Agomelatine#Pharmacology

Agomelatine is used for the treatment of major depressive episodes in adults in Europe and Australia. 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. 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. The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. One meta-analysis found agomelatine to be as effective as standard antidepressants, with an effect size ({{Abbrlink|SMD|standardized mean difference}}) of 0.24.{{cite journal | vauthors = Cleare A, Pariante CM, Young AH, Anderson IM, Christmas D, Cowen PJ, Dickens C, Ferrier IN, Geddes J, Gilbody S, Haddad PM, Katona C, Lewis G, Malizia A, McAllister-Williams RH, Ramchandani P, Scott J, Taylor D, Uher R | title = Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines | journal = J Psychopharmacol | volume = 29 | issue = 5 | pages = 459–525 | date = May 2015 | pmid = 25969470 | doi = 10.1177/0269881115581093 | s2cid = 8142581 | url = https://kclpure.kcl.ac.uk/ws/files/52545391/PMH_24_3_15_British_Association_forPsychopharmacology_Final_Reconciliation_Draft_2_.docx | access-date = 2023-01-24 | archive-date = 2023-03-07 | archive-url = https://web.archive.org/web/20230307221823/https://kclpure.kcl.ac.uk/ws/files/52545391/PMH_24_3_15_British_Association_forPsychopharmacology_Final_Reconciliation_Draft_2_.docx | url-status = live }}

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.{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 }}

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.{{cite journal | vauthors = Montgomery SA, Kasper S | title = Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine | journal = International Clinical Psychopharmacology | volume = 22 | issue = 5 | pages = 283–91 | date = September 2007 | pmid = 17690597 | doi = 10.1097/YIC.0b013e3280c56b13 | s2cid = 21796064 }} 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.{{cite journal | vauthors = Singh SP, Singh V, Kar N | title = Efficacy of agomelatine in major depressive disorder: meta-analysis and appraisal | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 3 | pages = 417–28 | date = April 2012 | pmid = 21859514 | doi = 10.1017/S1461145711001301 | doi-access = }} A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants.

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.{{cite journal | vauthors = Koesters M, Guaiana G, Cipriani A, Becker T, Barbui C | title = Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials | journal = The British Journal of Psychiatry | volume = 203 | issue = 3 | pages = 179–87 | date = September 2013 | pmid = 23999482 | doi = 10.1192/bjp.bp.112.120196 | doi-access = free }}{{cite journal | vauthors = Howland RH | title = A benefit-risk assessment of agomelatine in the treatment of major depression | journal = Drug Safety | volume = 34 | issue = 9 | pages = 709–31 | date = September 2011 | pmid = 21830835 | doi = 10.2165/11593960-000000000-00000 | s2cid = 21808090 }} 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", being only slightly above placebo. 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.

Agomelatine is also approved for the treatment of generalized anxiety disorder in adults in Australia. 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.{{cite journal | vauthors = De Berardis D, Conti CM, Marini S, Ferri F, Iasevoli F, Valchera A, Fornaro M, Cavuto M, Srinivasan V, Perna G, Carano A, Piersanti M, Martinotti G, Di Giannantonio M | title = Is there a role for agomelatine in the treatment of anxiety disorders?A review of published data | journal = International Journal of Immunopathology and Pharmacology | volume = 26 | issue = 2 | pages = 299–304 | year = 2013 | pmid = 23755745 | doi = 10.1177/039463201302600203 | s2cid = 40152863 | doi-access = free }}{{cite journal | vauthors = Stein DJ, Ahokas A, Márquez MS, Höschl C, Seob Oh K, Jarema M, Avedisova AS, Albarran C, Olivier V | title = Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study | journal = Journal of Clinical Psychiatry | volume = 75| issue = 4| pages = 362–8 | year = 2014 | pmid = 24569045 | doi = 10.4088/JCP.13m08433 | s2cid = 24860538 }}{{cite journal | vauthors = Stein DJ, Khoo JP, Picarel-Blanchot F, Olivier V, Van Ameringen M | title = Efficacy of Agomelatine 25-50 mg for the Treatment of Anxious Symptoms and Functional Impairment in Generalized Anxiety Disorder: A Meta-Analysis of Three Placebo-Controlled Studies | journal = Advances in Therapy | volume = 38 | issue = 3 | pages = 1567–1583 | year = 2021 | pmid = 33537871 | doi = 10.1007/s12325-020-01583-9 | pmc = 7932987 }}{{cite journal | vauthors = Stein DJ, Ahokas AA, de Bodinat C | title = Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 5 | pages = 561–566 | year = 2008 | pmid = 18794654 | doi = 10.1097/JCP.0b013e318184ff5b | s2cid = 5569226 }}{{cite journal | vauthors = Stein DJ, Ahokas AA, Jarema M, Avedisova AS, Vavrusova L, Chaban O, Gruget C, Olivier V, Picarel-Blanchot F, de Bodinat C | title = 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 | journal = European Neuropsychopharmacology | volume = 27 | issue = 5 | pages = 526–537 | year = 2017| pmid = 28298261| doi = 10.1097/JCP.0b013e318184ff5b | s2cid = 5569226 }}

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

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. 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.{{cite journal | vauthors = Arango C, Buitelaar JK, Fegert JM, Olivier V, Pénélaud P, Marx U, Chimits D, Falissard B | title = Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries | journal = Lancet Psychiatry | volume = 9 | issue = 2 | pages = 113–124 | year = 2022| pmid = 34919834| doi = 10.1016/S2215-0366(21)00390-4 | s2cid = 245167558 | doi-access = free }}{{cite web|title=Agomelatine Effective for Children, Adolescents With Depression|url=https://dgnews.docguide.com/agomelatine-effective-children-adolescents-depression|access-date=2020-09-21|website=dgnews.docguide.com|language=en|archive-date=2021-12-06|archive-url=https://web.archive.org/web/20211206134649/https://dgnews.docguide.com/agomelatine-effective-children-adolescents-depression|url-status=live}} Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.

It is not recommended during pregnancy or breastfeeding.

Agomelatine is contraindicated in patients with kidney or liver impairment. 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.{{cite web |url=http://www.servier.com/content/information-about-valdoxan-patients | title = Information about Valdoxan for patients |access-date=2012-12-10 |url-status=dead |archive-url=https://web.archive.org/web/20121210222021/http://www.servier.com/content/information-about-valdoxan-patients |archive-date=2012-12-10 | publisher = Servier }} 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 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.{{cite journal | vauthors = Quera Salva MA, Vanier B, Laredo J, Hartley S, Chapotot F, Moulin C, Lofaso F, Guilleminault C | title = Major depressive disorder, sleep EEG and agomelatine: an open-label study | journal = The International Journal of Neuropsychopharmacology | volume = 10 | issue = 5 | pages = 691–696 | date = October 2007 | pmid = 17477886 | doi = 10.1017/S1461145707007754 | s2cid = 5997517 | doi-access = }} 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 appears to cause fewer sexual side effects and discontinuation effects than paroxetine.

; Common (1–10% incidence) adverse effects include{{cite book|title=British National Formulary (BNF) 65|year=2013|publisher=Pharmaceutical Press|location=London, UK|isbn=978-0857110848|page=253|author=Joint Formulary Committee and Royal Pharmaceutical Society of Great Britain|url=https://books.google.com/books?id=fZLvtHELVdMC|access-date=2018-07-24|archive-date=2023-01-14|archive-url=https://web.archive.org/web/20230114034625/https://books.google.com/books?id=fZLvtHELVdMC|url-status=live}}

{{div col|colwidth=30em}}

• Headache
• Nausea
• Dizziness
• Somnolence
• Diarrhea
• Insomnia
• Fatigue
• Back pain
• Abdominal pain
• Anxiety
• Increased ALAT and ASAT (liver enzymes), possibly > 3× the upper limit of normal{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/27342740/ | pmid=27342740 | date=2016 | title=Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients | journal=CNS Drugs | volume=30 | issue=9 | pages=877–888 | doi=10.1007/s40263-016-0351-6 | vauthors = Perlemuter G, Cacoub P, Valla D, Guyader D, Saba B, Batailler C, Moore K }}
• Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature)
• Constipation
• Vomiting
• Migraine

{{div col end}}

; Uncommon (0.1–1%) adverse effects include

{{div col|colwidth=30em}}

• Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves)
• Blurred vision
• Eczema
• Pruritus (itching)
• Urticaria
• Agitation
• Irritability
• Restlessness
• Aggression
• Nightmares
• Abnormal dreams

{{div col end}}

; Rare (0.01–0.1%) adverse effects include

{{div col|colwidth=30em}}

• Mania
• Hypomania
• Suicidal ideation
• Suicidal behaviour
• Hallucinations
• Steatohepatitis
• Increased GGT and/or alkaline phosphatase
• Liver failure
• Jaundice
• Erythematous rash
• Face oedema and angioedema
• Weight gain or loss, which tends to be less significant than with SSRIs{{cite journal | vauthors = Kennedy SH, Rizvi SJ | title = Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness | journal = CNS Drugs | volume = 24 | issue = 6 | pages = 479–99 | date = June 2010 | pmid = 20192279 | doi = 10.2165/11534420-000000000-00000 | s2cid = 41069663 }}

{{div col end}}

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.

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. 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.{{cite journal | vauthors = Pladevall-Vila M, Pottegård A, Schink T, Reutfors J, Morros R, Poblador-Plou B, Timmer A, Forns J, Hellfritzsch M, Reinders T, Hägg D, Giner-Soriano M, Prados-Torres A, Cainzos-Achirica M, Hallas J, Brandt L, Cortés J, Aguado J, Perlemuter G, Falissard B, Castellsagué J, Jacquot E, Deltour N, Perez-Gutthann S | title = 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 | journal = CNS Drugs | volume = 33 | issue = 4 | pages = 383–395 | date = April 2019 | pmid = 30830574 | pmc = 6441103 | doi = 10.1007/s40263-019-00611-9 }}

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

Agomelatine is expected to be relatively safe in overdose.{{cite book | isbn = 978-0-470-97948-8 | title = The Maudsley prescribing guidelines in psychiatry | vauthors = Taylor D, Paton C, Shitij K | year = 2012 | publisher = Wiley-Blackwell | location = West Sussex | url = https://books.google.com/books?id=ZjEDDQAAQBAJ | access-date = 2018-07-24 | archive-date = 2023-01-14 | archive-url = https://web.archive.org/web/20230114104159/https://books.google.com/books?id=ZjEDDQAAQBAJ | url-status = live }}

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.{{cite book|title=Australian Medicines Handbook 2013|year=2013|publisher=The Australian Medicines Handbook Unit Trust|location=Adelaide|isbn=9780980579093|url=https://books.google.com/books?id=tn3-swEACAAJ}} There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity.

Agomelatine acts as a highly potent and selective melatonin MT₁ and MT₂ receptor agonist (K_i = 0.1{{nbsp}}nM and 0.12{{nbsp}}nM, respectively) and also as a relatively weak serotonin 5-HT_2B and 5-HT_2C receptor antagonist (K_i = 660{{nbsp}}nM and 631{{nbsp}}nM, respectively; ~6,000-fold lower than for the melatonin receptors).{{cite journal | vauthors = Norman TR, Olver JS | title = Agomelatine for depression: expanding the horizons? | journal = Expert Opin Pharmacother | volume = 20 | issue = 6 | pages = 647–656 | date = April 2019 | pmid = 30759026 | doi = 10.1080/14656566.2019.1574747 | url = | quote = 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. }}{{cite journal |vauthors=Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D |date=September 2003 |title=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 |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=306 |issue=3 |pages=954–64 |doi=10.1124/jpet.103.051797 |pmid=12750432 |s2cid=18753440 | quote=[...] 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. }} It is a silent antagonist rather than an inverse agonist of the serotonin 5-HT_2C receptor.{{cite journal | vauthors = Millan MJ | title = Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action | journal = Ther Adv Psychopharmacol | volume = 12 | issue = | pages = 20451253221105128 | date = 2022 | pmid = 35795687 | pmc = 9251978 | doi = 10.1177/20451253221105128 | url = | quote = [...] 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 }} The drug has negligible affinity for the serotonin 5-HT_2A receptor or for a variety of other targets.

By antagonizing the serotonin 5-HT_2C 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.{{cite journal | vauthors = Chagraoui A, Thibaut F, Skiba M, Thuillez C, Bourin M | title = 5-HT2C receptors in psychiatric disorders: A review | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 66 | issue = | pages = 120–135 | date = April 2016 | pmid = 26739950 | doi = 10.1016/j.pnpbp.2015.12.006 | url = | quote = 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). }} In contrast to agomelatine, other serotonin 5-HT_2C 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.{{cite journal | vauthors = Jensen NH, Cremers TI, Sotty F | title = Therapeutic potential of 5-HT2C receptor ligands | journal = ScientificWorldJournal | volume = 10 | issue = | pages = 1870–1885 | date = September 2010 | pmid = 20852829 | pmc = 5763985 | doi = 10.1100/tsw.2010.180 | doi-access = free | url = | quote = [...] 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]. }} These differences may in part be related to constitutive activity of the serotonin 5-HT_2C receptor and resulting differences between neutral antagonists and inverse agonists of the receptor.{{cite journal | vauthors = Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA | title = Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors | journal = Pharmacol Ther | volume = 121 | issue = 2 | pages = 160–173 | date = February 2009 | pmid = 19109993 | doi = 10.1016/j.pharmthera.2008.10.010 | url = | quote = 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. }}{{cite journal | vauthors = De Deurwaerdère P, Navailles S, Berg KA, Clarke WP, Spampinato U | title = Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens | journal = J Neurosci | volume = 24 | issue = 13 | pages = 3235–3241 | date = March 2004 | pmid = 15056702 | pmc = 6730027 | doi = 10.1523/JNEUROSCI.0112-04.2004 | url = }} In addition, there are multiple isoforms of the serotonin 5-HT_2C receptor with different properties. In other studies, while agomelatine alone did not affect the firing rates of ventral tegmental area (VTA) dopaminergic neurons, it abolished the inhibition of these neurons by the serotonin 5-HT_2C receptor agonist Ro60-0175. Due to the increase in norepinephrine and dopamine levels in the frontal cortex with agomelatine, the drug has sometimes been referred to as a norepinephrine–dopamine disinhibitor (NDDI).{{cite journal | vauthors = Fasipe OJ | title = The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents | journal = IBRO Rep | volume = 6 | issue = | pages = 95–110 | date = June 2019 | pmid = 31211282 | pmc = 6562183 | doi = 10.1016/j.ibror.2019.01.001 | url = | quote = 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). }}{{cite journal | last=Fasipe | first=OlumuyiwaJohn | title=Neuropharmacological classification of antidepressant agents based on their mechanisms of action | journal=Archives of Medicine and Health Sciences | volume=6 | issue=1 | date=2018 | issn=2321-4848 | doi=10.4103/amhs.amhs_7_18 | doi-access=free | page=81 | quote=By antagonizing 5-HT2C receptors, it disinhibits/increases norepinephrine and dopamine release specifically in the prefrontal cortex. Therefore, it is sometimes classified as a norepinephrine–dopamine disinhibitor (NDD). It has no influence on the extracellular levels of serotonin. }}

Although agomelatine is widely claimed to act as a serotonin 5-HT_2C receptor antagonist, the clinical significance of this action has been disputed by some researchers.{{cite journal | vauthors = Sharpley AL, Cowen PJ |date= May 2012 |title=In response to "The effect of agomelatine on 5HT2C receptors in humans: a clinically relevant mechanism?" by Trevor Norman |journal=Psychopharmacology |language=en |volume=221 |issue=1 |pages=179 |doi=10.1007/s00213-012-2659-3 |issn=1432-2072|doi-access=free }} Unlike with other serotonin 5-HT_2C receptor antagonists, therapeutic doses of agomelatine fail to acutely increase slow-wave sleep in humans.{{cite journal | vauthors = Norman TR | title = The effect of agomelatine on 5HT(2C) receptors in humans: a clinically relevant mechanism? | journal = Psychopharmacology | volume = 221 | issue = 1 | pages = 177–8; author reply 179 | date = May 2012 | pmid = 22349274 | doi = 10.1007/s00213-012-2656-6 | s2cid = 253752682 }}{{cite journal | vauthors = Quera Salva MA, Vanier B, Laredo J, Hartley S, Chapotot F, Moulin C, Lofaso F, Guilleminault C | title = Major depressive disorder, sleep EEG and agomelatine: an open-label study | journal = The International Journal of Neuropsychopharmacology | volume = 10 | issue = 5 | pages = 691–696 | date = October 2007 | pmid = 17477886 | doi = 10.1017/S1461145707007754 | s2cid = 5997517 }} Additionally, no receptor occupancy studies of agomelatine have been conducted in humans to demonstrate significant occupancy of serotonin 5-HT_2C receptors at therapeutic doses.

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).{{cite journal | vauthors = Le Strat Y, Gorwood P | title = Agomelatine, an innovative pharmacological response to unmet needs | journal = Journal of Psychopharmacology | volume = 22 | issue = 7 Suppl | pages = 4–8 | date = September 2008 | pmid = 18753276 | doi = 10.1177/0269881108092593 | s2cid = 29745284 }} In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset.

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.{{cite web |title=Annex I: Summary of Product Characteristics |url=https://www.ema.europa.eu/en/documents/product-information/valdoxan-epar-product-information_en.pdf |website=European Medicines Agency |access-date=29 January 2025 |page=5}} Agomelatine is well-absorbed with oral administration (≥80%), but it has very low oral bioavailability (~1%) due to extensive first-pass metabolism. The elimination half-life of agomelatine is 1 to 2{{nbsp}}hours.{{cite journal | vauthors = Buoli M, Mauri MC, Altamura AC | title = Pharmacokinetic evaluation of agomelatine for the treatment of generalised anxiety disorder | journal = Expert Opin Drug Metab Toxicol | volume = 10 | issue = 6 | pages = 885–892 | date = June 2014 | pmid = 24717138 | doi = 10.1517/17425255.2014.907794 | url = | quote = 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. }} The half-life of agomelatine does not change with repeated administration. There is no accumulation of agomelatine with continuous administration.

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

The chemical structure of agomelatine is very similar to that of melatonin.{{cite journal | vauthors = San L, Arranz B | title = Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system | journal = Eur Psychiatry | volume = 23 | issue = 6 | pages = 396–402 | date = September 2008 | pmid = 18583104 | doi = 10.1016/j.eurpsy.2008.04.002 | url = }} Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead.{{ cite journal | journal = Acta Crystallogr. C | volume = 50 | issue = 6 | year = 1994 | pages = 907–910 | title = N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, a potent melatonin analog | vauthors = Tinant B, Declercq JP, Poupaert JH, Yous S, Lesieur D | doi = 10.1107/S0108270193012922 | bibcode = 1994AcCrC..50..907T }}

File:Agomelatine-synthesis.svg

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. 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.{{cite news|url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-656-657-RQ&A-en.pdf|archive-url=https://wayback.archive-it.org/all/20100806131004/http://www.ema.europa.eu/ema/index.jsp?curl%3D/url_not_found_header.jsp|url-status=dead|archive-date=6 August 2010|title=Questions and Answers on Recommendation for Refusal of Marketing Authorisation|date=18 November 2006|publisher=European Medicines Agency|access-date=6 July 2009}} In September 2007, Servier submitted a new marketing application to the EMA.{{cite news|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000915/WC500046226.pdf|title=CHMP Assessment Report for Valdoxan|date=20 November 2008|publisher=European Medicines Agency|access-date=6 July 2009|url-status=live|archive-url=https://web.archive.org/web/20110424023843/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000915/WC500046226.pdf|archive-date=24 April 2011}}

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis.{{cite news|url=http://www.servier.co.uk/news/news-details.asp?StoryID=76|title=Servier and Novartis sign licensing agreement for agomelatine, a novel treatment for depression| vauthors = Bentham C |date=2006-03-29|publisher=Servier UK|access-date=2009-05-15|archive-url=https://web.archive.org/web/20090416210513/http://www.servier.co.uk/news/news-details.asp?StoryID=76|archive-date=16 April 2009|url-status=dead}} 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.{{cite web|url=http://clinicaltrials.gov/ct2/results?term=agomelatine|title=Clinical trials for agomelatine|work=ClinicalTrials.gov|publisher=National Institutes of Health|access-date=6 July 2009|url-status=live|archive-url=http://archive.wikiwix.com/cache/20111004081245/http://clinicaltrials.gov/ct2/results?term=agomelatine|archive-date=4 October 2011}} However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.{{cite web | vauthors = Malone E | url = http://www.scripintelligence.com/home/Novartis-drops-future-blockbuster-agomelatine-322880 | title = Novartis drops future blockbuster agomelatine. | archive-url = https://web.archive.org/web/20111111121308/http://www.scripintelligence.com/home/Novartis-drops-future-blockbuster-agomelatine-322880 | work = Scrip Intelligence | date = 25 October 2011 | archive-date = 11 November 2011 }}

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

Agomelatine has been investigated for its effects on sleep regulation due its actions as a melatonin receptor agonist.{{cite journal | vauthors = Williams WP, McLin DE, Dressman MA, Neubauer DN | title = Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders | journal = Pharmacotherapy | volume = 36 | issue = 9 | pages = 1028–41 | date = September 2016 | pmid = 27500861 | pmc = 5108473 | doi = 10.1002/phar.1822 | url = }} Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm sleep disorders.{{cite news|url=http://www.medicalnewstoday.com/articles/22334.php|title=Valdoxan: A New Approach to The Treatment of Depression|date=2005-04-05|work=Medical News Today|publisher=MediLexicon International Ltd.|access-date=14 May 2009| archive-url= https://web.archive.org/web/20090415070653/http://www.medicalnewstoday.com/articles/22334.php| archive-date= 15 April 2009 | url-status= live}} However, research is very limited (e.g., case reports) and agomelatine is not approved for use in the treatment of sleep disorders.

A 2019 Cochrane review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder.{{cite journal | vauthors = Nussbaumer-Streit B, Greenblatt A, Kaminski-Hartenthaler A, Van Noord MG, Forneris CA, Morgan LC, Gaynes BN, Wipplinger J, Lux LJ, Winkler D, Gartlehner G | title = Melatonin and agomelatine for preventing seasonal affective disorder | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 6 | pages = CD011271 | date = June 2019 | pmid = 31206585 | pmc = 6578031 | doi = 10.1002/14651858.CD011271.pub3 }}

• SPT-320 (LYT-320) – an experimental agomelatine prodrug

{{Reflist}}

• Genf interaction table- https://www.hug.ch/sites/interhug/files/structures/pharmacologie_et_toxicologie_cliniques/carte_cytochromes_2016_final.pdf

{{Antidepressants}}

{{Hypnotics}}

{{Insomnia pharmacotherapies}}

{{Melatonin receptor modulators}}

{{Serotonin receptor modulators}}

{{Phenethylamines}}

{{Portal bar | Medicine}}

Category:5-HT2B antagonists

Category:5-HT2C antagonists

Category:Acetamides

Category:Antidepressants

Category:Laboratoires Servier

Category:Melatonin receptor agonists

Category:Methoxyphenethylamines

Category:Naphthol ethers

Category:Naphthylethylamines

Category:Phenethylamines

Category:Wikipedia medicine articles ready to translate