Nature Reviews Drug Discovery | AOP, published online 25 June 2010; doi:10.1038/nrd3140 REVIEWS CASE HISTORY Agomelatine, the first melatonergic antidepressant: discovery, characterization and development Christian de Bodinat*, Béatrice Guardiola-Lemaitre‡, Elisabeth Mocaër*, Pierre Renard§, Carmen Muñoz|| and Mark J. Millan¶ 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. Depression is a complex, heterogeneous and incapacitating soon became apparent1–3,7. In their wake, the 1980s and disorder that is associated with a heavy burden to the 1990s witnessed the introduction of more specific patients and their families, and to society. Although inhibitors of serotonin (also known as 5-hydroxytrypt- *Institut de Recherches currently available antidepressants have genuine value in amine; 5-HT) and/or noradrenaline reuptake. Selective Internationales Servier, 6 Place des Pléiades, 92415 the treatment of this disorder, they take several weeks to serotonin reuptake inhibitors (SSRIs), noradrenaline Courbevoie, Cedex, France. exert full efficacy, many patients respond inadequately, reuptake inhibitors (NARIs) and serotonin/noradrena- ‡Servier Monde, 22 co-morbid symptoms are often not well controlled and line reuptake inhibitors (SNRIs) possess improved safety rue Garnier, 92578 Neuilly- all can present problems of poor tolerance1–3. Given margins as well as utility for treating co-morbid anxiety, sur-Seine Cedex, France. §Prospective et Valorisation this, increasing attention is being paid to cognitive and but offer no real gain in efficacy over their first-generation 2,3,9,10 Scientifique, Institut de behavioural interventions. In addition, electroconvulsive counterparts . Furthermore, they all, including mirt- Recherches Servier, therapy remains an option for refractory patients, deep- azapine, an atypical agent that does not modify serotonin 11 rue des Moulineaux, brain stimulation may eventually become of broader or noradrenaline reuptake, act through monoaminergic 92150 Suresnes, France. 2,11 || utility and the importance of preventative self-help in mechanisms . Servier International, 1,2,4,5 35 rue de Verdun, vulnerable subjects should not be underestimated . Since then, the development of new antidepressants 92284 Suresnes, France. Nonetheless, pharmacotherapy is likely to remain at the can be characterized primarily as variations on a theme ¶Division of core of treatment for an established episode of major (although no two agents are identical so it is important Neuropharmacology, depression, so there is a clear need for new and improved to have several drugs per class)1,2,6,7, rather than genuine Institut de Recherches 1,2,6–8 Servier, 125 Chemin de antidepressants . mechanistic originality. Nonetheless, it would be naive Ronde, 78290 Croissy The first antidepressants — tricyclics (such as to think that improved monoaminergic antidepressants sur Seine, France. amitriptyline), which suppress the reuptake of mono- could not be developed, as a palette of around 30 receptors Correspondence to M.J.M. amines, and monoamine oxidase inhibitors (such as awaits more sophisticated exploitation2,11. Furthermore, e-mail: phenalzine), which interfere with their catabolism the association of a monoaminergic antidepressant with [email protected] doi:10.1038/nrd3140 — were introduced in the 1960s and the 1970s. Their an additional mechanism, such as the co-administration Published online availability transformed the treatment of depression, of an SSRI with lithium for resistant depression, remains 25 June 2010 but their limitations, in terms of side effects and safety, an attractive and clinically validated option2,12,13. NATURE REVIEWS | DRUG DISCOVERY ADVANCE ONLINE PUBLICATION | 1 © 2010 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | Melatonin, circadian rhythms and depression by Lerner in 1958 (REFS 24,26). Although high-affinity melatonin binding sites had been pharmacologically Major depression is frequently accompanied by alterations in circadian rhythms characterized in the bovine brain by 1979 (REF. 27), and of behaviour, sleep, core temperature and the secretion of cortisol and other were subsequently identified in the rat hypothalamus hormones21–23. Although changes are heterogeneous, frequent findings in patients with in the 1980s28, it took another 40 years until the first depression include a blunted amplitude of daily rhythms and poor responsiveness to environmental (photic and non-photic) entraining stimuli. Phase advances tend melatonergic receptor was cloned from melanophores 29 to predominate, but phase delays have also been described and they are typical of of Xenopus laevis in the 1990s . seasonal affective disorder46,119. Circadian disruption is linked to, and may partially The impetus for launching a research and develop- be a consequence of, the changes in behaviour and sleep patterns that accompany ment programme dedicated to melatonergic agonists at depression; desynchronization may also be triggered by an intrinsic disorganization Servier Research Group goes back to 1988, when one of the suprachiasmatic nucleus2,127. of the authors (B.G.-L.) arrived following completion of On the other hand, circadian disturbances may be provoked by an abnormal pineal a doctoral thesis on melatonin. Before the 1980s, the output of melatonin, a key synchronizer of biological rhythms and sleep, of which the principal function of melatonin was thought to be in 34,101 secretion is tightly coupled to light–dark and seasonal cycles (FIG. 1). In line with the control of reproduction30,31. However, it had become this view, depression is associated with an altered diurnal rhythm of melatonin output, clear that melatonin behaves as a non-photic ‘message’ including a blunted night time surge21–23,34,101,127. Furthermore, although data are limited, melatonin production may be lower in depression, and an enhancement in that interacts with photic signals in the control of circa- circulating levels of melatonin has been correlated with effective treatment by certain dian and diurnal cycles (FIG. 1). This was a particularly antidepressants2,21,127. Administration of melatonin itself is ineffective in major important observation as plasma concentrations of mela- depression128. However, it can improve sleep patterns, and ‘chronotherapeutics’ tonin display marked circadian periodicity, with a peak such as light and circadian behavioural therapy are also useful in this regard46,101. during the nocturnal phase in both diurnal and nocturnal Taken together, the above observations support the notion that the re-coordination mammalian species. Overall, melatonin emerged to have of biological rhythms by recruitment of melatonergic mechanisms is a therapeutically a fundamental role in the synchronization of circadian relevant strategy for improving depressed states. rhythms26,30 that are disorganized in central nervous system disorders such as depression21–23,32 (BOX 1). The notion of exploiting melatonergic ligands as Non-monoaminergic mechanisms have also been therapeutic agents33,34 was enthusiastically received explored in the quest for improved antidepressants. Such and a series of naphthalene derivatives of melatonin research programmes have focused mainly on highly were prepared35,36. These structures were intended to selective ligands of targets such as neurokinin 1 and cor- be both patentable and at least as potent as melatonin. ticotropin-releasing factor 1 receptors14,15. Unfortunately, Furthermore, inasmuch as the naphthalene ring of the clinical trials have been disappointing16,17, perhaps, derivatives is more lipophilic than the indole of mela- 2 Major depression ironically, precisely because these drugs are so selective . tonin, an additional objective was improved penetration A serious disorder Pilot therapeutic trials have reported rapid antidepres- into the brain. At that time, no cloned melatonergic recep- characterized by depressed sant actions of NMDA (N-methyl-d-aspartate) receptor tors were available for study and procedures for perform- mood (sadness) and anhedonia antagonists but, even for subunit-selective agents, reser- ing binding studies in rodents had not been described. (inability to experience 18 125 pleasure). Other important vations remain concerning psychomimetic side effects . Consequently, using the radioligand [ I]iodomelatonin, features include feelings of Agents designed to directly manipulate intracellular sig- it was decided to examine the interaction of ligands with despair, worthlessness, nals controlling neurogenesis and ‘neuronal resilience’