Key Points
-
Major depression is a serious and debilitating disease for which current pharmacotherapy is inadequate in terms of limited efficacy, a long delay to onset of action and induction of side effects.
-
All currently available antidepressants act by monoaminergic mechanisms of action, generally through the suppression of monoamine reuptake.
-
Circadian rhythms, which are under the control of the suprachiasmatic nucleus, are often disrupted in depressed states. Accordingly, suprachiasmatic nucleus-localized melatonergic receptors, which are known to synchronize circadian rhythms, are an attractive target for the treatment of depression.
-
Agomelatine, the first melatonergic antidepressant, was designed to improve depressed states by resynchronizing perturbed biological rhythms. Its 'synergistic' agonist properties at melatonin receptors plus antagonist properties at 5-hydroxytryptamine 2C (5-HT2C) receptors account for its beneficial influence on depressed states.
-
In extensive preclinical studies using cellular, neurochemical and behavioural procedures, agomelatine displayed a broad-based profile of actions that were predictive of antidepressant activity.
-
Therapeutic trials showed that agomelatine displays both short-term and long-term efficacy in major depression, including an early improvement in sleep quality and daytime functioning, preservation of sexual function, lack of weight gain, lack of withdrawal symptoms after discontinuation, and good tolerability.
-
On the basis of the above data, agomelatine was granted marketing authorization in 2009 for the treatment of major depression in Europe.
Abstract
Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
18 August 2010
In figure 2 and figure 3 of the article, there was an error in the chemical structure of agomelatine; the amide group was omitted. This has been corrected.
References
Sartorius, N. et al. Antidepressant medications and other treatments of depressive disorders: a CINP task force report based on a review of evidence. Int. J. Neuropsychopharmacol. 10, S1–S207 (2007).
Millan, M. J. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol. Ther. 110, 135–370 (2006).
Papakostas, G. I. Tolerability of modern antidepressants. J. Clin. Psychiatry 69, 8–13 (2008).
Eitan, R. & Lerer, B. Neuropharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities. Dialogues Clin. Neurosci. 8, 241–258 (2006).
DeRubeis, R. J., Siegle, G. J. & Hollon, S. D. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nature Rev. Neurosci. 9, 788–796 (2008).
Millan, M. J. Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs. Neurotherapeutics 6, 53–77 (2009).
Mathew, S. J., Manji, H. K. & Charney, D. S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 33, 2080–2092 (2008).
Rozas, I. Improving antidepressant drugs: update on recently patented compounds. Expert Opin. Ther. Patents 19, 827–845 (2009).
Papakostas, G. I., Thase, M. E., Fava, M., Nelson, J. C. & Shelton, R. C. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol. Psychiatry 62, 1217–1227 (2007).
Montgomery, S. A. et al. Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int. Clin. Psychopharmacol. 22, 323–329 (2007).
Morilak, D. A. & Frazer, A. Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int. J. Neuropsychopharmacol. 7, 193–218 (2007).
McIntyre, M. & Moral, M. A. Augmentation in treatment-resistant depression. Drugs Future 31, 1069–1081 (2006).
Wong, E. H., Nikam, S. S. & Shahid, M. Multi- and single-target agents for major psychiatric diseases: therapeutic opportunities and challenges. Curr. Opin. Investig. Drugs 9, 28–36 (2008).
Kehne, J. H. The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders. CNS Neurol. Disord. Drug Targets 6, 163–182 (2007).
Ebner, K., Sartori, S. B. & Singewald, N. Tachykinin receptors as therapeutic targets in stress-related disorders. Curr. Pharm. Des. 154, 1647–1674 (2009).
Kramer, M. S. et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29, 385–392 (2004).
Binneman, B. et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 165, 617–620 (2008).
Preskorn, S. H. et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective, N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J. Clin. Psychopharmacol. 28, 631–637 (2008).
Manji, H. K. et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult to treat depression. Biol. Psychiatry 53, 707–742 (2003).
Pittenger, C. & Duman, R. S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109 (2008).
Souetre, E. et al. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psych. Res. 28, 263–278 (1989).
Duncan, W. C. Circadian rhythms and the pharmacology of affective illness. Pharmacol. Ther. 71, 253–312 (1996).
Germain, A. & Kupfer, D. J. Circadian rhythm disturbances in depression. Hum. Psychopharmacol. 23, 571–585 (2008).
Filadelfi, A. M. & Castrucci, A. M. Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates. J. Pineal Res. 20, 175–186 (1996).
Pandi-Perumal, S. R. et al. Melatonin: nature's most versatile biological signal? FEBS J. 273, 2813–2838 (2006).
Arendt, J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev. Reproduction 3, 13–22 (1998).
Cardinali, D. P., Vacas, M. I. & Boyer, E. E. Specific binding of melatonin in bovine brain. Endocrinology 105, 437–441 (1979).
Vanecek, J., Pavlik, A. & Illerova, H. Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Res. 435, 359–362 (1987).
Reppert, S. M., Weaver, D. R. & Godson, C. Melatonin receptors step into the light: cloning and classification of subtypes. Trends Pharmacol. Sci. 17, 100–102 (1996).
Morgan, P. J., Barrett, P., Howell, H. E. & Helliwell, R. Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem. Int. 24, 101–146 (1994).
Macchi, M. M. & Bruce, J. N. Human pineal physiology and functional significance of melatonin. Front. Neuroendocrinol. 25, 177–195 (2004).
Racagni, G., Riva, M. A. & Popoli, M. The interaction between the internal clock and antidepressant efficacy. Int. Clin. Psychopharmacol. 22, S9–S14 (2007).
Guardiola-Lemaitre, B. in Advances in Pineal Research. (eds Foldes, A. & Reiter, R. J.) 351–363 (John Libbey, London, 1991).
Guardiola-Lemaitre, B. & Delagrange, P. Melatonin analogues: from pharmacology to clinical application. Eur. J. Med. Chem. 30, S643–S651 (1995).
Adam, G. et al. New naphthalenic ligands of melatoninergic receptors J. Pharm. Belg. 47, 374–380 (1992).
Yous, S. et al. Novel naphthalenic ligands with high affinity for the melatonin receptor. J. Med. Chem. 35, 1484–1485 (1992). Identification of agomelatine as a high potency ligand of melatonin receptors.
Van Reeth, O. et al. Comparative effects of a melatonin agonist on the circadian system in mice and syrian hamsters. Brain Res. 762, 185–194 (1997).
Ying, S. W. et al. Melatonin analogues as agonists and antagonists in the circadian system and other brain areas. Eur. J. Pharmacol. 296, 33–42 (1996). Demonstration that agomelatine possesses agonist properties at a crucial population of melatonin receptors in the suprachiasmatic nucleus.
Audinot, V. et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmeidebergs Arch. Pharmacol. 36, 553–561 (2003).
Witt-Enderby, P. A., Bennett, J., Jarzynka, M. J., Firestine, S. & Melan, M. A. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci. 72, 2183–2198 (2003).
Gerdin, M. J. et al. Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 receptors. J. Pharmacol. Exp. Ther. 304, 931–939 (2003).
Gerdin, M. J. et al. Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J. 18, 1646–1656 (2004).
Ying, S. W., Rusak, B. & Mocaër, E. Chronic exposure to melatonin receptor agonists does not alter their effects on suprachiasmatic nucleus neurons. Eur. J. Pharmacol. 342, 29–37 (1998).
Martinet, L., Guardiola-Lemaître, B. & Mocaër, E. Entrainment of circadian rhythms by S20098 a melatonin agonist is dose and plasma concentration dependent. Pharmacol. Biochem. Behav. 54, 713–718 (1996).
Redman, J. R., Guardiola-Lemaître, B., Brown, M., Delagrange, P. & Armstrong, S. M. Dose-dependent effects of, S20098, a melatonin agonist on direction of re-entrainment of rat circadian rhythms. Psychopharmacology 118, 385–390 (1995).
Armstrong, S. M., McNulty, O. M., Guardiola-Lemaître, B. & Redman, J. R. Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome. Pharmacol. Biochem. Behav. 46, 45–49 (1993). In vivo study demonstrating that agomelatine can effectively modify circadian rhythms.
Wirz-Justice, A. et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol. Med. 35, 939–944 (2005).
Emens, J., Lewy, A., Kinzie, J. M., Arntz, D. & Rough, J. Circadian misalignment in major depressive disorder. Psychiatry Res. 168, 259–261 (2009).
Van Reeth, O. et al. Melatonin or a melatonin agonist corrects age-related changes in circadian response to an environmental stimulus. Am. J. Physiol. 280, 1582–1591 (2001).
Koster-van Hoffen, G. C. et al. Effects of a novel melatonin analog on circadian rhythms of body temperature and activity in young, middle-aged, and old rats. Neurobiol. Aging 14, 565–569 (1993).
Grassi-Zucconi, G., Semprevivo, M., Mocaër, E., Kristensson, K. & Bentivoglio, M. Melatonin and its new agonist, S20098 restore synchronised sleep fragmented by experimental trypanosome infection in the rat. Brain Research Bull. 39, 63–68 (1996).
Van Reeth, O., Olivares, E., Turek, F. W., Granjon, L. & Mocaër, E. Resynchronisation of a diurnal rodent circadian clock accelerated by a melatonin agonist. Neuroreport 9, 1901–1905 (1998).
Wirz-Justice, A. et al. Early evening melatonin and, S20098 advance circadian phase and nocturnal regulation of core body temperature. Am. J. Physiol. 272, R1178–R1188 (1997).
Redman, J. R. & Francis, A. J. Entrainment of rat circadian rhythms by the melatonin agonist, S20098 requires intact suprachiasmatic nuclei but not the pineal. J. Biol. Rhythms 13, 39–51 (1998).
Pitrosky, B., Kirsch, R., Malan, A., Mocaër, E. & Pevet, P. Organization of rat circadian rhythms during daily infusion of melatonin or, S20098, a melatonin agonist. Am. J. Physiol. Regul. Integr. Comp. Physiol. 277, 812–828 (1999).
Jockers, R., Maurice, P., Boutin, J. A. & Delagrange, P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new? Br. J. Pharmacol. 154, 1182–1195 (2008).
Cajochen, C., Kräuchi, K., Möri, D., Graw, P. & Wirz-Justice, A. Melatonin and S20098 increase REM and wake-up propensity without modifying NREM sleep homeostasis. Am. J. Physiol. Regul. Integrative Comp. Physiol. 272, R1189–R1196 (1997).
Kräuchi, K., Cajochen, C., Möri, D., Graw, P. & Wirz-Justice, A. Early evening melatonin and S20098 advance circadian phase and nocturnal regulation of core body temperature. Am. J. Physiol. Regul. Integrative Comp. Physiol. 272, R1178–R1188 (1997). Study showing that in human volunteers, evening administration of agomelatine has a significant and sustained influence on circadian rhythms over 24 hours.
Burns, C. M. et al. Regulation of serotonin2C receptor, G-protein coupling by RNA editing. Nature 387, 303–308 (1997).
Millan, M. J., Marin, P., Bockaert, J. & la Cour, C. M. Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol. Sci. 29, 454–464 (2008).
Aloyo, V. J., Berg, K. A., Spampinato, U., Clarke, W. P. & Harvey, J. A. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol. Ther. 121, 160–173 (2009).
Chanrion, B. et al. Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol. Pharmacol. 73, 748–757 (2008).
Berg, K. A. et al. Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol. Pharmacol. 54, 94–104 (1998).
Millan, M. J. 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. 306, 954–964 (2003). Demonstration that agomelatine behaves as an antagonist at cloned, human and native, cerebral populations of 5-HT 2C receptor.
Giorgetti, M. & Tecott, L. H. Contributions of 5-HT2C receptors to multiple actions of central serotonin systems. Eur. J. Pharmacol. 488, 1–9 (2004).
Millan, M. J. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Thérapie 60, 441–460 (2005).
Kennaway, D. J. & Moyer, R. W. Serotonin 5-HT2C agonists mimic the effect of light pulses on circadian rhythms. Brain Res. 806, 257–270 (1998).
Barassin, S. et al. Circadian tryptophan hydroxylase levels and serotonin release in the suprachiasmatic nucleus of the rat. Eur. J. Neurosci. 15, 833–840 (2002).
Varcoe, T. J. & Kennaway, D. J. Activation of 5-HT2C receptors acutely induces Per1 gene expression in the rat SCN in vitro. Brain Res. 1209, 19–28 (2008).
Cuesta, M., Clesse, D., Pévet, P. & Challet, E. New light on the serotonergic paradox in the rat circadian system. J. Neurochem. 110, 231–243 (2009).
Gannon, R. L. & Millan, M. J. Serotonin1A autoreceptor activation by, S15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors. Neuroscience 137, 287–299 (2006).
Stahl, S. M., Grady, M. M., Moret, C. & Briley, M. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 10, 732–747 (2005).
Kasper, S. & Hamon, M. Beyond the monoaminergic hypothesis: agomelatine, a new antidepressant with an innovative mechanism of action. World J. Biol. Psychiatry 10, 117–126 (2009).
Linnik, I. V. et al. The novel antidepressant, agomelatine, blocks cerebral 5-HT2C receptors in vivo: a phMRI challenge study in rats. Eur. Neuropsychopharmacol. 19, S259 (2009).
Papp, M., Gruca, P., Boyer, P. A. & Mocaër, E. Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 28, 694–703 (2003). Using a model of anhedonia, the first evidence that agomelatine possesses robust antidepressant properties that are expressed by a mechanism involving both melatonergic and 5-HT 2C receptors.
Bourin, M., Mocaër, E. & Porsolt, R. Antidepressant-like activity of S20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J. Psychiatry Neurosci. 29, 126–133 (2004).
Alex, K. D. & Pehek, E. A. Pharmacological mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol. Ther. 113, 296–320 (2007).
Banasr, M., Hery, M., Mocaër, E. & Daszuta, A. Agomelatine, a new antidepressant drug, increases cell proliferation, maturation and survival of newly generated granule cells in adult hippocampus. Biol. Psychiatry 59, 1087–1096 (2006). Long-term treatment with agomelatine enhances cellular proliferation and neurogenesis in the hippocampus, a mechanism common to other classes of antidepressant and implicated in the improvement of mood.
Soumier, A. et al. Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology 34, 2390–2403 (2009).
Barden, N. et al. Antidepressant action of agomelatine (S20098) in a transgenic mouse model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 908–916 (2005).
Norman, T. R., Cranston, I. & Irons, J. Effect of the novel antidepressant agomelatine in the olfactory bulbectomised rat. Int. J. Neuropsychopharmacol. 7, S461 (2004).
Dekeyne, A. et al. S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology 199, 549–568 (2008).
Bertaina-Anglade, V., la Rochelle, C. D., Boyer, P. A. & Mocaër, E. Antidepressant-like effects of agomelatine (S20098) in the learned helplessness model. Behav. Pharmacol. 17, 703–713 (2006).
Corbach, S., Schmelting, B., Fuchs, E. & Mocaër, E. Comparison of agomelatine and melatonin for effects in chronically stressed tree shrews, an animal model of depression. Eur. Neuropsychopharmacol. 17, S364 (2007).
Corbach-Söhle, S. et al. Effects of agomelatine and S32006, a selective 5-HT2C receptor antagonist, in chronically-stressed tree shrews. Eur. Neuropsychopharmacol. 18, S348 (2008).
Overstreet, D. H., Pucilowski, O., Rettori, M. C., Delagrange, P. & Guardiola-Lemaitre, B. Effects of melatonin receptor ligands on swim test immobility. Neuroreport 29, 249–253 (1998).
Weil, Z. M., Hotchkiss, A. K., Gatien, M. L., Pieke-Dahl, S. & Nelson, R. J. Melatonin receptor (MT1) knockout mice display depression-like behaviours and deficits in sensorimotor gating. Brain Res. Bull. 68, 425–429 (2006).
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, 661–673 (2007).
Descamps, A. et al. Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep–wake cycle architecture. Psychopharmacology 205, 93–106 (2009).
Quera-Salva, M. A. et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int. J. Neuropsychopharmacol. 10, 691–696 (2007).
Wilson, S. & Argyropoulos, S. Antidepressants and sleep: a qualitative review of the literature. Drugs 65, 927–947 (2005).
Leproult, R., Van Onderbergen, A., L'Hermite-Baleriaux, M., Van Cauter, E. & Copinschi, G. Phase-shifts of 24h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin. Endocrinol. 63, 298–304 (2005).
Kennedy, S. J. & Rizvi, S. J. Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness. CNS Drugs 24, 479–499 (2010).
Loo, H., Hale, A. & D'haenen, H. Determination of the dose of agomelatine, a melatonergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int. Clin. Psychopharmacol. 17, 239–247 (2002). Pivotal study demonstrating the clinical utility of agomelatine in the treatment of major depression.
Leuchter, A. F. et al. Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression. Psychopharmacology 177, 15–22 (2004).
Berk, M. & Dodd, S. Antidepressants and the placebo response. Hum. Psychopharmacol. Clin. Exp. 20, 305–307 (2005).
Kennedy, S. H. & Emsley, R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur. Neuropsychopharmacol. 16, 93–100 (2006).
Lemoine, P., Guilleminault, C. & Alvarez, E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double blind comparison with venlafaxine. J. Clin. Psychiatry 68, 1723–1732 (2007).
Kasper, S. et al. Efficacy of the novel antidepressant agomelatine on the circadian and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J. Clin. Psychiatry 71, 109–120 (2010).
Kennedy, S. H., Rizvi, S., Fulton, K. & Rasmussen, J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J. Clin. Psychopharmacol. 28, 329–333 (2008).
Srinivasan, V. et al. Pathophysiology of depression: role of sleep and the melatonergic system. Psychiatry Res. 165, 201–214 (2009).
Goodwin, G. M., Emsley, R., Rembry, S., Rouillon, F. & Agomelatine Study Group. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 70, 1128–1137 (2009). The antidepressant properties of agomelatine are maintained upon sustained 6 months of treatment and it is effective in preventing relapse.
Goodwin, G., Rouillon, F. & Emsley, R. Long-term treatment with agomelatine: prevention of relapse in patients with major depressive disorder over 10 months. Eur. Neuropsychopharmacol. 18, S338 (2009).
Montgomery, S. A., Kennedy, S. H., Burrows, G. D., Lejoyeux, M. & Hindmarch, I. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int. Clin. Psychopharmacol. 19, 271–280 (2004). Demonstration that discontinuation of agomelatine treatment in major depression is not associated with symptoms of withdrawal in contrast to the SSRI paroxetine.
Baldwin, D. S., Montgomery, S. A., Nil, R. & Lader, M. Discontinuation symptoms in depression and anxiety disorders. Int. J. Neuropsychopharmacol. 10, 73–84 (2007).
Aronne, L. J. & Segal, K. R. Weight gain in the treatment of mood disorders. J. Clin. Psychiatry. 64 (Suppl. 8), 22–29 (2003).
Serretti, A. & Chiesa, A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J. Clin. Psychopharmacol. 29, 259–266 (2009).
Drago, F. & Busa, L. Acute low doses of melatonin restore full sexual activity in impotent male rats. Brain Res. 878, 98–104 (2000).
Brotto, L. A., Gorzalka, B. B. & LaMarre, A. K. Melatonin protects against the effects of chronic stress on sexual behaviour in male rats. Neuroreport 12, 3465–3469 (2001).
Hull, E. M., Muschamp, J. W. & Sato, S. Dopamine and serotonin influences on male sexual behaviour. Physiol. Behav. 83, 291–307 (2004).
Montejo, A. et al. Better sexual acceptability of agomelatine (25 and 50 mg) compared with paroxetine (20 mg) in healthy male volunteers. An 8-week, placebo-controlled study using the PRSEXDQ-SALSEX scale. J. Psychopharmacol. 24, 111–120 (2009).
Musazzi, L. et al. Stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS One 5, e8566 (2010).
Walker, M. P. & Stickgold, R. Sleep, memory, and plasticity. Annu. Rev. Psychol. 57, 139–166 (2006).
Bruel-Jungerman, E., Rampon, C. & Laroche, S. Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev. Neurosci. 18, 93–114 (2007).
Eckel-Mahan, K. L. & Storm, D. R. Circadian rhythms and memory: not so simple as cogs and gears. EMBO Rep. 10, 584–591 (2009).
Austin, M. P., Mitchell, P. & Goodwin, G. M. Cognitive deficits in depression: possible implications for functional neuropathology. Br. J. Psychiatry 178, 200–206 (2001).
Conboy, L. et al. The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats. Int. J. Neuropsychopharmacol. 12, 329–341 (2009).
Castro-Costa, E. et al. Prevalence of depressive symptoms and syndromes in later life in ten European countries, the SHARE study. Br. J. Psychiatry 191, 393–401 (2007).
Magnusson, A. & Partonen, T. The diagnosis, symptomatology, and epidemiology of seasonal affective disorder. CNS Spectr. 10, 625–634 (2005).
Pjrek, E. et al. Agomelatine in the treatment of seasonal affective disorder. Psychopharmacology 190, 575–579 (2007).
Schoevers, R. A., Van, H. L., Koppelmans, V., Kool, S. & Dekker, J. J. Managing the patient with co-morbid depression and an anxiety disorder. Drugs 68, 1621–1634 (2008).
Tuma, J., Strubbe, J. H., Mocaër, E. & Koolhaas, J. M. Anxiolytic-like action of the antidepressant agomelatine (S20098) after a social defeat requires the integrity of the SCN. Eur. Neuropsychopharmacol. 15, 545–555 (2005).
Heisler, L. K., Zhou, L., Bajwa, P., Hsu, J. & Tecott, L. H. Serotonin 5-HT2C receptors regulate anxiety-like behaviour. Genes Brain Behav. 6, 491–496 (2007).
Millan, M. J., Brocco, M., Gobert, A. & Dekeyne, A. Anxiolytic properties of agomelatine, and antidepressant with melatonergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology 177, 448–458 (2005).
Papp, M., Litwa, E., Gruca, P. & Mocaër, E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav. Pharmacol. 17, 9–18 (2006).
Stein, D. J., Ahokas, A. A. & de Bodinat, C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 28, 561–566 (2008). First demonstration of the clinical efficacy of agomelatine in treating generalized anxiety disorder.
Boivin, D. B. Influence of sleep–wake and circadian rhythm disturbance in psychiatric disorders. J. Psychiatry Neurosci. 25, 446–458 (2000).
Srinivasan, V. et al. Melatonin in mood disorders. World J. Biol. Psychiatry 7, 138–151 (2006).
Luo, A. H. & Aston-Jones, G. Circuit projection from suprachiasmatic nucleus to ventral tegmental area: a novel circadian output pathway. Eur. J. Neurosci. 29, 748–760 (2009).
Acknowledgements
We would like to thank J.-M. Rivet, C. Mannoury la Cour and A. Gobert for expert help with graphics; M. Soubeyran and A. Dekeyne for excellent logistical assistance; L. Alliot, E. Canet, P. Delagrange and B. Renaud for helpful comments on the manuscript; and, in particular, our many, many colleagues for their efforts, dedication and skill in bringing this project to fruition.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
All authors are full-title employees of Servier Pharmaceuticals.
Related links
Glossary
- Major depression
-
A serious disorder characterized by depressed mood (sadness) and anhedonia (inability to experience pleasure). Other important features include feelings of despair, worthlessness, suicidal ideation, lethargy or agitation, and insomnia (or hypersomnia). Co-morbid anxiety, cognitive impairment, sexual dysfunction and circadian desynchronization are common. For diagnosis, symptoms must be intense, disruptive and present more or less constantly for at least a fortnight. The lifetime risk of major depression is ∼10%.
- Tricyclics
-
Named after their chemical structure, tricyclic antidepressants inhibit the reuptake of serotonin and/or noradrenaline, activity of which are thought to be deficient in (at least some) patients with depression. Tricyclics can be highly effective, but their use is complicated by side effects due to other actions at, for example, central muscarinic receptors and cardiac ion channels.
- Monoamine oxidase inhibitors
-
These antidepressants mainly act by inhibiting the breakdown of serotonin and noradrenaline by monoamine oxidase A. They are clincially efficacious but, in particular for non-reversible inhibitors, blockade of the catabolism of dietary amines like tyramine can provoke a potentially dangerous hypertension.
- Suprachiasmatic nucleus
-
(SCN). The bilateral SCN, which is located just above the optic tract at the base of the hypothalamus, acts as the master pacemaker for the body's circadian rhythms. Its neurons discharge rhythmically even when isolated. In situ, they are entrained to the daily light–dark cycle by information received via the retinohypothalamic pathway. Suprachiasmatic output influences the secretion of melatonin, which itself modulates the activity of the SCN.
- Agomelatine
-
In 1997, following an application to the World Health Organization, S20098 was attributed the international non-proprietary name agomelatine in recognition of its innovative melatonergic profile, as compared with other antidepressants acting via monoaminergic mechanisms.
- Phase advance and phase delay
-
Exposure to stimuli such as light and melatonin can shift circadian rhythms of the sleep–wake cycle and motor activity either forward (phase advance) or backwards (phase delay). For example, a brief pulse of light just after the onset of the dark period leads to a phase delay. Phase advances and phase delays in patients with depression are symptomatic of circadian disorganization and probably reflect a dysfunction of the suprachiasmatic nucleus.
- Unedited 5-HT2C receptors
-
5-HT2C receptors in humans and other species are present in 20 or more isoforms, reflecting a contrasting (three) amino acid sequence located in the second intracellular loop, which is involved in signal transduction. Alterations in this sequence are caused by post-translational (adenosine to inosine) editing of mRNA. Unedited (INI) sites are constitutively active, whereas highly edited sites (like VSV) are not.
- Constitutive activity
-
Some G protein-coupled receptors are active even in the absence of agonists. This reflects the spontaneous interaction of the receptor with G proteins and other transduction mechanisms, and is usually reflected in a resting level of agonist-independent signal transduction and/or receptor endocytosis into the interior of the cell.
- Inverse agonist
-
Inverse agonists suppress the resting (constitutive) activity of G protein-coupled receptors in the absence of agonists.
- Neutral antagonist
-
Neutral antagonists alone do not affect basal activity. Instead, they normalize signalling by blocking the actions of both agonists and of inverse agonists, thereby returning activity to baseline values.
- Forced swim test
-
In this test of potential antidepressant properties, rodents are placed for 15 minutes in a cylinder of water (room temperature) from which they cannot escape. The following day, in the course of a second session, the time of immobility is measured as an index of despair. Given either chronically or acutely (on the test day), antidepressants reduce immobility time.
- Chronic mild stress
-
A procedure whereby rodents are exposed for a period of about 5 weeks to minor daily stressors like wetting the sawdust, noise, moving the cage and so on. This leads to a progressive state of anhedonia (inability to experience reward), reflected in a reduction in the preference of sucrose over water. This state can be reversed by chronic administration of antidepressants.
- Learned helplessness
-
This refers to the observation that exposure to uncontrollable stress can compromise the ability to learn to escape from a subsequent aversive situation. In the learned helplessness procedure, rats are exposed to a sequence of inescapable foot-shocks in a chamber and then evaluated in an avoidance-conditioning test (escape from acute shock) in a two-compartment box. The number of escape failures is considered an index of helplessness. Antidepressants given before the test reinstate escape-directed behaviour.
- Tree shrew
-
(Also known as Scandentia) Tree shrews are united with primates in the super-order Euarchonta, itself fused with rodents and lagomorphs in the Euarchontoglires. They are diurnal, territorial animals that live in family-based social groups. Contact of a defeated subordinate with a dominant male provokes marked stress-related changes in behaviour, endocrine secretion (hypothalamic–pituitary–adrenal axis overactivity) and physiology, as well as disruption of circadian rhythms.
- Hamilton depression rating scale
-
(HAM-D). This scale is used to assess depressive states in patients. It incorporates various parameters, like depressed mood, feelings of guilt, insomnia and so forth. Severity is estimated numerically from zero (essentially normal); the higher the score, the more serious the depressed states.
- Leeds sleep evaluation questionnaire
-
This is a simple and standardized instrument for pseudo-quantifying the influence of therapy on sleep and early morning behaviour. It consists of a number of items like the quality of, and latency to, sleep. The questionnaire is completed by patients themselves.
- Discontinuation syndrome
-
In particular for antidepressants with short half-lives, following long-term (6 weeks or more) treatment, abrupt discontinuation, non-compliance and sometimes even dose reductions can trigger a discontinuation syndrome comprising psychological (agitation, anxiety, irritability) and somatic (nausea, dizziness, sensory and sleep disturbances, flu-like chills, myalgia and fatigue) symptoms. Although usually mild and self-limiting (a week or so), this discontinuation syndrome is distressing and disruptive. Moreover, it can occasionally be quite severe and mistaken for relapse.
Rights and permissions
About this article
Cite this article
de Bodinat, C., Guardiola-Lemaitre, B., Mocaër, E. et al. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov 9, 628–642 (2010). https://doi.org/10.1038/nrd3140
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrd3140
This article is cited by
-
Significance of Melatonin in the Regulation of Circadian Rhythms and Disease Management
Molecular Neurobiology (2024)
-
Evidence-Based Pharmacotherapy of Anxiety Symptoms in Patients with Major Depressive Disorder: Focus on Agomelatine
Neurology and Therapy (2023)
-
Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway
Journal of Neuroinflammation (2022)
-
Melatonin’s neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders
Translational Psychiatry (2021)
-
Dissecting diagnostic heterogeneity in depression by integrating neuroimaging and genetics
Neuropsychopharmacology (2021)