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  • Review Article
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Agomelatine, the first melatonergic antidepressant: discovery, characterization and development

Nature Reviews Drug Discovery volume 9, pages 628–642 (2010)Cite this article

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An Erratum to this article was published on 01 September 2010

This article has been updated

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.

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Figure 1: The relationship between melatonin, the suprachiasmatic nucleus and circadian rhythms: melatonergic actions of agomelatine in vivo.
Figure 2: Agonist properties of agomelatine at melatonergic receptors coupled via Gαi to inhibit adenylyl cyclase.
Figure 3: Antagonist properties of agomelatine at 5-HT2C receptors coupled via Gαq to activation of phospholipase C.
Figure 4: Overview of the mechanism of antidepressant action of agomelatine.
Figure 5: Reinforcement of corticolimbic adrenergic and dopaminergic transmission by agomelatine.
Figure 6: Actions of agomelatine in major depression: its prevention of relapse and its low rate of patient dropout compared with comparators.
Figure 7: Timeline for the discovery, characterization, development and authorization of agomelatine.

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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.

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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.

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Authors and Affiliations

  1. Institut de Recherches Internationales Servier, 6 Place des Pléiades, Courbevoie, 92415, Cedex, France

    Christian de Bodinat & Elisabeth Mocaër

  2. Servier Monde, 22 rue Garnier, Neuilly-sur-Seine Cedex, 92578, France

    Béatrice Guardiola-Lemaitre

  3. Prospective et Valorisation Scientifique, Institut de Recherches Servier, 11 rue des Moulineaux, Suresnes, 92150, France

    Pierre Renard

  4. Servier International, 35 rue de Verdun, 92284, Suresnes, France

    Carmen Muñoz

  5. Division of Neuropharmacology, Institut de Recherches Servier, 125 Chemin de Ronde, Croissy sur Seine, 78290, France

    Mark J. Millan

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  1. Christian de Bodinat
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Correspondence to Mark J. Millan.

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DATABASES

OMIM

Depression

IUPHAR Database of Receptors and Ion Channels

5-HT2C

MT1

MT2

FURTHER INFORMATION

European Public Assessment Report — Valdoxan

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.

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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

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