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Agomelatine: A novel mechanism of antidepressant action involving the melatonergic and the serotonergic system

Published online by Cambridge University Press:  16 April 2020

Luis San  and
Belen Arranz
Luis San
Affiliation:
Department of Psychiatry, Hospital San Rafael, Barcelona, Spain
Belen Arranz*
Affiliation:
Sant Joan de Déu, Serveis de Salut Mental, Antoni Pujades, 42, 08830, Sant Boi de Llobregat, Barcelona, Spain
*
*Corresponding author. E-mail address: 24439bam@comb.es (B. Arranz).
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Abstract

The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential. Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex). The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placebo–controlled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25 mg/day, with the possibility of increasing doses to 50 mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatine's efficacy over a longer treatment period.

Keywords

Circadian rhythmsDepressionSleep disordersMelatoninAgomelatine
Type
Review
Information
European Psychiatry , Volume 23 , Issue 6 , September 2008 , pp. 396 - 402
Copyright
Copyright © Elsevier Masson SAS 2008

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References

Alonso, J.Angermeyer, M.C.Lepine, J.P.The European study of the Epidemiology of mental disorders (ESEMeD) project Acta Psychiatr Scand. 420 2004 5–7CrossRefGoogle Scholar
Agid, Y.Buzsaki, G.Diamond, D.M.Frackowiak, R.Giedd, J.Girault, J.A.et al.How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov. 6 2007 189–201CrossRefGoogle ScholarPubMed
Boivin, D.B.Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders J Psychiatry Neurosci. 35 2000 446–458Google Scholar
Brainard, G.C.Hanifin, J.P.Greeson, J.M.Byrne, B.Glickman, G.Gerner, E.et al.Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor J Neurosci. 21 2002 6405–6412CrossRefGoogle Scholar
Barden, N.Shink, E.Labbé, M.Vacher, R.Rochford, J.Mocaër, E.Antidepressant action of agomelatine (S 20098) in a transgenic mouse model Prog Neuropsychopharmacol Biol Psychiatry. 29 2005 908–916CrossRefGoogle Scholar
Benca, R.M.Obermeyer, W.H.Thisted, R.A.Gillin, J.C.Sleep and psychiatric disorders. A meta-analysis Arch Gen Psychiatry. 49 1992 651–668CrossRefGoogle ScholarPubMed
Claustrat, B.Chazot, G.Brun, J.Jordan, D.Sassolas, G.A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression Biol Psychiatry. 19 1984 1215–1228Google ScholarPubMed
Crasson, M.Kjiri, S.Colin, A.Kriri, K.L'Hermite-Baleriaux, M.Ansseau, M.et al.Serum melatonin and urinary 6-sulphatoxymelatonin in major depression Psychoneuroendocrinology. 29 2004 1–12CrossRefGoogle ScholarPubMed
Carvalho, L.A.Gorenstein, C.Moreno, R.A.Markus, R.P.Melatonin levels in drug-free patients with major depression from the southern hemisphere Psychoneuroendocrinology. 31 2006 761–768CrossRefGoogle ScholarPubMed
Calabrese, J.R.Guelfi, J.D.Perdrizet-Chevallier, C.Agomelatine bipolar study group. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data Bipolar Disord. 9 2007 628–635CrossRefGoogle Scholar
Cole, M.G.Dendukuri, N.Risk factors for depression among elderly community subjects: a systematic review and meta-analysis Am J Psychiatry. 160 2003 1147–1156CrossRefGoogle ScholarPubMed
Cajochen, C.Krauchi, K.Mori, D.Graw, P.Wirz-Justice, A.Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis Am J Physiol. 272 4 Pt. 2 1997 R1189–R1196Google ScholarPubMed
Dalton, E.J.Rotondi, D.Levitan, R.D.Kennedy, S.H.Brown, G.M.Use of slow-release melatonin in treatment-resistant depression J Psychiatry Neurosci. 25 2000 48–52Google ScholarPubMed
Delagrange, P.Boutin, J.A.Therapeutic potential of melatonin ligands Chronobiol Int. 23 2006 413–418CrossRefGoogle ScholarPubMed
Dubocovich, M.L.Drug evaluation: agomelatine targets a range of major depressive disorder symptoms Curr Opin Investig Drugs. 7 2006 670–680Google ScholarPubMed
Gruca, P.Przegalinski, E.Mrowiec, S.Lason, M.Papp, M.Evidence for antidepressant and anxiolytic-like activities of melatonin and agomelatine in animal models Eur Neuropsychopharmacol. 14 2004 S230CrossRefGoogle Scholar
Gurevich, I.Tamir, H.Arango, V.Dwork, A.J.Mann, J.J.Schmauss, C.Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims Neuron. 34 2002 349–356CrossRefGoogle ScholarPubMed
Hattar, S.Lucas, R.J.Mrosovsky, N.Thompson, S.Douglas, R.H.Hankins, M.W.et al.Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice Nature. 424 2003 76–81CrossRefGoogle ScholarPubMed
Holmes, M.C.French, K.L.Seckl, J.R.Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids J Neurosci. 17 1997 4056–4065CrossRefGoogle ScholarPubMed
Hanoun, N.Mocaer, E.Boyer, P.A.Hamon, M.Lanfumey, L.Differential effects of the novel antidepressant agomelatine (S 20098) versus fluoxetine on 5-HT1A receptors in the rat brain Neuropharmacology. 47 2004 515–526CrossRefGoogle ScholarPubMed
Kessler, R.C.Chiu, W.T.Demler, O.Walters, E.E.Prevalence, severity and comorbidity of twelve month DSM IV disorders in the National Comorbidity Survey Replication Arch Gen Psychiatry. 62 2005 617–627CrossRefGoogle ScholarPubMed
Kennaway, D.J.Moyer, R.W.Voultsios, A.Varcoe, T.J.Serotonin, excitatory amino acids and the photic control of melatonin rhythms and SCN c-FOS in the rat Brain Res. 897 2001 36–43CrossRefGoogle ScholarPubMed
Kennaway, D.J.Moyer, R.W.Serotonin 5-HT2c agonists mimic the effect of light pulses on circadian rhythms Brain Res. 806 1998 257–270CrossRefGoogle ScholarPubMed
Kennedy, S.Emsley, R.A.Placebo–controlled trial of agomelatine in the treatment of major depressive disorder Eur Neuropsychopharmacol. 16 2 2006 93–100CrossRefGoogle ScholarPubMed
Leproult, R.Van Onderbergen, A.L'Hermite-Baleriaux, M.Van Cauter, E.Copinschi, G.Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men Clin Endocrinol. 63 2005 298–304CrossRefGoogle ScholarPubMed
Lôo, H.Hale, A.D'Haenen, H.Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo–controlled dose range study Int Clin Psychopharmacol. 17 2002 239–247Google Scholar
Lopes, M.C.Quera-Salva, M.A.Guilleminault, C.Cyclic alternating pattern in the nREM sleep of patients with major depressive disorder: baseline results and change overtime with a new antidepressant: agomelatine Sleep Med. 6 Suppl. 2 2005 87–88Google Scholar
Moore, R.Y.Circadian rhythms: basic neurobiology and clinical applications Annu Rev Med. 48 1997 253–266CrossRefGoogle ScholarPubMed
Macchi, M.M.Bruce, J.N.Human pineal physiology and functional significance of melatonin Front Neuroendocrinol. 25 2004 177–195CrossRefGoogle ScholarPubMed
Millan, M.J.Gobert, A.Lejeune, F.Dekeyne, A.Newman-Tancredi, A.Pasteau, V.et al.The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine 2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways J Pharmacol Exp Ther. 306 2003 954–964CrossRefGoogle ScholarPubMed
Masana, M.I.Benloucif, S.Dubocovich, M.L.Circadian rhythm of MT1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse J Pineal Res. 28 2000 185–192CrossRefGoogle ScholarPubMed
Martinet, L.Guardiola-Lemaitre, B.Mocaer, E.Entrainment of circadian rhythms by S-20098, a melatonin agonist, is dose and plasma concentration dependent Pharmacol Biochem Behav. 54 1996 713–718CrossRefGoogle ScholarPubMed
Millan, M.J.Brocco, M.Gobert, A.Dekeyne, A.Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade Psychopharmacology (Berl). 177 2005 448–458CrossRefGoogle ScholarPubMed
Montgomery, S.A.Kasper, S.Severe depression and antidepressants: focus on a pooled analysis of placebo–controlled studies on agomelatine Int Clin Psychopharmacol. 22 2007 283–291CrossRefGoogle ScholarPubMed
Montgomery, S.A.Kennedy, S.H.Burrows, G.D.Lejoyeux, M.Hindmarch, I.Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation with paroxetine: a randomized, double-blind, placebo–controlled discontinuation study Int Clin Psychopharmacol. 19 2004 271–280CrossRefGoogle ScholarPubMed
Olié, J.P.Kasper, S.Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder Int J Neuropsychopharmacol. 10 5 2007 661–673Google ScholarPubMed
Pandi-Perumal, S.R.Srinivasan, V.Maestroni, G.J.M.Cardinali, D.P.Poeggeler, B.Hardeland, R.Melatonin: nature's most versatile biological signal? FEBS J. 273 2006 2813–2838CrossRefGoogle ScholarPubMed
Pandi-Perumal, S.R.Srinivasan, V.Spence, D.W.Cardinali, D.P.Role of melatonin system in the control of sleep CNS Drugs. 21 12 2007 995–1018CrossRefGoogle Scholar
Paccierotti, C.Iapichino, S.Bossini, L.Pieraccini, F.Castrogiovanni, P.Melatonin in psychiatric disorders: a review on the melatonin involvement in psychiatry Front Neuroendocrinol. 22 2001 18–32CrossRefGoogle Scholar
Palazidou, E.Papadopoulos, A.Ratcliff, H.Dawling, S.Checkley, S.A.Noradrenaline uptake inhibition increases melatonin secretion, a measure of noradrenergic neurotransmission, in depressed patients Psychol Med. 22 1992 309–315CrossRefGoogle ScholarPubMed
Papp, M.Gruca, P.Boyer, P.A.Mocaer, E.Effect of agomelatine in the chronic mild stress model of depression in the rat Neuropsychopharmacology. 28 2003 694–703CrossRefGoogle ScholarPubMed
Pitrosky, B.Kirsch, R.Malan, A.Mocaer, E.Pevert, P.Organisation of rat circadian rhythms during daily infusion of melatonin or S20098, a melatonin agonist Am J Physiol. 277 1999 812–828Google ScholarPubMed
Papp, M.Litwa, E.Gruca, P.Mocaër, E.Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety Behav Pharmacol. 17 2006 9–18Google ScholarPubMed
Quera-Salva, M.A.Vanier, B.Laredo, J.Hartley, S.Chapopot, F.Moulin, C.et al.Major depressive disorder, sleep EEG and agomelatine: an open-label study Int J Neuropsychopharmacol. 10 5 2007 691–696Google ScholarPubMed
Riedel, W.J.Klaassen, T.Griez, E.Honig, A.Menheere, P.P.C.A.Van Praag, H.M.Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood Neuropsychopharmacology. 26 2002 358–367CrossRefGoogle ScholarPubMed
Redman, J.R.Guardiola-Lemaitre, B.Brown, M.Delagrange, P.Armstrong, S.M.Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms Psychopharmacology (Berl). 118 1995 385–390CrossRefGoogle ScholarPubMed
Riemann, D.Berger, M.Vodelholzer, U.Sleep and depression; results from psychobiological studies: an overview Biol Psychol. 57 2001 67–103CrossRefGoogle ScholarPubMed
Schildkraut, J.J.The catecholamine hypothesis of affective disorders: a review of supporting evidence Am J Psychiatry. 122 1965 509–522CrossRefGoogle ScholarPubMed
Turek, F.W.From circadian rhythms to clock genes in depression Int Clin Psychopharmacol. 22 Suppl. 2 2007 S1–S8CrossRefGoogle ScholarPubMed
Tsujimoto, T.Yamada, N.Shimoda, K.Kanada, K.Takahashi, S.Circadian rhythms in depression. Part II: circadian rhythms in inpatients with various mental disorders J Affect Disord. 18 1990 199–210CrossRefGoogle ScholarPubMed
Van Cauter, E.Leproult, R.Kupfer, D.J.Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol J Clin Endocrinol Metab. 81 1996 2468–2473Google ScholarPubMed
Van Reeth, O.Weibel, L.Olivares, E.Maccari, S.Mocaer, E.Turek, F.W.Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus Am J Physiol Regul Integr Comp Physiol. 280 2001 1582–1591CrossRefGoogle ScholarPubMed
Varcoe, T.J.Kennaway, D.J.Voultsios, A.Activation of 5-HT2C receptors acutely induces per gene expression in the rat suprachiasmatic nucleus at night Brain Res Mol Brain Res. 119 2003 192–200CrossRefGoogle ScholarPubMed
Wells, K.B.Stewart, A.Hays, R.D.Burnam, M.A.Rogers, W.Daniels, M.et al.The functioning and well-being of depressed patients: results from the medical outcomes study JAMA. 262 1989 914–919CrossRefGoogle ScholarPubMed
Wehr, T.A.Wirz-Justice, A.Circadian rhythm mechanisms in affective illness and in antidepressant drug action Pharmacopsychiatria. 15 1982 31–39CrossRefGoogle ScholarPubMed
Wirz-Justice, A.Biological rhythm disturbances in mood disorders Int Clin Psychopharmacol. 21 2006 11–15CrossRefGoogle ScholarPubMed
Yamada, J.Sugimoto, Y.Effects of 5-HT2 receptor antagonists on the anti-immobility effects of imipramine in the forced swimming test with mice Eur J Pharmacol. 427 2001 221–225CrossRefGoogle Scholar
Zupancic, M.Guilleminault, C.Agomelatine: a preliminary review of a new antidepressant CNS Drugs. 20 12 2006 981–992CrossRefGoogle ScholarPubMed
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