Agomelatine

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Agomelatine
Agomelatine formula.svg
Agomelatine-3D-ball.png
Clinical data
Trade names Melitor, Thymanax, Valdoxan, others
Other namesAGO-178; AGO178C; S-20098; S-20098-F55
AHFS/Drugs.com International Drug Names
License data
Pregnancy
category
  • AU:B1
Dependence
liability 		Low [1]
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~1% [2] [7]
Protein binding 95% [2]
Metabolism Liver (90% CYP1A2 and 10% CYP2C9) [2]
Elimination half-life 1–2 hours [2] [7]
Excretion Kidney (80%, mostly as metabolites) [2]
Identifiers
  • N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.157.896 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H17NO2
Molar mass 243.306 g·mol−1
3D model (JSmol)
  • O=C(NCCc1c2c(ccc1)ccc(OC)c2)C
  • 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) Yes check.svgY
  • Key:YJYPHIXNFHFHND-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. [8] One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects. [8] [9] Another review also found it was similarly effective to many other antidepressants. [10]

Contents

Common side effects include headaches, nausea, and dizziness, which usually subside in the first few weeks, as well as liver problems [2] [11] – due to the potential effect on the liver, ongoing blood tests are recommended. [12] Its use is not recommended in people with dementia, or who are under the age of 18 or over 75. [13] [2] There is tentative evidence that it may have fewer side effects than some other antidepressants. [8] It acts by blocking certain serotonin receptors and activating melatonin receptors. [12]

Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010. [12] Its use is not approved in the United States and efforts to get approval were ended in 2011. [12] It was developed by the pharmaceutical company Servier. [12]

Medical uses

Major depressive disorder

Agomelatine is used for the treatment of major depressive episodes in adults in Europe and Australia. [11] [2] Ten 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 six of the ten short-term double-blind placebo-controlled studies. [11] Two were considered "failed" trials, as comparators of established efficacy failed to differentiate from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies. [11] The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. [11] One meta-analysis found agomelatine to be as effective as standard antidepressants, with an effect size (SMD Tooltip standardized mean difference) of 0.24. [9] [14]

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed agomelatine to be one of the most effective and one of only two medications found to be more tolerable than placebo. [15]

A meta-analysis found that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In people 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 at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, and fluoxetine in the treatment of major depression. [17] A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants. [10]

However, the body of research on agomelatine has been substantially affected by publication bias, prompting analyses which take into account both published and unpublished studies. [9] [18] [19] These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as "marginally clinically relevant", [19] being only slightly above placebo. [18] [19] According to a 2013 review, agomelatine did not seem to provide an advantage in efficacy over other antidepressants for the acute-phase treatment of major depression. [8]

Generalized anxiety disorder

Agomelatine is also approved for the treatment of generalized anxiety disorder in adults in Australia. [2] It has been found more effective than placebo in the treatment of in a number of short-term double-blind placebo-controlled studies and in long term relapse prevention. [20] [21] [22] [23] [24]

Use of agomelatine in GAD is off-label in Europe. Agomelatine has been evaluated in a number of other off-label indications besides GAD. [12]

Use in special populations

It is not recommended in Europe or Australia for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. [11] [2] However, a recent 12 week study first reported in September 2020, and published in 2022 showed greater efficacy vs. placebo for agomelatine 25 mg per day in youth age 7–17 years and an acceptable tolerability profile with similar efficacy to fluoxetine. [25] [26] Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes. [11]

It is not recommended during pregnancy or breastfeeding. [13]

Contraindications

Agomelatine is contraindicated in patients with kidney or liver impairment. [11] According to information disclosed by Servier in 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decide whether to pursue the treatment or not. [27] 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. [11]

Adverse effects

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. [28] 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] [11]

Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine. [2]

Common (1–10% incidence) adverse effects include [2] [11] [29] [30]
Uncommon (0.1–1%) adverse effects include [2] [11] [29] [30]
Rare (0.01–0.1%) adverse effects include [2] [11] [29] [30]

Excepting effects on the liver, the above adverse effects were usually mild to moderate and occurred in the first two weeks of treatment, subsiding thereafter. [2] A 2019 study found no difference in rates of acute liver injury between users of citalopram and agomelatine, though this rate could be decreased due to the precautionary liver enzyme monitoring in the European Union. [33]

Dependence and withdrawal

No dosage tapering is needed on treatment discontinuation. [11] Agomelatine has no abuse potential as measured in healthy volunteer studies. [2] [11]

Overdose

Agomelatine is expected to be relatively safe in overdose. [34]

Interactions

Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can lead to an increase in agomelatine exposure, and possibly serotonin syndrome . [2] [29] There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity. [2] [29]

Pharmacology

Pharmacodynamics

Agomelatine acts as a highly potent and selective melatonin MT1 and MT2 receptor agonist (Ki = 0.1 nM and 0.12 nM, respectively) and also as a relatively weak serotonin 5-HT2B and 5-HT2C receptor antagonist (Ki = 660 nM and 631 nM, respectively; ~6,000-fold lower than for the melatonin receptors). [35] [36] It is a silent antagonist rather than an inverse agonist of the serotonin 5-HT2C receptor. [37] The drug has negligible affinity for the serotonin 5-HT2A receptor or for a variety of other targets. [35]

By antagonizing the serotonin 5-HT2C receptor, agomelatine has been found to disinhibit and increase norepinephrine and dopamine release in the frontal cortex in animals, although notably not in the striatum or nucleus accumbens. [35] [38] [36] In contrast to agomelatine, other serotonin 5-HT2C receptor antagonists and inverse agonists, such as SB-242084 and SB-206553, have been found to increase dopamine and norepinephrine levels in the nucleus accumbens. [39] [40] These differences may in part be related to constitutive activity of the serotonin 5-HT2C receptor and resulting differences between neutral antagonists and inverse agonists of the receptor. [41] [40] In addition, there are multiple isoforms of the serotonin 5-HT2C receptor with different properties. [35] Although agomelatine is widely claimed to act as a serotonin 5-HT2C receptor antagonist, the clinical significance of this action has been disputed by some researchers. [42] Unlike with other serotonin 5-HT2C receptor antagonists, therapeutic doses of agomelatine fail to acutely increase slow-wave sleep in humans. [43] [44] Additionally, no receptor occupancy studies of agomelatine have been conducted in humans to demonstrate significant occupancy of serotonin 5-HT2C receptors at therapeutic doses. [43]

Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, behavioral despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. Agomelatine has been found to resynchronize circadian rhythms in animal models of delayed sleep phase syndrome (DSPS). [45] In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset. [11]

Pharmacokinetics

The main route of metabolism for agomelatine is hepatic through the CYP1A2 (90%) and CYP2C9/19 (10%); co-administration of strong CYP1A2 inhibitors (e.g., fluvoxamine) is contraindicated. [46] Agomelatine is well-absorbed with oral administration (≥80%), but it has very low oral bioavailability (~1%) due to extensive first-pass metabolism. [7] The elimination half-life of agomelatine is 1 to 2 hours. [7] The half-life of agomelatine does not change with repeated administration. [7] There is no accumulation of agomelatine with continuous administration. [7]

Chemistry

Structure

melatonin (top) vs. agomelatine (bottom). Agomelatine-vs-melatonin-2D-skeletal.png
melatonin (top) vs. agomelatine (bottom).

The chemical structure of agomelatine is very similar to that of melatonin. [47] Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead. [47] [48]

Synthesis

Agomelatine-synthesis: and structure-activity studies: Agomelatine-synthesis.svg
Agomelatine-synthesis: and structure-activity studies:

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 (EMA) under the trade names Valdoxan and Thymanax. [53] On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects. [53] In September 2007, Servier submitted a new marketing application to the EMA. [54]

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. [55] 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. [56] However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available. [57]

It received approval from the European Medicines Agency (EMA) for marketing in the European Union in February 2009 [11] and approval from the Therapeutic Goods Administration (TGA) for marketing in Australia in August 2010. [2]

Research

Circadian rhythm sleep disorders

Agomelatine has been investigated for its effects on sleep regulation due its actions as a melatonin receptor agonist. [58] Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm sleep disorders. [58] [9] [45] [59] However, research is very limited (e.g., case reports) and agomelatine is not approved for use in the treatment of sleep disorders. [58]

Seasonal affective disorder

A 2019 Cochrane review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder. [60]

See also

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  32. ↑ Kennedy SH, Rizvi SJ (June 2010). "Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness". CNS Drugs. 24 (6): 479–99. doi:10.2165/11534420-000000000-00000. PMID   20192279. S2CID   41069663.
  33. ↑ Pladevall-Vila M, Pottegård A, Schink T, Reutfors J, Morros R, Poblador-Plou B, et al. (April 2019). "Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources". CNS Drugs. 33 (4): 383–395. doi:10.1007/s40263-019-00611-9. PMC   6441103 . PMID   30830574.
  34. ↑ Taylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN   978-0-470-97948-8. Archived from the original on 2023-01-14. Retrieved 2018-07-24.
  35. 1 2 3 4 Norman TR, Olver JS (April 2019). "Agomelatine for depression: expanding the horizons?". Expert Opin Pharmacother. 20 (6): 647–656. doi:10.1080/14656566.2019.1574747. PMID   30759026. Binding studies show that [agomelatine] has a high affinity for human melatonin MT1- and MT2-receptors (Ki: 0.1nM; 0.12nM respectively) and acts as an agonist at these receptors [7]. It has little affinity (Ki > 10μM) for most other receptors, [...] [Agomelatine] binds to the 5-HT2C receptor (Ki = 631nM) as well as cloned, human 5-HT2B receptors (Ki = 660nM), but has negligible affinity at 5-HT2A receptors [7]. At 5-HT2B and 5-HT2C receptors agomelatine acts as an antagonist. The interaction with 5-HT2C receptors may be more nuanced than simple antagonism since this receptor is subject to RNA editing, which can generate multiple isoforms of the receptor with various properties (e.g., affinity, coupling and constitutive activity) [9]. Blockade of the 5-HT2C receptor is believed to be responsible for the dose dependent increase in the extracellular concentrations of both noradrenaline and dopamine observed in the prefrontal cortex following acute drug administration [7]. By contrast dopamine concentrations in the nucleus accumbens or the striatum were not affected by agomelatine [7]. Furthermore, there was no change in extracellular concentrations of serotonin.
  36. 1 2 Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, et al. (September 2003). "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". The Journal of Pharmacology and Experimental Therapeutics. 306 (3): 954–64. doi:10.1124/jpet.103.051797. PMID   12750432. S2CID   18753440. [...] agomelatine dose dependently enhanced dialysis levels of dopamine in frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum. Although the electrical activity of ventrotegmental dopaminergic neurons was unaffected agomelatine, it abolished their inhibition by [the 5-HT2C agonist] Ro60,0175. Extracellular levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus coeruleus. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N-[2-(5-ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely reflect blockade of 5-HT2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways.
  37. ↑ Millan MJ (2022). "Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action". Ther Adv Psychopharmacol. 12: 20451253221105128. doi:10.1177/20451253221105128. PMC   9251978 . PMID   35795687. [...] agomelatine is a neutral antagonist rather than inverse agonist at 5-HT2C receptors, so it is does not decrease 5-HT2C receptor–mediated transmission to below 'normal or default' levels.69,70 These characteristics suggest that agomelatine has a low risk of metabolic perturbation and obesity, an assertion underscored by clinical observations in studies of both GAD and major depression.22,28 There is also a correspondingly low risk of rebound anxiety or a discontinuation syndrome at the end of treatment.22,28,70,71
  38. ↑ Chagraoui A, Thibaut F, Skiba M, Thuillez C, Bourin M (April 2016). "5-HT2C receptors in psychiatric disorders: A review". Prog Neuropsychopharmacol Biol Psychiatry. 66: 120–135. doi:10.1016/j.pnpbp.2015.12.006. PMID   26739950. Agomelatine induces an increase in extracellular DA in the FC but not in the striatum or NAc (Millan et al., 2003) without any changes in extracellular 5-HT (Millan, 2005). Otherwise, it has been shown that the activation of 5-HT2CR exerts an inhibitory effect on the dopaminergic pathways in the FC (Di Giovanni et al., 1999, 2006).
  39. ↑ Jensen NH, Cremers TI, Sotty F (September 2010). "Therapeutic potential of 5-HT2C receptor ligands". ScientificWorldJournal. 10: 1870–1885. doi: 10.1100/tsw.2010.180 . PMC   5763985 . PMID   20852829. [...] the selective 5-HT2C receptor antagonist SB-242084 was shown to enhance DA levels in the nucleus accumbens, an effect attributed to the disinhibition of DA firing via 5-HT2C receptors expressed on GABAergic interneurons in the VTA[17]. In agreement with this, SB-242084 dose dependently increased the firing rate and bursting activity of DA neurons in the VTA[28]. Behaviorally, SB-242084 was found to potentiate dexamphetamine-induced locomotor hyperactivity in rats[21].
  40. 1 2 De Deurwaerdère P, Navailles S, Berg KA, Clarke WP, Spampinato U (March 2004). "Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens". J Neurosci. 24 (13): 3235–3241. doi:10.1523/JNEUROSCI.0112-04.2004. PMC   6730027 . PMID   15056702.
  41. ↑ Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA (February 2009). "Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors". Pharmacol Ther. 121 (2): 160–173. doi:10.1016/j.pharmthera.2008.10.010. PMID   19109993. In accord with this view, and with the proposal that central 5-HT2C receptors exert a tonic inhibitory control of DA neuron activity (Di Giovanni et al., 1999), systemic administration of purported 5-HT2C receptor antagonists (SB 242084, SB 206553) have been shown to significantly enhance basal DA release in DA innervated areas of the rat brain, such as the frontal cortex, the nucleus accumbens, and the striatum (De Deurwaerdere & Spampinato, 2001; Gobert et al., 2000). However, the magnitude of this effect differs for different antagonists (De Deurwaerdere et al., 2004; De Deurwaerdere & Spampinato, 2001), with SB 206553 being more efficacious than SB 242084 in enhancing basal DA release (see Fig. 11). As discussed elsewhere (De Deurwaerdere et al., 2004) the differences observed cannot be explained if both drugs act as 5-HT2C receptor antagonists that block the effect of endogenous 5-HT. Rather, these effects must reflect distinct intrinsic pharmacological properties of SB 206553 and SB 242084. Indeed, as revealed by in vitro experiments in CHO cells expressing the 5-HT2C receptor (see Figs. 5 and 6), SB 206553 behaves as a strong inverse agonist at the PLC pathway in contrast with the protean ligand SB 242084.
  42. ↑ Sharpley AL, Cowen PJ (May 2012). "In response to "The effect of agomelatine on 5HT2C receptors in humans: a clinically relevant mechanism?" by Trevor Norman". Psychopharmacology. 221 (1): 179. doi: 10.1007/s00213-012-2659-3 . ISSN   1432-2072.
  43. 1 2 Norman TR (May 2012). "The effect of agomelatine on 5HT(2C) receptors in humans: a clinically relevant mechanism?". Psychopharmacology. 221 (1): 177–8, author reply 179. doi:10.1007/s00213-012-2656-6. PMID   22349274. S2CID   253752682.
  44. ↑ Quera Salva MA, Vanier B, Laredo J, Hartley S, Chapotot F, Moulin C, et al. (October 2007). "Major depressive disorder, sleep EEG and agomelatine: an open-label study". The International Journal of Neuropsychopharmacology. 10 (5): 691–696. doi:10.1017/S1461145707007754. PMID   17477886. S2CID   5997517.
  45. 1 2 Le Strat Y, Gorwood P (September 2008). "Agomelatine, an innovative pharmacological response to unmet needs". Journal of Psychopharmacology. 22 (7 Suppl): 4–8. doi:10.1177/0269881108092593. PMID   18753276. S2CID   29745284.
  46. ↑ "Annex I: Summary of Product Characteristics" (PDF). European Medicines Agency. p. 5. Retrieved 29 January 2025.
  47. 1 2 San L, Arranz B (September 2008). "Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system". Eur Psychiatry. 23 (6): 396–402. doi:10.1016/j.eurpsy.2008.04.002. PMID   18583104.
  48. ↑ Tinant B, Declercq JP, Poupaert JH, Yous S, Lesieur D (1994). "N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, a potent melatonin analog". Acta Crystallogr. C . 50 (6): 907–910. Bibcode:1994AcCrC..50..907T. doi:10.1107/S0108270193012922.
  49. ↑ EPapplication 447285,Andrieux J, Houssin R, Yous S, Guardiola B, Lesieur D,"Naphthalene derivatives, procedure for their preparation and pharmaceutical compositions containing them.",published 1991-09-18, assigned to Adir
  50. ↑ USgranted 5225442,Andrieux J, Houssin R, Yous S, Guardiola B, Lesieur D,"Compounds having a naphthalene structure",issued 6 July 1993, assigned to Adir
  51. ↑ Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeiffer B, et al. (April 1992). "Novel naphthalenic ligands with high affinity for the melatonin receptor". Journal of Medicinal Chemistry. 35 (8): 1484–6. doi:10.1021/jm00086a018. PMID   1315395.
  52. ↑ Depreux P, Lesieur D, Mansour HA, Morgan P, Howell HE, Renard P, et al. (September 1994). "Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands". Journal of Medicinal Chemistry. 37 (20): 3231–9. doi:10.1021/jm00046a006. PMID   7932550.
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  55. ↑ Bentham C (2006-03-29). "Servier and Novartis sign licensing agreement for agomelatine, a novel treatment for depression". Servier UK. Archived from the original on 16 April 2009. Retrieved 2009-05-15.
  56. ↑ "Clinical trials for agomelatine". ClinicalTrials.gov . National Institutes of Health. Archived from the original on 4 October 2011. Retrieved 6 July 2009.
  57. ↑ Malone E (25 October 2011). "Novartis drops future blockbuster agomelatine". Scrip Intelligence. Archived from the original on 11 November 2011.
  58. 1 2 3 Williams WP, McLin DE, Dressman MA, Neubauer DN (September 2016). "Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders". Pharmacotherapy. 36 (9): 1028–41. doi:10.1002/phar.1822. PMC   5108473 . PMID   27500861.
  59. ↑ "Valdoxan: A New Approach to The Treatment of Depression". Medical News Today. MediLexicon International Ltd. 2005-04-05. Archived from the original on 15 April 2009. Retrieved 14 May 2009.
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