Agomelatine, sold under the brand nameThymanax among others, is anatypical antidepressant most commonly used to treatmajor depressive disorder andgeneralized 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]
Common side effects include headaches, nausea, and dizziness, which usually subside in the first few weeks, as well asliver problems[2][11] – due to the potential effect on the liver, blood tests before treatment initiation, at specific time-points after initiation, and after dose increase is recommended.[12] Its use is not recommended in people withdementia, 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 byblocking certain serotonin receptors andactivating melatonin receptors.[12]
Agomelatine was authorized for medical use in the European Union in 2009 and Australia in 2010.[12] Its use in the United States is not approved.[12] It was developed by the pharmaceutical companyServier.[12]
Agomelatine is used for the treatment ofmajor depressive episodes in adults in the European Union 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-blindplacebo-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 aneffect size (SMDTooltip 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]
Ameta-analysis found that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In people with a greaterbaseline 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 theSSRI antidepressantsparoxetine,sertraline,escitalopram, andfluoxetine in the treatment ofmajor 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 bypublication 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]
Use of agomelatine ingeneral anxiety disorder isoff-label in Europe. Agomelatine has been evaluated in a number of other off-label indications besides general anxiety disorder.[12]
It is not recommended in the European Union or Australia for use inchildren andadolescents below 18 years of age due to a lack of data onsafety andefficacy.[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 tofluoxetine.[25][26] Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.[11]
Agomelatine is contraindicated in patients with kidney orliver 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 theEuropean 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 moderaterenal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.[11]
Agomelatine does not alter daytimevigilance andmemory in healthy volunteers. In depressed patients, treatment with the drug increasedslow-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]
Weight gain or loss, which tends to be less significant than withSSRIs[32]
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]
36.1% of patients with elevated enzyme levels normalize on their own without discontinuing agomelatine. For those who choose to discontinue the drug, the median time to liver enzyme level recovery is 14 days.[31] 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. The EU recommends checking liver enzyme levels before treatment initiation, and then after 3, 6, 12, and 24 weeks and following a dose increase.[33]
Agomelatine is a substrate ofCYP1A2,CYP2C9 andCYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressantfluvoxamine, 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 withalcohol to increase the risk ofhepatotoxicity.[2][29]
By antagonizing the serotonin 5-HT2C receptor, agomelatine has been found to disinhibit and increasenorepinephrine anddopamine release in thefrontal cortex in animals, although notably not in thestriatum ornucleus accumbens.[35][38][36] In contrast to agomelatine, other serotonin 5-HT2C receptor antagonists and inverse agonists, such asSB-242084 andSB-206553, have been found to increase dopamine and norepinephrine levels in the nucleus accumbens.[39][40] These differences may in part be related toconstitutive 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 multipleisoforms of the serotonin 5-HT2C receptor with different properties.[35] In other studies, while agomelatine alone did not affect thefiring rates ofventral tegmental area (VTA)dopaminergicneurons, it abolished the inhibition of these neurons by the serotonin 5-HT2C receptor agonistRo60-0175.[35] Due to the increase in norepinephrine and dopamine levels in the frontal cortex with agomelatine, the drug has sometimes been referred to as anorepinephrine–dopamine disinhibitor (NDDI).[42][43]
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.[44] Unlike with other serotonin 5-HT2C receptor antagonists, therapeutic doses of agomelatine fail to acutely increaseslow-wave sleep in humans.[45][46] Additionally, noreceptor occupancy studies of agomelatine have been conducted in humans to demonstrate significant occupancy of serotonin 5-HT2C receptors at therapeutic doses.[45]
The main route of metabolism for agomelatine is hepatic through theCYP1A2 (90%) andCYP2C9/19 (10%); co-administration of strong CYP1A2 inhibitors (e.g.,fluvoxamine) is contraindicated.[48] Agomelatine is well-absorbed withoral administration (≥80%), but it has very low oralbioavailability (~1%) due to extensivefirst-pass metabolism.[7] Theelimination half-life of agomelatine is 1 to 2hours.[7] The half-life of agomelatine does not change with repeated administration.[7] There is noaccumulation of agomelatine with continuous administration.[7]
In March 2005, Servier submitted agomelatine to theEuropean Medicines Agency (EMA) under the brand names Valdoxan and Thymanax.[55] In July 2006, theCommittee for Medicinal Products for Human Use 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 aboutside effects.[55] In September 2007, Servier submitted a new marketing application to the EMA.[56]
In March 2006,Servier announced it had sold the rights to market agomelatine in the United States toNovartis.[57] 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.[58] However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.[59]
It was authorized for medical use in the European Union in February 2009,[11] and in Australia in August 2010.[2]
^abcdefBuoli M, Mauri MC, Altamura AC (June 2014). "Pharmacokinetic evaluation of agomelatine for the treatment of generalised anxiety disorder".Expert Opin Drug Metab Toxicol.10 (6):885–892.doi:10.1517/17425255.2014.907794.PMID24717138.Elimination is rapid, the mean plasma half-life is between 1 and 2 h and the clearance is high (about 1100 ml/min). This is unaffected by repeated dosing and there is no evidence of drug accumulation or auto-induction.
^Montgomery SA, Kasper S (September 2007). "Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine".International Clinical Psychopharmacology.22 (5):283–91.doi:10.1097/YIC.0b013e3280c56b13.PMID17690597.S2CID21796064.
^Singh SP, Singh V, Kar N (April 2012). "Efficacy of agomelatine in major depressive disorder: meta-analysis and appraisal".The International Journal of Neuropsychopharmacology.15 (3):417–28.doi:10.1017/S1461145711001301.PMID21859514.
^Stein DJ, Ahokas A, Márquez MS, Höschl C, Seob Oh K, Jarema M, et al. (2014). "Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study".Journal of Clinical Psychiatry.75 (4):362–8.doi:10.4088/JCP.13m08433.PMID24569045.S2CID24860538.
^Stein DJ, Ahokas AA, 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.PMID18794654.S2CID5569226.
^Stein DJ, Ahokas AA, Jarema M, Avedisova AS, Vavrusova L, Chaban O, et al. (2017). "Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: A 12-week, double-blind, placebo-controlled study".European Neuropsychopharmacology.27 (5):526–537.doi:10.1097/JCP.0b013e318184ff5b.PMID28298261.S2CID5569226.
^abPerlemuter G, Cacoub P, Valla D, Guyader D, Saba B, Batailler C, et al. (2016). "Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients".CNS Drugs.30 (9):877–888.doi:10.1007/s40263-016-0351-6.PMID27342740.
^abcdeNorman TR, Olver JS (April 2019). "Agomelatine for depression: expanding the horizons?".Expert Opin Pharmacother.20 (6):647–656.doi:10.1080/14656566.2019.1574747.PMID30759026.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.
^abMillan 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.PMID12750432.S2CID18753440.[...] 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.
^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.PMC9251978.PMID35795687.[...] agomelatine is a neutral antagonist rather than inverse agonist at 5-HT2C receptors, so it 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
^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.PMID26739950.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).
^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.PMC5763985.PMID20852829.[...] 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].
^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.PMID19109993.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.
^Fasipe OJ (June 2019)."The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents".IBRO Rep.6:95–110.doi:10.1016/j.ibror.2019.01.001.PMC6562183.PMID31211282.By antagonizing the neocortical postsynaptic serotonergic 5-HT2C receptors, Agomelatine disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens. Therefore, it is sometimes referred to as a norepinephrine–dopamine disinhibitor (NDD) (Heun et al., 2013; Koesters et al., 2013; Cipriani et al., 2018).
^abNorman 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.PMID22349274.S2CID253752682.
^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.PMID17477886.S2CID5997517.
^abSan 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.PMID18583104.
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^US granted 5225442, Andrieux J, Houssin R, Yous S, Guardiola B, Lesieur D, "Compounds having a naphthalene structure", issued 6 July 1993, assigned to Adir
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^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.PMID7932550.
