2/results?term=agomelatine. Retrieved 6 July 2009. 
9. ^ Novartis drops future blockbuster agomelatine. Scrip Intelligence, Oct 25 2011 (retrieved Oct 30, 2011).
10. ^ Le Strat, Y; Philip Gorwood (27 August 2008). "Agomelatine, an innovative pharmacological response to unmet needs". J Psychopharmacol (SagePub) 22 (7): suppl 4–8. doi:10.1177/0269881108092593. PMID 18753276. http://jop.sagepub.com/content/22/7_suppl/4.abstract. Retrieved 2010-10-15. 
11. ^ Lemoine, P; Guilleminault, C; Alvarez, E (November 2007). "Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine.". J Clin Psychiatry 68 (11): 1723–32. doi:10.4088/JCP.v68n1112. PMID 18052566. 
12. ^ Olié, JP; Kasper, S (October 2007). "Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder.". Int J Neuropsychopharmacol. 10 (5): 661–73. doi:10.1017/S1461145707007766. PMID 17477888. 
13. ^ "Valdoxan: A New Approach to The Treatment of Depression". Medical News Today (MediLexicon International Ltd). 2005-04-05. http://www.medicalnewstoday.com/articles/22334.php. Retrieved 14 May 2009. 
14. ^ Millan MJ, Brocco M, Gobert A, Dekeyne A (February 2005). "Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade". Psychopharmacology (Berl.) 177 (4): 448–58. doi:10.1007/s00213-004-1962-z. PMID 15289999. 
15. ^ Stein, D.; Ahokas, A.; De Bodinat, C. (2008). "Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study.". Journal of clinical psychopharmacology 28 (5): 561–566. doi:10.1097/JCP.0b013e318184ff5b. PMID 18794654.  edit
16. ^ Montgomery, SA; Kasper, S (September 2007). "Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine.". Int Clin Psychopharmacol. 22 (5): 283–91. doi:10.1097/YIC.0b013e3280c56b13. PMID 17690597. 
17. ^ Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, Smeraldi E, Rybakowski JK, Quera-Salva MA, Wirz-Justice AM, Picarel-Blanchot F, Baylé FJ (February 2010). "Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline". J Clin Psychiatry 71 (2): 109–20. doi:10.4088/JCP.09m05347blu. PMID 20193645. 
18. ^ Howland RH (2009). "Critical appraisal and update on the clinical utility of agomelatine, a melatonergic agonist, for the treatment of major depressive disease in adults". Neuropsychiatr Dis Treat 5: 563–76. PMC 2785860. PMID 19966905. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2785860. 
19. ^ "A benefit-risk assessment of agomelatine in the treatment of major depression.". http://www.ncbi.nlm.nih.gov/pubmed/21830835. 
20. ^ B. Tinant, J.-P. Declercq, J. H. Poupaert, S. Yous, D. Lesieur (1994). "N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, a potent melatonin analog". Acta Cryst. C 50 (6): 907–910. doi:10.1107/S0108270193012922. 

External links

• Official product site
• Manufacturer web site
• Agomelatine Psychonauts Google Group
• Novartis pipeline
• Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors
• The Novel Melatonin Agonist Agomelatine (S20098) Is an Antagonist at 5-Hydroxytryptamine2C Receptors, Blockade of Which Enhances the Activity of Frontocortical Dopaminergic and Adrenergic Pathways
• Agomelatine treatment has promising results in transgenic murine model
• Clinical trial data in the United Kingdom via the NHS' National electronic Library of Medicines (NeLM)
• Clinical trial data in the United States via ClinicalTrials.gov