Abstract
Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence.
Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT1 and MT2 receptors, as well as a 5-HT2C receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system.
Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep—wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.
Similar content being viewed by others
References
Alonso J, Angermeyer MC, Bernert S, et al. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl 2004(420): 21–7
Sobocki P, Jonsson B, Angst J, et al. Cost of depression in Europe. J Ment Health Policy Econ 2006 Jun; 9(2): 87–98
Baghai TC, Volz HP, Moller HJ. Drug treatment of depression in the 2000s: an overview of achievements in the last 10 years and future possibilities. World J Biol Psychiatry 2006; 7(4): 198–222
Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000 Apr; 58(1): 19–36
Danish University Antidepressant Group. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group.J Affect Disord 1990 Apr; 18(4): 289–99
Sonawalla SB, Fava M. Severe depression: is there a best approach? CNS Drugs 2001; 15(10): 765–76
Vestergaard P, Gram LF, Kragh-Sorensen P, et al. Therapeutic potentials of recently introduced antidepressants. Danish University Antidepressant Group. Psychopharmacol Ser 1993; 10: 190–8
Hindmarch I, Kimber S, Cockle SM. Abrupt and brief discontinuation of antidepressant treatment: effects on cognitive function and psychomotor performance. Int Clin Psychopharmacol 2000 Nov; 15(6): 305–18
Judge R, Parry MG, Quail D, et al. Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment. Int Clin Psychopharmacol 2002 Sep; 17(5): 217–25
Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial. Br J Psychiatry 2000 Apr; 176: 363–8
Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998 Jul 15; 44(2): 77–87
Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006 Feb; 7(2): 137–51
Richelson E. Synaptic effects of antidepressants. J Clin Psychopharmacol 1996 Jun; 16(3 Suppl. 2): 1S–7S; discussion 75-95
Montgomery SA, Kennedy SH, Burrows GD, et al. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol 2004 Sep; 19(5): 271–80
Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin Psychopharmacol 2006; 21Suppl. 1: S11–15
Wehr TA, Wirz-Justice A. Circadian rhythm mechanisms in affective illness and in antidepressant drug action. Pharmacopsychiatria 1982 Jan; 15(1): 31–9
Tylee A, Gastpar M, Lepine JP, et al. DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. DEPRES Steering Committee. Int Clin Psychopharmacol 1999 May; 14(3): 139–51
Lopes MC, Quera-Salva MA, Guilleminault C. Cyclic alternating pattern in the NREM sleep of patients within major depression disorder: baseline results and change overtime wirh a new antidepressant: agomelatine. Sleep Med 2005; 6Suppl. 2: 87–8
Quera-Salva MA, Vanier B, Chapotot F. Effect of agomelatine on the sleep EEG in patients with major depressive disorder. Eur Neuropsychopharmacol 2005; 15Suppl. 3: S435–6
Kupfer DJ. Sleep research in depressive illness: clinical implications — a tasting menu. Biol Psychiatry 1995 Sep 15; 38(6): 391–403
Souetre E, Salvati E, Belugou JL, et al. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res 1989 Jun; 28(3): 263–78
Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry 2004; 65Suppl. 16: 27–32
Moore RY. Organization and function of a central nervous system circadian oscillator: the suprachiasmatic hypothalamic nucleus. Fed Proc 1983 Aug; 42(11): 2783–9
Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry 1998; 155: 1119–21
Audinot V, Mailliet F, Lahaye-Brasseur C, et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol 2003 Jun; 367(6): 553–61
Millan MJ, Gobert A, Lejeune F, et al. 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. J Pharmacol Exp Ther 2003 Sep; 306(3): 954–64
Racagni G, Riva MA, Popoli M. The interaction between the internal clock and antidepressant efficacy. Int Clin Psychopharmacol 2007 Oct; 22Suppl. 2: S9–14
Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs 2006; 20(12): 981–92
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 1996 Aug; 54(4): 713–18
Masana MI, Benloucif S, Dubocovich ML. Circadian rhythm of mt1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse. J Pineal Res 2000 Apr; 28(3): 185–92
Papp M, Gruca P, Boyer PA, et al. Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 2003 Apr; 28(4): 694–703
Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J Psychiatry Neurosci 2004 Mar; 29(2): 126–33
Bertaina-Anglade V, la Rochelle CD, Boyer PA, et al. Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model. Behav Pharmacol 2006 Dec; 17(8): 703–13
Fuchs E, Simon M, Schmelting B. Pharmacology of a new antidepressant: benefit of the implication of the melatonergic system. Int Clin Psychopharmacol 2006 Feb; 21Suppl. 1: S17–20
Armstrong SM, McNulty OM, Guardiola-Lemaitre B, et al. Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS). Pharmacol Biochem Behav 1993 Sep; 46(1): 45–9
Van Reeth O, Weibel L, Olivares E, et al. Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus. Am J Physiol Regul Integr Comp Physiol 2001 May; 280(5): R1582–91
Weibel L, Turek FW, Mocaer E, et al. A melatonin agonist facilitates circadian resynchronization in old hamsters after abrupt shifts in the light-dark cycle. Brain Res 2000 Oct 13; 880(1–2): 207–11
Redman JR, Francis AJ. Entrainment of rat circadian rhythms by the melatonin agonist S-20098 requires intact suprachiasmatic nuclei but not the pineal. J Biol Rhythms 1998 Feb; 13(1): 39–51
Shirayama M, Shirayama Y, Iida H, et al. The psychological aspects of patients with delayed sleep phase syndrome (DSPS). Sleep Med 2003 Sep; 4(5): 427–33
Cornbach S, Schmelting B, Fuchs E, et al. Comparison of agomelatine and melatonin for effects in chronically stressed tree shrews, an animal model of depression [Poster P.2.d.005]. In: 20th European College of Neuropsychopharmacology congress; 2007 Oct 13–17; Vienna, Austria. Eur Neuropsychopharmacol 2007; 17Suppl. 4: S364–5
Barbiero V, Zappettini S, Mocaer E, et al. The novel antidepressant agomelatine reduces release of glutamate and related presynaptic mechanisms in rat hippocampus [Poster P.2.d.006]. In: 20th European College of Neuropsychopharmacology congress; 2007 Oct 13–17; Vienna, Austria. Eur Neuropsychopharmacol 2007; 17Suppl. 4: S365
Bonanno G, Giambelli R, Raiteri L, et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci 2005 Mar 30; 25(13): 3270–9
Acknowledgements
Medical writing support was provided by Nila Bhana from Wolters Kluwer Health and was funded by Servier.
The author declares that he has performed consulting for Servier.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Popoli, M. Agomelatine. CNS Drugs 23 (Suppl 2), 27–34 (2009). https://doi.org/10.2165/11318640-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11318640-000000000-00000