Agomelatine, the First Melatonergic Antidepressant: Discovery, Characterization and Development

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.

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’ melatonin binding sites located in the posterior pituitary suicidal ideation, lethargy or are also of interest, but pose questions of specificity and of sheep28. As illustrated in FIG. 2, melatonergic recep- agitation, and insomnia safety2,7,19,20. tors couple via a Gα protein to adenylyl cyclase. Hence, (or hypersomnia). Co-morbid i/o anxiety, cognitive impairment, An alternative, appealing and innovative approach using an enzymatic assay, the functional actions of ligands sexual dysfunction and towards improved treatment of depression focuses on were evaluated in vitro by determination of their influ- circadian desynchronization melatonin, an important regulator of circadian rhythms, ence on forskolin-stimulated cyclic AMP production in are common. For diagnosis, which are perturbed in depression21–23 (BOX 1). This case cells derived from ovine pars tuberalis36. Further more, symptoms must be intense, disruptive and present more History chronicles the discovery, characterization and in electrophysiological investigations, agonist properties or less constantly for at least a development of the novel melatonergic antidepressant of the derivatives were verified at the crucial population fortnight. The lifetime risk of agomelatine, which represents two significant firsts: the of melatonergic receptors localized in the suprachiasmatic major depression is ~10%. first antidepressant designed to counter the perturbed nucleus (ScN). This work was performed in Syrian ham- biological rhythms linked to depressed states, and the sters, a classical species used for the study of circadian Tricyclics 37,38 Named after their chemical first clinically available antidepressant to incorporate a rhythms . structure, tricyclic non-monoaminergic mechanism of action. collectively, these studies showed that the naphthalene antidepressants inhibit the derivatives of melatonin behaved as high-affinity ago- reuptake of serotonin and/or From the pineal gland to agomelatine nists. The compound known as S20098 — later named noradrenaline, activity of which agomelatine are thought to be deficient in The pineal gland, which produces melatonin, is a phylo- — was identified as the most promising drug 36,38,39 (at least some) patients with genetically ancient structure. It has been discussed in based on its overall profile . Agomelatine potently depression. Tricyclics can be scientific tracts since antiquity24,25, but melatonin itself binds to melatonin receptors, suppresses cAMP for- highly effective, but their use was discovered only about 100 years ago (in 1917) when mation and mimics the actions of melatonin by dose- is complicated by side effects Mccord and Allen showed that extracts of the bovine dependently inhibiting the firing rate of ScN neurons38. due to other actions at, for example, central muscarinic pineal gland altered skin pigmentation in tadpoles. Forty These observations were later substantiated when it was receptors and cardiac ion years were to pass before the isolation and chemical iden- shown that agomelatine also potently activates cloned channels. 39 (FIG. 2) tification of melatonin (N-acetyl-5-methoxytryptamine) human melatonin 1 (MT1) and MT2 receptors .

a Organization c Dark Night Phase-delay model in rats (Stimulation Pineal of melatonin) gland Hours + 6:00 18:00 6:00 0 Retina + Peak of –+ melatonin 10 + RHT NA secretion 20 (GLU) Raphe nucleus 125 30 SCN b [ I]iodomelatonin Monoamine oxidase – ys SCG autoradiography inhibitors Light MT1, MT2 Da 40 These antidepressants mainly (Inhibition 5-HT 2C –+ act by inhibiting the breakdown of melatonin) receptors 50 of serotonin and noradrenaline Circadian rhythms 60 by monoamine oxidase A. (e.g., hormones, They are clincially efficacious core temperature, but, in particular for Modulation SCN 70 sleep, appetite) (e.g., mood, meals, non-reversible inhibitors, work, sleep, 80 Agomelatine blockade of the catabolism of activity) dietary amines like tyramine Rat SCN can provoke a potentially Figure 1 | The relationship between melatonin, the suprachiasmatic nucleus and circadian rhythms: Nature Reviews | Drug Discovery dangerous hypertension. melatonergic actions of agomelatine in vivo. a | Light activates the glutamate (GLU)-containing retinohypothalamic tract (RHT) that runs from the eye to the suprachiasmatic nucleus (SCN). Through a polysynaptic projection, the SCN Suprachiasmatic nucleus functionally inhibits the activity of the superior cervical ganglia (SCG), which supply the pineal gland with an excitatory, (sCN). The bilateral sCN, noradrenaline (NA)-containing input. This circuit allows light to suppress the production and release of melatonin from which is located just above the the pineal gland and, correspondingly, melatonin secretion is increased in the dark period. Melatonin reciprocally optic tract at the base of the hypothalamus, acts as activates neurons in the SCN by actions at melatonin 1 (MT1) and MT2 receptors. Serotonergic input from the raphe the master pacemaker for the nucleus modulates the SCN through actions at serotonin (also known as 5-hydroxytryptamine; 5-HT) receptor 5-HT2C body’s circadian rhythms. Its and other classes of 5-HT receptor. Daily behaviours likewise influence output from the SCN, the neuronal master clock neurons discharge rhythmically for coordinating circadian rhythms. b | Melatonergic receptors recognized autoradiographically in the SCN using [125I] even when isolated. In situ, iodomelatonin. c | Locomotor activity rhythms of rats drift backwards when the onset of the dark period is delayed by they are entrained to the several hours. Daily administration of agomelatine (3.0 mg per kg, intraperitoneally) resynchronizes rhythms to their usual daily light–dark cycle by circadian pattern (dark period commencing at 18:00 hours)45. information received via the retinohypothalamic pathway. suprachiasmatic output 40–43 influences the secretion Studies relevant to another interesting issue — how Ageing is also associated with a weakened responsive- of melatonin, which itself agomelatine affects the responsiveness of MT1 and MT2 ness of the circadian clock to environmental stimuli. modulates the activity of receptors — are discussed later. Agomelatine reinstated both circadian rhythms of the sCN. The bioavailability of agomelatine was discovered wheel-running activity in aged hamsters49, as well as Agomelatine to be modest. Nevertheless, it displayed robust in vivo diurnal rhythms of motor activity and core tempera- In 1997, following an activity both in animals and in humans, as described in ture in aged (about 2 years old) rats50. These findings are application to the World Health the next section. relevant to depression as the blunted amplitude of diur- Organization, s20098 was nal rhythms in aged rats resembles the alterations seen attributed the international 21–23 (BOX 1) non-proprietary name resynchronizing properties of agomelatine in certain patients with depression . Finally, agomelatine in recognition of A major goal of the in vivo studies of agomelatine was agomelatine reinstated normal circadian rhythms its innovative melatonergic to show that it normalizes disturbances of circadian in trypanosome-infected rats displaying a disrupted profile, as compared with other rhythms, especially in models related to depressed sleep–wake cycle51. These studies were all performed in antidepressants acting via monoaminergic mechanisms. states. In rats maintained in total darkness, the normal nocturnal animals (rodents and hamsters), so the resyn- time for onset of locomotor activity drifted backwards chronizing actions of agomelatine were later corroborated Phase advance and and chronic administration of agomelatine reversed in the African rat, Arvicanthis mordax, a diurnal species phase delay this shift, an effect well documented for melatonin44. like humans52. exposure to stimuli such as It was subsequently discovered that agomelatine shows collectively, the above observations prompted a light and melatonin can shift circadian rhythms of the resynchronizing actions in several other conditions. For study in healthy volunteers in which agomelatine phase- sleep–wake cycle and motor instance, it restored circadian rhythms in a model of jet advanced rhythms of body temperature without modify- activity either forward (phase lag that involved a phase advance of the light–dark cycle45. ing circulating levels of melatonin53. This observation advance) or backwards It also resynchronized circadian rhythms in a paradigm coincided with experiments showing that pinealectomy (phase delay). For example, phase delay a brief pulse of light just after involving a , an observation pertinent both to does not modify the influence of agomelatine on cir- 54,55 the onset of the dark period clinically defined delayed sleep disorder syndrome and cadian rhythms in rodents . Independence from the leads to a phase delay. to the disruption of circadian rhythms seen in seasonal pineal gland suggested that agomelatine was acting, as Phase advances and phase depression46,47 (BOX 1; FIG. 1). Interestingly, it was recently suspected, in the ScN. However, melatonergic recep- delays in patients with reported that the intensity of symptoms in major depres- tors are also present in other cerebral regions30,56 (see depression are symptomatic of circadian disorganization and sion is correlated with circadian misalignment; that is, below), so the finding that lesions of the ScN abolished probably reflect a dysfunction the more delayed the pacemaker relative to the timing of the resynchronizing activity of agomelatine was an of the suprachiasmatic nucleus. sleep, the more severe the depressed state48. important one54.

Binding G protein Cellular signals

O cAMP ATP + N O H H3C AC PKA Gαi N – H + Gβ Gγ Melatonin

O Protein + phosphorylation

O H3C

MT1 /MT2 Agomelatine

MT1 occupation Gαi coupling Adenylyl cyclase inhibition ([3H]-melatonin) (specific antibody) (enzymatic assay) 140 125 125 120 100 100 100

onin 75 75 80 onin) onin) at

at at 60 S binding oduction

50 γ 50 Unedited 5-HT2C receptors 40 5-HT receptors in humans 2C binding (%) 25 25 20 I]iodomel S]-GTP

and other species are present (% of mel (% of mel cAMP pr 125 35 [ ↓ [ 0 in 20 or more isoforms, 0 0 reflecting a contrasting (three) –13 –12 –11 –10 –9 –8 –7 –6 –13 –12 –11 –10 –9 –8 –7 –6 –5 –14 –13 –12 –11 –10 –9 –8 –7 –6 amino acid sequence located Log [agomelatine] (M) in the second intracellular loop, Log [agomelatine] (M) Log [agomelatine] (M) which is involved in signal Figure 2 | Agonist properties of agomelatine at melatonergic receptors coupled via g to inhibit adenylyl transduction. Alterations in αi cyclase. Both melatonin receptors (MT and MT ) couple via G to inhibit adenylyl cyclaseNa (AC).ture ReThisvie leadsws | Drug to reduced Discover y this sequence are caused by 1 2 αi post-translational (adenosine formation of cyclic AMP (cAMP) from ATP and hence decreased activity of protein kinase A (PKA), which phosphorylates to inosine) editing of mRNA. a variety of cellular substrates. Melatonin is the endogenous ligand of MT1 and MT2 receptors and its actions are

Unedited (INI) sites are mimicked by the naphthalene analogue agomelatine. This is illustrated for MT1 receptors in the lower panels, which show constitutively active, whereas 125 35 displacement of the MT1 radioligand [ I]iodomelatonin by agomelatine, enhancement of [ S]-GTPγS binding to Gαi and highly edited sites (like VsV) 41 suppression of cAMP production (similar data are seen with MT2 sites ). are not.

Constitutive activity some G protein-coupled A major circadian effect of agomelatine turned out to screen. Interestingly, post-transcriptional modification receptors are active even be a phase advance, which was expressed most markedly of 5-HT2c receptors by mRNA editing had just been dis- in the absence of agonists. 59–61 This reflects the spontaneous at the moment of the light–dark transition. That is, its covered to generate structurally distinct isoforms . interaction of the receptor maximal effectiveness coincided with the onset of the Unedited 5-HT2C receptors have constitutive activity, with G proteins and other elevation in night time melatonin secretion and with meaning that inverse agonists decrease baseline signal- transduction mechanisms, and 25,26,30,37 the time of maximal melatonin receptor sensitivity . ling and encourage the migration of 5-HT2c receptors is usually reflected in a resting 61,62 level of agonist-independent Furthermore, short-term (1 hour) exposure to agomelatine from the cytoplasm to the plasma membrane . signal transduction and/or was sufficient for expression of its resynchronizing activity conversely, neutral antagonists have no activity alone, receptor endocytosis into in humans, which was even seen the following day53,57,58. yet block the actions of agonists and inverse agonists. the interior of the cell. This was a significant finding as the half-life of agomelatine A further intriguing feature of 5-HT2c sites was their in humans is around 2 hours. Subsequent work confirmed coupling to several cellular signals that could be differ- Inverse agonist Inverse agonists suppress the that transient activation of melatonergic receptors at the entially influenced by various ligands, a phenomenon 60,63 resting (constitutive) activity crucial time point is sufficient for enduring effects. This termed ligand-biased signalling . Nonetheless, the of G protein-coupled receptors could be due to the induction of kinase-mediated cascades canonical signalling pathway of 5-HT2c receptors was in the absence of agonists. of protein phosphorylation, to alterations in the release of well established to be Gαq-mediated activation of (FIG. 3) Neutral antagonist neurotransmitters that are only slowly cleared from the phospholipase c . Thus, after confirming that Neutral antagonists alone synaptic cleft and to long-term modifications of synaptic agomelatine displaces the radiolabelled antagonist, 19,54,55 3 do not affect basal activity. plasticity in the ScN and elsewhere . [ H]mesulergine, from recombinant human 5-HT2c Instead, they normalize receptors, it was shown to competitively antagonize the signalling by blocking the interaction with 5-ht receptors activation of Gαq and phospholipase c by serotonin64 actions of both agonists and 2C (FIG. 3) of inverse agonists, thereby In the late 1990s, it was decided to investigate the potential . These observations were extended to a further returning activity to baseline effects of agomelatine at 5-HT2c receptors, an interaction G protein, Gαi, suggesting that agomelatine acted as a values. that had just been detected in a standardized binding broad-based antagonist at 5-HT2c receptors coupled to

Binding G protein Cellular signals

2+ [3H]IP Ca [3H]IP 2 ER 3 HO NH2 [ H]InP3 3 [ H]PIP2 N 2+ H DAG Ca 5-HT PLC + PKC Gαi O + Gβ + Gγ

O Protein H C 3 – phosphorylation

Agomelatine

5-HT2C

5-HT2C occupation Gαq/11 coupling PLC activation ([3H]mesulergine) (specific antibody) (enzymatic assay)

125 125 125 + 5-HT + 5-HT (10 nM) 100 100 (10 nM) 100

75 75 75 S binding gine binding γ depletion 50 50 2 50 (% of 5-HT) (% of 5-HT) (% of 5-HT) H]PIP

S]-GTP 25

25 3

25 [ 35 [ H]mesuler 3 [ 0 0 0 –9 –8 –7 –6 –5 –4 –3 –9 –8 –7 –6 –5 –4 –3 –9 –8 –7 –6 –5 –4 –3 Log [agomelatine] (M) Log [agomelatine] (M) Log [agomelatine] (M) Figure 3 | Antagonist properties of agomelatine at 5-HT receptors coupled via g q to activation of 2c Naα ture Reviews | Drug Discovery phospholipase c. 5-hydroxytryptamine 2C (5-HT2C) receptors couple via Gαq/11 to activate phospholipase C (PLC),

which generates diaminoglycerol (DAG) and inositol-1,4,5-triphosphate (InsP3) from membrane-localized

phosphoinositides (phosphatidylinositol 4,5-bisphosphate; PIP2). InsP3 stimulates the release of calcium from the endoplasmic reticulum (ER), which, together with DAG, activates protein kinase C (PKC), leading to the

phosphorylation of various cellular substrates. The actions of 5-HT at 5-HT2C receptors are blocked by the neutral 64 antagonist agomelatine (inactive alone) . Illustrated in the lower panels is the displacement of the 5-HT2C radioligand [3H]mesulergine by agomelatine, blockade of 5-HT-elicited [35S]-GTPγS binding to Gαq/11 and antagonism of 3 5-HT-induced depletion of [ H]PIP2. IP, inositol phosphate; IP2, inositol 1,4-bisphosphate.

(FIG. 3) diverse signalling pathways . Moreover, agomela- actions at melatonergic and 5-ht2C receptors

tine normalized signalling at 5-HT2c sites, rather than The discovery of 5-HT2c antagonist properties for ago- suppressing it below basal levels, which is consistent with melatine was clearly important. However, it was neces- neutral antagonist properties60,64. sary to understand the issue of the disparity between

The observation that agomelatine blocked 5-HT2c its high affinity for human MT1 and human MT2 sites receptors was of considerable interest as they fulfil major and its substantially (more than 100-fold) lower affinity 65,66 roles in the control of mood and the response to stress at human 5-HT2c receptors. Although it is hard to (BOX 2). Furthermore, serotonin synthesis is highly cir- compare potencies for agonism at one site with antago- cadian, the ScN is intensely innervated by serotonergic nism at another, the question of whether the affinity

pathways emanating from the raphe nucleus, and ScN- of agomelatine for 5-HT2c receptors is biologically

localized 5-HT2c receptors contribute to the integration meaningful had to be asked. The best way to address of photic and non-photic modulation of circadian this question was through in vivo experiments using rhythms67–70 (FIG. 1). Owing to species differences, the several behavioural and neurochemical procedures.

precise role of 5-HT2c receptors as modulators of ScN It was shown that agomelatine, but not melatonin, 70,71 activity in humans remains uncertain . Nevertheless, blocked cerebral populations of 5-HT2c receptors in 64 actions of agomelatine at melatonergic and 5-HT2c rodents . These effects of agomelatine were seen at doses receptors co-localized in the ScN may participate in its (2.5–40.0 mg per kg, intraperitoneally) yielding low micro- influence on circadian rhythms and in its resynchronizing molar levels in the brain, comparable to its affinity for

actions in depression. 5-HT2c receptors. Moreover, in comparison with other

influence of agomelatine on neurobiological parameters Box 2 | 5-ht2C receptors, mood and depression known to be dysfunctional in depression was explored: 5-hydroxytryptamine (5-HT ) receptors are present in the suprachiasmatic nucleus 2C 2C frontocortical dopaminergic and adrenergic transmission 67,69,70 (SCN), where they modify the response of intrinsic neurons to photic input . (compromised); hippocampal neurogenesis (suppressed), Interestingly, a polysynaptic circuit runs from the SCN to the ventrotegmental 129 and activity of the hypothalamic–pituitary–adrenal nucleus, the origin of mesocortical and mesolimbic dopaminergic pathways . This 2,7,20 neural link provides an anatomical substrate for an indirect influence of SCN-localized (HPA) axis (overactivated) . One major issue with evident clinical repercussions 5-HT2C receptors on ascending dopaminergic transmission. Furthermore, 5-HT2C receptors are enriched in the ventrotegmental area itself and in the locus coeruleus, was when to administer agomelatine. At least for its the source of forebrain adrenergic pathways2,77. In these nuclei, as in the frontal melatonergic properties, this was likely to make a real

cortex, excitatory 5-HT2C receptors are localized on GABA (γ-aminobutyric acid)-ergic difference and, as a general principle, it is important not interneurons. Hence, their blockade disinhibits frontocortical dopaminergic and only to give the right medicine, but also to give it at the adrenergic transmission (FIG. 5), the activity of which may be compromised in right time. consistent with our original supposition (see depression2,61. 5-HT receptors are also concentrated in limbic structures such as the 2C above), evening administration seemed preferable since frontal cortex, the amygdala, the hippocampus and the septum, which have major this corresponds to the onset of night time melatonin roles in the control of mood and in the aetiology of anxio-depressive states65,66. secretion for both diurnal and nocturnal species26,31,33 Activity at 5-HT receptors seems to be enhanced in depression, whereas a 2C (FIG. 1) decrease is elicited by long-term administration of certain antidepressants, as well . Moreover, the resynchronizing effects of ago- as sleep deprivation and electroconvulsive therapy that similarly alleviate depressed melatine had been observed when taken in the evening. mood2,4,65,66. Antidepressants such as the tricyclic clomipramine, and the atypical Thus, it was decided to continue with this basic schedule, 61,62 agent mirtazapine, antagonize 5-HT2C receptors , and small-scale investigations with the exception of some acute studies.

of mixed 5-HT2C/5-HT2A antagonists such as ritanserin suggested that mood early results showing that agomelatine had activity 66 may be improved . Furthermore, selective 5-HT2C receptor antagonists display in the forced-swim test and the chronic mild stress proce- antidepressant and anxiolytic properties in rodents, and both reduced sensitivity to dures were vital for initiation of the clinical programme stress and an anxiolytic phenotype have been reported in mice genetically deprived in depression75,76 (TABLe 1). Furthermore, enhanced of 5-HT receptors65,66,82,123. Finally, 5-HT receptor antagonists promote slow-wave 2C 2C dopamine and noradrenaline release in the frontal sleep89,91 and libido2,110. Collectively, these observations suggest that 5-HT receptor 2C cortex provided a compelling basis for therapeutic antagonism should favourably influence mood, circadian synchronization and sleep 64 (BOX 2; FIG. 5) quality, while preserving sexual function. efficacy . Interestingly, in comparison to many other antidepressants, agomelatine selectively reinforced frontocortical versus subcortical dopamin- selective antagonists, the potency of agomelatine in vivo ergic transmission2,77. Subsequently, it was discovered

correlated well with its affinity for 5-HT2c receptors that agomelatine shares two other interrelated actions in vitro66. of antidepressants that were beginning to attract con- In fact, there is nothing unusual about such modest siderable attention: it promoted neurogenesis and it potency for a drug. For example, the SNRI venlafaxine enhanced levels of brain-derived neurotrophic factor in possesses only micromolar affinity for noradrenaline the hippocampus19,20,78,79. transporters, yet exerts adrenergic actions in rats and 2,11,72 humans . encouragingly, the difference between the Synergistic roles for melatonin agonism and 5-HT2C

Forced swim test doses at which substantial 5-HT2c antagonist and mela- antagonism. The breadth of evidence supporting the In this test of potential tonergic agonist actions of agomelatine (shown at doses antidepressant properties of agomelatine (TABLe 1), antidepressant properties, 1.0–3.0 mg per kg, intraperitoneally) were observed together with the resynchronizing actions outlined rodents are placed for 15 was far less pronounced in vivo than in vitro. Possibly, a above, provided a convincing rationale to initiate clini- minutes in a cylinder of water (room temperature) from which very high degree of occupation of melatonergic sites is cal trials. However, the question of how agomelatine 56 they cannot escape. The needed for their robust activation . This issue remains was exerting its antidepressant actions remained. could following day, in the course of a to be further evaluated. its effects be attributed to its melatonergic agonism, to its second session, the time of Irrespective of the explanation, at the dose range over 5-HT receptor antagonism and/or to a combination of immobility is measured as an 2c index of despair. Given either which agomelatine possesses antidepressant properties in these effects? It was unlikely that there was going to be a chronically or acutely (on the rodents, both melatonergic and 5-HT2c receptors should unitary answer, so the actions of agomelatine were com- test day), antidepressants be activated and blocked, respectively, and this prob- pared to those of both melatonin and 5-HT2c antagonists. reduce immobility time. ably also applies for humans73 (FIG. 4). Recent magnetic Furthermore, in certain studies, mechanistic insights resonance imaging work has confirmed that agomelatine were afforded by the use of melatonergic antagonists. Chronic mild stress 74 A procedure whereby rodents blocks 5-HT2c sites in the rat brain and a similar study The possibility that melatonergic mechanisms par- are exposed for a period of is planned in humans. ticipate in the antidepressant actions of agomelatine is about 5 weeks to minor daily supported by the presence of MT1 and/or MT2 receptors stressors like wetting the antidepressant profile of agomelatine in human hippocampus, nucleus accumbens and frontal sawdust, noise, moving the cage and so on. This leads Actions in diverse experimental models. In experimental cortex, where they are thought to have a role in the con- 56 to a progressive state of studies designed to explore the antidepressant potential trol of mood . underscoring the possible participation of anhedonia (inability to of agomelatine, three complementary strategies were melatonergic receptors in the antidepressant properties experience reward), reflected adopted (TABLe 1). First, its actions were evaluated in of agomelatine, melatonin mimicked its ability to coun- in a reduction in the preference several well-established procedures reflecting core clini- ter circadian disruption in transgenic mice expressing a of sucrose over water. This state can be reversed cal features of depression. Second, potential resynchro- mutant glucocorticoid gene, which leads to disinhibition 80 by chronic administration nizing properties were examined in depression models of the HPA axis . On the other hand, 5-HT2c receptor of antidepressants. characterized by disrupted circadian rhythms. Third, the antagonists mimicked the reinforcement by agomelatine

Resynchronization collectively, the above results support the assertion of circadian rhythms that neither melatonin agonism nor 5-HT2c receptor antagonism can fully account for the antidepressant Antidepressant properties properties of agomelatine. Instead, dual actions at both + + melatonin and 5-HT2c receptors underpin its broad- based antidepressant profile in animal models, which Synergistic MT /MT 5-HT 1 2 mechanism 2C was progressively elucidated in parallel with the clinical agonist antagonist of action studies described below73,88.

+ Anxiolytic + transition to the clinic properties early Phase I trials showed that agomelatine + + (5–1,200 mg) was well tolerated, and 800 mg was defined Improved sleep as the maximal, well-tolerated dose based on one subject quality/patterns who experienced postural dizziness at 1,200 mg. even + + at high doses, agomelatine was not associated with pro- Preservation of nounced adverse effects; the most common adverse sexual function effects were mild sedation and headache73,88. This was Figure 4 | overview of the mechanism of encouraging, considering the problems of tolerability Agomelatine associated with other antidepressants1–3. antidepressant action of agomelatine.Nature Reviews | Drug Discovery possesses both melatonin receptor (MT1 and MT2) agonist Moreover, the good tolerability of agomelatine rep-

and 5-hydroxytryptamine receptor (5-HT2C) antagonist resents a reassuring safety cushion in the event of high properties. These properties act in a complementary and exposure in certain patients. This was considered possible perhaps synergistic manner to improve depressed states owing to inter-individual variability in the metabolism by resynchronization of circadian rhythms, enhancement of agomelatine by the hepatic cytochrome P450 1A2, its of dopaminergic and adrenergic input to the frontal major enzyme for degradation73,88. As anticipated from cortex, induction of neurogenesis, as well as through other mechanisms (TABLe 1). Furthermore, melatonergic agonism in silico metabolic predictions, in vitro studies of human microsomes and hepatocytes, and from in vivo work in and 5-HT2C receptor antagonism also act in harmony to favourably influence anxious symptoms, sleep and sexual animals, absorption of agomelatine was rapid and com- function. plete. However, bioavailability following oral administra- Learned helplessness tion was limited owing to a pronounced hepatic first-pass This refers to the observation effect. Furthermore, as mentioned above, elimination that exposure to uncontrollable stress can compromise the was swift, with a half-life of about 2 hours. ability to learn to escape of frontocortical dopaminergic and adrenergic input, Nonetheless, several reasons strongly suggested that from a subsequent aversive and its reduction of hyperactivity in rats subjected to this profile was compatible with therapeutic activity situation. In the learned olfactory bulbectomy, a model of depression-related in patients with depression. First, preclinical work helplessness procedure, rats 64,66,81,82 are exposed to a sequence of agitation . Intriguingly, however, although a mela- had shown robust activity of agomelatine in animals, inescapable foot-shocks in a tonin antagonist abrogated the effect of agomelatine in including models of resynchronization and antidepres- chamber and then evaluated in the learned helplessness procedure, its actions were not sant properties. Second, as pointed out above, it should an avoidance-conditioning test reproduced by melatonin or by 5-HT2c receptor antago- not be necessary to achieve full and 24 hour occupa- (escape from acute shock) nists83. It could therefore be inferred that the combined tion of target receptors for clinical actions, and a half- in a two-compartment box. The number of escape failures actions of agomelatine at melatonergic and 5-HT2c sites life of 2 hours corresponded well to the dark-onset is considered an index of were required for efficacy. consistent with this notion, peak of melatonin release. Third, studies in volunteers helplessness. Antidepressants although 5-HT2c antagonists mimic the induction by given doses of 5 mg to 100 mg showed persistent phase given before the test reinstate agomelatine of cellular proliferation in the hippocam- advances of circadian rhythms, apparent even the day escape-directed behaviour. pus, they do not reproduce its enhancement of cellular after treatment57,58. Finally, at similar doses, agomelatine Tree shrew survival or of levels of brain-derived neurotrophic factor, slightly decreased core body temperature and elicited (Also known as scandentia) which are only slightly increased by melatonin79. mild sedation57,58, as would be expected on melatonin Tree shrews are united with In a further model with a prominent circadian element, receptor stimulation31. primates in the super-order psychosocial stress in the tree shrew, Tupaia belangeri, euarchonta, itself fused with rodents and lagomorphs in agomelatine opposed the disruption of diurnal rhythms selection of doses for exploration of efficacy the euarchontoglires. They are of cortisol secretion and core temperature. Again, mela- A further important issue was the choice of dosage. diurnal, territorial animals that tonin was inactive, whereas a 5-HT2c antagonist merely Paradoxically, the good tolerance of agomelatine com- live in family-based social blunted hypercortisolaemia84,85. An elegant illustration plicated this question, as maximal testable drug doses groups. Contact of a defeated subordinate with a dominant of the roles of both melatonin and 5-HT2c receptors was are often capped by unwanted side effects. The transi- male provokes marked acquired in the above mentioned study of chronic mild tion from Phase I to Phase II/III efficacy studies could stress-related changes in stress. Agomelatine was active on administration both in not then be guided using now familiar tools such as behaviour, endocrine secretion the evening (mirrored by melatonin) and in the morning pharmacological magnetic resonance imaging. In addi- (hypothalamic–pituitary– (mimicked by a 5-HT antagonist)75. by contrast, and tion, efforts to develop positron emission tomography adrenal axis overactivity) 2c and physiology, as well as dependent on experimental conditions, both melatonin ligands for quantification of melatonin and 5-HT2c disruption of circadian and 5-HT2c antagonists are active in the forced-swim receptor occupancy in humans had been, and remain, rhythms. test66,82,86,87. unsuccessful. In fact, the selection of 1 mg, 5 mg and

Electrophysiology, locus coeruleus Dialysis Electrophysiology abcd Agomelatine

a Frontal cortex 200 ) te ra 50 NA om baseline

0 Serotonin d Locus oeruleus firing coeruleus os c os (% change fr

DA Loc –50

Vehicle 1 2 4 8 16 Dose (mg per kg, intravenously)

c Dorsal raphe nucleus b Ventral tegmental area Vehicle 80.0 40.0 Agomelatine 20.0 (mg per kg, intraperitoneally) 10.0 Dialysis, frontal cortex 2.5 Serotonin Dopamine Noradrenaline 250 400 250 350 els 200 300 200

om basal) 250 150 200 150 150 Monoamine lev Monoamine 100 (% change fr change (% 100 100

0 60 120 180 0 60 120 180 0 60 120 180 ↑ Time (min) ↑ Time (min) ↑ Time (min) Figure 5 | reinforcement of corticolimbic adrenergic and dopaminergic transmission by agomelatine. The frontal cortex is innervated by ascending adrenergic, dopaminergic and serotonergic pathways originating in the locus coeruleus, the ventrotegmental area and the dorsal raphe nucleus, respectively. The influence of agomelatine on the activity of monoaminergic tracts has been measured in freely moving rats using dialysis coupled to high performance liquid chromatography and electrochemical detection to quantify extracellular levels of monoamines. In addition, the influence of agomelatine on the electrical activity of monoaminergic cell bodies has been evaluated in anaesthetized rats, as depicted here for the locus coeruleus (top right). Adrenergic and dopaminergic pathways are

subject to indirect inhibition by 5-hydroxytryptamine 2C (5-HT2C) receptors, which act through the excitation of GABA (γ-aminobutyric acid)-ergic interneurons. Accordingly, agomelatine dose-dependently increases the release of dopamine (DA) and noradrenaline (NA), but not serotonin in the frontal cortex. In parallel, it increases the firing rate of adrenergic neurons in the locus coeruleus64. Arrows represent injection of agomelatine. Stars represent P < 0.01 to vehicle (Dunnett’s test after ANOVA). Nature Reviews | Drug Discovery

25 mg for an initial dose-ranging trial was mainly guided Thus, despite the current predilection for imaging, this by the above mentioned studies of phase-shifting in vol- is a good example of how a traditional pharmacody- unteers57,58. with hindsight, electroencephalography may namic approach could have been, and still can be, useful have been instructive as we now know that both in rats89 in estimating centrally active doses of a new drug. and in patients90, agomelatine enhances restorative slow- Indeed, it did prove possible to establish doses of

wave sleep, an effect characteristic of 5-HT2c receptor agomelatine that were effective in treating major depres- antagonists66,89. It should be noted that, in contrast to sion. The following section summarizes the progression antidepressants suppressing monoamine reuptake2,91, of efficacy and safety studies undertaken in almost 5,000 agomelatine does not reduce rapid eye movement sleep patients, primarily in europe, but also in South Africa, either in patients with depression90 or in volunteers92. South America, Australia and North America.

Table 1 | overview of the actions of agomelatine in experimental models relevant to depression characteristic Model species Major observation refs Cardinal symptom Forced swim test Rat Decrease in immobility time 76 (despair) Learned helplessness Rat Disinhibition of suppressed responses 83 (resignation) Chronic mild stress Rat Restored sucrose consumption 75 (anhedonia) Olfactory bulbectomy Rat Decrease in hyperactivity 81 (motor agitation) Circadian disruption Mutated glucocorticoid Mouse Decrease in perturbation of rhythms 80 receptor of corticosterone secretion Psychosocial stress Tree shrew Decrease in perturbation of rhythms 84,85 of corticosterone secretion and core temperature Biological substrate Noradrenaline/dopamine Rat Increase in extracellular levels 64 in frontal cortex Hippocampal Rat Increase in cellular proliferation and 78,79 neurogenesis survival Levels of brain-derived Rat Increase in mRNA levels 79 neurotrophic factor

Clinical evaluation for treating major depression of 47–58% in the placebo arm negatively affected these The clinical evaluation of agomelatine in major depression investigations. As discussed elsewhere, this complex was designed around the requirements of the european problem has compromised many trials of antidepressants Medicines Agency (eMA): first, demonstration of effi- and reflects multiple factors; notably, that patients were cacy compared with placebo; second, maintenance of ‘insufficiently’ ill at inclusion, and that placebo is tanta- long-term effectiveness (prevention of relapse); third, mount to a form of psychotherapy not encountered in comparisons to other clinically used antidepressants; and the ‘real world’5,95,96. To minimize the risk of an untoward fourth, demonstration of a favourable risk–benefit pro- placebo response, several methodological innovations file. The results of all clinical trials, of which 3 out of 6 were introduced. Only patients with moderate to severe were positive, were submitted to the eMA and are publicly depression were enrolled by imposing strict entry criteria available online (see further information for the link to at baseline. Furthermore, a disability scale of social and the assessment report for agomelatine). In addition, in a occupational dysfunction was adopted. These meas- recent publication, the complete data set from both posi- ures proved effective as two key Phase III studies using tive and negative trials is analysed in detail93. The following variable doses of agomelatine (25–50 mg) unambigu- discussion focuses on the core clinical observations that ously substantiated its efficacy compared with placebo drove further development, and which ultimately led to (response rates now approximately 35%)73,88,97. the recommendation of marketing authorization by the eMA under the trade names valdoxan and Thymanax. Demonstration of efficacy compared with other antidepressants. Several other head-to-head Phase III Short-term efficacy compared with placebo. A double- investigations were launched to compare agomelatine blind, paroxetine (SSRI)-validated, dose-ranging investi- (25–50 mg) with the SNRI venlafaxine (75–150 mg) gation was performed over 8 weeks at doses of 1 mg, 5 mg and with the SSRI sertraline (50–100 mg). Agomelatine and 25 mg. It transpired that the 25 mg dose was the most showed efficacy at least comparable to these established effective based on the primary outcome criterion, the drugs. In fact, it proved superior both to venlafaxine 17 item Hamilton depression rating scale (HAM–D)–total and to sertraline as judged by the HAM–D and cGI 94 98–100 Hamilton depression score (HAM–T) . This conclusion was underpinned (improvement) secondary end points, respectively . rating scale by the secondary outcome criteria: the percentage of Notably, agomelatine was active across the whole patient (HAM-D). This scale is used patients that exhibited a greater than 50% reduction of sample and in patients with more severe depression to assess depressive states in patients. It incorporates HAM–T from baseline, and the clinical global impres- (HAM–D ≥25; cGI–S ≥5 at baseline). In addition, the various parameters, like sion severity (cGI–S) scores. Interestingly, as quantified proportion of patients completing the 6-month treat- depressed mood, feelings by the Hamilton anxiety rating scale, agomelatine also ment period was significantly higher for agomelatine of guilt, insomnia and so alleviated anxiety. In addition, in corroboration with than for the comparators99,100 (FIG. 6b). forth. severity is estimated Phase I findings, tolerance was good. In view of the delay to full efficacy of other antide- numerically from zero 1,2,7 (essentially normal); the higher The successful completion of this study triggered pressants , there was particular interest in the rate of the score, the more serious several other short-term Phase II efficacy trials against onset, which had appeared more rapidly (week 2) in the depressed states. placebo. unfortunately, an excessively high response rate the first placebo-controlled study94. Furthermore, the

observation that the proportion of responders at week with agomelatine should not lead to deleterious effects 2 was greater in patients on agomelatine than those on due to activation by serotonin of re-exposed and hyper- 99 sertraline was intriguing as, in another study, the bene- responsive 5-HT2c receptors. However, this notion awaits fits of agomelatine translated into a greater early percep- formal proof. tion of well-being compared with venlafaxine at week 1 (ReF. 98). The investigation evaluating agomelatine onset Good tolerability compared with other antidepressants. with venlafaxine highlighted two possible contributions One consistent finding throughout clinical testing of ago- to early symptomatic improvement: better daily func- melatine has been its good tolerability, a potentially key tioning and improved sleep, which is often perturbed by benefit for initiation of treatment and long-term adher- SSRIs and SNRIs2,3,91. Thus, using the Leeds sleep evaluation ence1,3. evidence for a favourable side-effect profile was questionnaire, the advantage of agomelatine relative to apparent in short-term studies in which emergent adverse venlafaxine was apparent for both getting to sleep and effects were almost indistinguishable from placebo88,94,97. quality of sleep by week 1, and persisted for 6 weeks98. Thus, based on the complete database of double-blind, These observations were consistent with findings pointing 6 month studies, the only emerging adverse effect signifi- to early improvement in subjective sleep and daytime cantly associated with agomelatine (1,120 patients) com- functioning for agomelatine compared with sertraline99. pared with placebo (998 patients) was dizziness: 5.9%

both melatonin agonism and 5-HT2c antagonism prob- compared with 3.5%, respectively (P<0.01). Notably, in ably participate in the ability of agomelatine to promote studies in which agomelatine was directly compared with sleep66,89,91,101. Further study to examine the rate of onset venlafaxine and sertraline, the favourable safety profile of antidepressant actions of agomelatine is warranted. of agomelatine translated into significantly fewer study dropouts due to side effects98–100 (FIG. 6b). Demonstration of relapse prevention compared with Poor gastrointestinal tolerability and weight gain can placebo. An initial, placebo-controlled investigation sometimes provoke early cessation of treatment with of relapse prevention was unsuccessful, largely due to other antidepressants3,106. by contrast, the gastrointes- a low rate of relapse in the placebo arm of the study. tinal tolerability of agomelatine was good and it was Nevertheless, this trial proved instructive in demon- weight-neutral. A lack of weight gain was especially strating that agomelatine was superior to placebo in reassuring as gene knockout studies in transgenic mice patients severely ill at baseline, an observation coinciding had suggested that obesity might be a drawback for the 65,66 well with the findings of the short-term trials described therapeutic use of 5-HT2c antagonists . above88,97. The follow-up relapse prevention study was even at supra-therapeutic doses, no clinically relevant modified to resolve concerns that arose in the course of changes were detected in biochemical, cardiac or car- Leeds sleep evaluation the first investigation. For example, a flexible dose regi- diovascular parameters. Some isolated and reversible questionnaire men was exploited, permitting the (blinded) increase increases in serum alanine and/or aspartate transami- This is a simple and in dose from 25 mg to 50 mg at week 2. Furthermore, nases were observed within the first months of treatment standardized instrument for after 8–10 weeks of open treatment, patients entering the across all patients: 1.1% for all doses of agomelatine pseudo-quantifying the influence of therapy on sleep randomized, 6 months, double-blind continuation phase compared with 0.7% for placebo. They were principally and early morning behaviour. had to present HAM–D and cGI–S scores of ≤10 and ≤2, observed with agomelatine at a dose of 50 mg per day, It consists of a number of items respectively, blinded both to the patient and the investi- for which the crude incidence rate (1.39%) was similar like the quality of, and latency gator. As exemplified by the primary outcome criterion to that documented in comparative studies with venla- to, sleep. The questionnaire is (HAM–D), this study showed a twofold lower relapse rate faxine at doses of 75–150 mg per day (1.53%) in pooled completed by patients 44,47 themselves. during continuation in patients treated with agomelatine analyses (unpublished data). This led to a recom- compared with patients treated with placebo102 (FIG. 6a). mendation by the eMA of liver function tests as a pre- Discontinuation syndrome Furthermore, a controlled extension of the study revealed cautionary measure at the onset of treatment, and then In particular for that this advantage was sustained for up to 10 months, periodically at 6 weeks, 12 weeks and 6 months, as well antidepressants with short half-lives, following long-term both in the entire population enrolled and in patients as subsequently if appropriate. Patients with depression 103 (6 weeks or more) treatment, with more severe depression . should be regularly followed up by their doctors, so this abrupt discontinuation, is less of a constraint than might be initially imagined. non-compliance and Lack of a discontinuation syndrome. In the studies of In addition, it should be noted that agomelatine is con- sometimes even dose agomelatine described above, the lack of early relapse traindicated in patients with hepatic impairment; for reductions can trigger a discon- discontinuation syndrome on switching to placebo argued for a minimal example, cirrhosis or active liver disease. comprising psychological tinuation syndrome. This attribute was underscored by a Finally, sexual dysfunction is a particularly unpopu- (agitation, anxiety, irritability) placebo-controlled study using paroxetine (20 mg) as lar and frequent side effect of many antidepressants that and somatic (nausea, an active comparator104. The comparative absence of an markedly interferes with quality of life and leads to poor dizziness, sensory and sleep 2,3,107 disturbances, flu-like agomelatine discontinuation syndrome is advantageous compliance . Melatonergic agonists and 5-HT2c antag- 2,108–110 chills, myalgia and fatigue) as withdrawal can be a major problem with certain SSRIs, onists actually promote sexual behaviour in animals . symptoms. Although usually and discourages their use by patients105. It is difficult to A substantially lower risk of sexual dysfunction with ago- mild and self-limiting (a week extrapolate from the clinic back to the cell; nonetheless, melatine treatment compared with venlafaxine treatment or so), this discontinuation long-term administration of 5-HT receptor inverse was shown in patients at equivalent effective doses100. syndrome is distressing and 2c disruptive. Moreover, it can agonists increases the cell surface density and sensitivity These findings prompted a further investigation that con- occasionally be quite severe of 5-HT2c sites, whereas the neutral antagonist, agomela- firmed the good acceptability of agomelatine compared and mistaken for relapse. tine, does not61,62,64. consequently, stopping treatment with paroxetine in sexually active healthy volunteers111.

a Time to relapse in remitted patients b Cumulative incidence of dropouts 1.0 50 0.9 Sertraline (n = 159) Venlafaxine (n = 307) 0.8 40 Agomelatine (n = 455) 0.7

ee 0.6 30 0.5

0.4 opouts (%) 20 Relapse-fr Dr 0.3 Agomelatine (n = 165) 0.2 Cumulative, 21.7% 10 Placebo (n = 174) 0.1 Cumulative, 46.6% 0.0 0 0 41822 16 20 4 0 41822 16 20 4 Time (weeks) Time (weeks) Figure 6 | Actions of agomelatine in major depression: its prevention of relapse and its low rate of patient dropout compared with comparators. a | Following treatment with agomelatine, as compared with placebo, there is a marked reduction in the risk for relapse over 6 months. This low rate of relapse hasNa sinceture beenRevie wsshown | Drug for Disc overy up to 10 months 88,97,102. b | The graph depicts the significantly reduced incidence of study dropouts and risk of poor compliance with agomelatine (25–50 mg per day) as compared with the selective serotonin reuptake inhibitor sertraline (50–100 mg per day) and the serotonin/noradrenaline reuptake inhibitor venlafaxine (75–150 mg per day)99,100.

Looking to the future: the next chapters agomelatine, and agonists can differentially affect the Further experimental characterization. like all other sensitivity of G protein-coupled receptors2, so findings drugs, agomelatine remains a work in progress. Although of desensitization with melatonin cannot automatically agomelatine has been thoroughly characterized, there is be extrapolated to agomelatine. Arguing against desen- still much to learn about its mechanism(s) of action and sitization, the influence of agomelatine on the activity therapeutic promise. Among issues expected to stimu- of ScN neurons in hamsters persisted on repeated late future research, the following may be emphasized. administration43. Furthermore, the comparatively short First, studies are underway to investigate the respec- half-life of agomelatine mimics the nocturnal pulse of

tive roles of MT1 compared with MT2 receptors in the melatonin secretion and should counter downregulation actions of agomelatine, the significance of (functional of melatonergic receptors40,42. Thus, under conditions of

or physical) crosstalk among melatonergic and 5-HT2c once-daily, night time administration of agomelatine,

receptors, and the influence of agomelatine on a host melatonergic (at least MT1) receptors in the ScN prob- of intracellular signals involved in the pathogenesis of ably retain their responsiveness, but this issue merits depressed states19,56,60,112. further investigation. Second, agomelatine possesses several complementary mechanisms that potentially favour cognitive perform- Further clinical characterization. Depression is com- ance: enhancement of dopaminergic and adrenergic mon but poorly treated in the elderly, who are especially input to the frontal cortex; increased hippocampal neuro- sensitive to distressing side effects of antidepressants and genesis; moderation of stress-induced HPA overactivity; frequently show pronounced perturbations of circadian reinforced slow-wave sleep without loss of rapid eye rhythms2,118. Accordingly, in agreement with the eMA, movement sleep; and circadian synchronization2,113–115. a study of agomelatine is underway93 in patients over 65 As cognition is severely impaired in depression2,116, and years of age. agomelatine counters the impairment of cognition by One obvious avenue for exploration is seasonal stress117, it would be interesting to pursue studies of its affective disorder, which is characterized by repeated influence on mnemonic function. depressive episodes at the same time of year, usually win- Third, the question arises as to how treatment with ter46,119. Sufferers display disrupted, generally delayed, agomelatine affects the responsiveness of melatonergic circadian rhythms and perturbed sleep, as well as receptors. Studies performed in chinese hamster ovary alterations in melatonin secretion. Analogous to major

cells suggest that human MT2 receptors are robustly depression, melatonin itself does not alleviate seasonal downregulated, decoupled and internalized by mela- affective disorder (BOX 1), but an open-label study of

tonin. On the other hand, human MT1 receptors are more agomelatine (25 mg per day in the evening) suggested resistant, and night time exposure to high levels of mela- good efficacy over 14 weeks120, encouraging further

tonin desensitizes MT2 but not necessarily MT1 receptors controlled studies. 40–42 in rat ScN . This lesser tendency of MT1 receptors to bipolar disorder is accompanied by a severe disrup- desensitize is intriguing, as they appear to predomi- tion of mood and cognition, desynchronization of daily nate in the ScN of humans25,29,31. long-term regulatory rhythms, and poor sleep19. There is evidence for a per- studies of cellular coupling remain to be performed with turbation of mechanisms controlling neuronal plasticity,

Discovery, development and authorization Preclinical safety/ Good Clinical antidepressant efficacy versus pharmacokinetics tolerance placebo and versus comparators Long-term Circadian rhythm prevention shifts in volunteers of relapse Novel Circadian No naphthalenic resynchronization Agomelatine discontinuation No sexual Improved Efficacy EMA melatonergic agonists in rodents INN syndrome dysfunction sleep in GAD approval

1992 1994 1996 1998 2000 2002 2004 2006 2008 2009

MT1 /MT2 agonism 5-HT2C antagonist ↑NA/DA release (FCX) Anxiolytic properties Antidepressant properties properties ↑Neurogenesis ↓Psychosocial stress ↓Despair ↓HPA overactivity ↑BDNF levels ↓Anhedonia Pharmacological characterization: key observations Figure 7 | Timeline for the discovery, characterization, development and authorization of agomelatine. Inherent in a case history is the arrow of time running from conception to discovery and pharmacologicalNature Reviews characterization | Drug Discovery to clinical development. This timeline indicates several key phases in the life cycle of agomelatine, culminating in its marketing authorization by the European Medicines Agency (EMA) for the treatment of major depression. However, time has not come to a halt and, in addition to Phase IV clinical surveillance, experimental and clinical exploration of its therapeutic utility continues (see main text). 5-HT, 5-hydroxytryptamine (also known as serotonin); BDNF, brain-derived neurotrophic factor; FCX, frontal cortex; GAD, generalized anxiety disorder; HPA, hypothalamic–pituitary–adrenal; INN, international non-propriety name; MT, melatonin; NA/DA, noradrenaline/dopamine.

such as those that involve glycogen synthase kinase 3β19, of drugs must continually be re-evaluated in the light of so it is intriguing that agomelatine modulates the activ- new developments, from the molecular to the clinical. ity of this cellular signal79,112. experimental and clinical For example, at the time the agomelatine project was

investigations have been launched to evaluate the poten- conceived, MT1, MT2 and 5-HT2c receptors had not tial utility of adjunctive agomelatine in the manage- even been cloned. Second, the discovery of agomela- ment of bipolar disorder. In addition, one might explore tine reflects a hypothesis-driven process of research the adjunctive use of agomelatine in major (unipolar) founded on the notion that depression is not a monolithic depression in combination with other antidepressants to disorder of mood but displays, among other factors, a improve efficacy and tolerance (such as sleep and sexual disruption of biological rhythms; this concept contin- function). Nonetheless, the principal benefits of agomel- ues to guide its characterization. Third, it is impossible atine are most probably expressed as monotherapy. to anticipate everything from the outset. As good for- The high prevalence of anxious states, and their fre- tune favours the prepared mind (and laboratory), flex- quent co-morbidity with depression2,121, underscores ibility and reactivity are crucial elements for successful interest in the anxiolytic properties of agomelatine. In research and development programmes. Accordingly,

a rat model of social defeat, agomelatine mimicked the the unexpected 5-HT2c receptor antagonist properties anxiolytic actions of melatonin, an effect abolished by of agomelatine were systematically validated as com- lesions of the ScN122. Furthermore, similar to pharmaco- plementary to its melatonin agonist actions. Finally, a 66,82,123 logical or genetic inactivation of 5-HT2c receptors , huge, long-term and risk-intensive effort from incep- agomelatine displayed robust anxiolytic properties tion to market authorization was needed to realize the (probably expressed in the amygdala and hippocampus) objective of making agomelatine available to patients in several procedures in rats66,124,125. These observations suffering from major depression (FIG. 7). provided a basis for the evaluation of the potential anxiolytic actions of agomelatine in humans, and the first Concluding comments positive findings in generalized anxiety disorder were Agomelatine represents an innovative approach to treat- recently disclosed126. ing depression73 as it is the first regulatory approved agent to incorporate a non-monoaminergic mecha- General messages for drug r&D nism. Its antidepressant activity across a broad range of The history of agomelatine exemplifies several funda- experimental procedures in animal models and its dis- mental facets of drug research and development that tinctive therapeutic profile in humans probably reflect merit emphasis in a broader context. First, it is crucial a synergistic interplay of its melatonergic (agonist) and

that experimental and clinical research is conducted in 5-HT2c (antagonist) properties. extensive clinical trials tan dem with development programmes throughout the life - have established both the short-term and long-term span of a new compound (FIG. 7). Accordingly, the properties efficacy of agomelatine in major depression in mildly

and severely ill patients, with an improvement of sleep or more, recommended for durable improvement of a quality, preservation of sexual function, absence of major depressive episode. Further studies and clinical weight gain and good tolerability. Moreover, discontinu- use will clarify the full potential of agomelatine as an ation is not associated with withdrawal symptoms. This antidepressant. There is also rich potential, as high- overall profile compares favourably to currently avail- lighted above, for exploration of the broader use of able antidepressants and should encourage adherence agomelatine in the treatment of other central nervous throughout the extensive treatment period, 6 months system disorders.

1. Sartorius, N. et al. Antidepressant medications 19. Manji, H. K. et al. Enhancing neuronal plasticity 40. Witt-Enderby, P. A., Bennett, J., Jarzynka, M. J., and other treatments of depressive disorders: and cellular resilience to develop novel, improved Firestine, S. & Melan, M. A. Melatonin receptors a CINP task force report based on a review of therapeutics for difficult to treat depression. and their regulation: biochemical and structural evidence. Int. J. Neuropsychopharmacol. 10, Biol. Psychiatry 53, 707–742 (2003). mechanisms. Life Sci. 72, 2183–2198 (2003). S1–S207 (2007). 20. Pittenger, C. & Duman, R. S. Stress, depression, 41. Gerdin, M. J. et al. Short-term exposure to melatonin 2. Millan, M. J. Multi-target strategies for the improved and neuroplasticity: a convergence of mechanisms. differentially affects the functional sensitivity and

treatment of depressive states: conceptual Neuropsychopharmacology 33, 88–109 (2008). trafficking of the hMT1 and hMT2 receptors. foundations and neuronal substrates, drug discovery 21. Souetre, E. et al. Circadian rhythms in depression J. Pharmacol. Exp. Ther. 304, 931–939 (2003). and therapeutic application. Pharmacol. Ther. 110, and recovery: evidence for blunted amplitude as the 42. Gerdin, M. J. et al. Melatonin desensitizes 135–370 (2006). main chronobiological abnormality. Psych. Res. 28, endogenous MT2 melatonin receptors in the rat 3. Papakostas, G. I. Tolerability of modern 263–278 (1989). suprachiasmatic nucleus: relevance for defining the antidepressants. J. Clin. Psychiatry 69, 8–13 (2008). 22. Duncan, W. C. Circadian rhythms and the periods of sensitivity of the mammalian circadian 4. Eitan, R. & Lerer, B. Neuropharmacological, somatic pharmacology of affective illness. Pharmacol. Ther. clock to melatonin. FASEB J. 18, 1646–1656 treatments of depression: electroconvulsive therapy 71, 253–312 (1996). (2004). and novel brain stimulation modalities. Dialogues 23. Germain, A. & Kupfer, D. J. Circadian rhythm 43. Ying, S. W., Rusak, B. & Mocaër, E. Chronic exposure Clin. Neurosci. 8, 241–258 (2006). disturbances in depression. Hum. Psychopharmacol. to melatonin receptor agonists does not alter 5. DeRubeis, R. J., Siegle, G. J. & Hollon, S. D. 23, 571–585 (2008). their effects on suprachiasmatic nucleus neurons. Cognitive therapy versus medication for depression: 24. Filadelfi, A. M. & Castrucci, A. M. Comparative Eur. J. Pharmacol. 342, 29–37 (1998). treatment outcomes and neural mechanisms. aspects of the pineal/melatonin system of 44. Martinet, L., Guardiola-Lemaître, B. & Mocaër, E. Nature Rev. Neurosci. 9, 788–796 (2008). poikilothermic vertebrates. J. Pineal Res. 20, Entrainment of circadian rhythms by S20098 a 6. Millan, M. J. Dual- and triple-acting agents for treating 175–186 (1996). melatonin agonist is dose and plasma concentration core and co-morbid symptoms of major depression: 25. Pandi-Perumal, S. R. et al. Melatonin: nature’s most dependent. Pharmacol. Biochem. Behav. 54, novel concepts, new drugs. Neurotherapeutics 6, versatile biological signal? FEBS J. 273, 2813–2838 713–718 (1996). 53–77 (2009). (2006). 45. Redman, J. R., Guardiola-Lemaître, B., Brown, M., 7. Mathew, S. J., Manji, H. K. & Charney, D. S. 26. Arendt, J. Melatonin and the pineal gland: influence Delagrange, P. & Armstrong, S. M. Dose-dependent Novel drugs and therapeutic targets for severe on mammalian seasonal and circadian physiology. effects of, S20098, a melatonin agonist on direction mood disorders. Neuropsychopharmacology 33, Rev. Reproduction 3, 13–22 (1998). of re-entrainment of rat circadian rhythms. 2080–2092 (2008). 27. Cardinali, D. P., Vacas, M. I. & Boyer, E. E. Specific Psychopharmacology 118, 385–390 (1995). 8. Rozas, I. Improving antidepressant drugs: update binding of melatonin in bovine brain. Endocrinology 46. Armstrong, S. M., McNulty, O. M., Guardiola- on recently patented compounds. Expert Opin. 105, 437–441 (1979). Lemaître, B. & Redman, J. R. Successful use of Ther. Patents 19, 827–845 (2009). 28. Vanecek, J., Pavlik, A. & Illerova, H. Hypothalamic S20098 and melatonin in an animal model of delayed 9. Papakostas, G. I., Thase, M. E., Fava, M., Nelson, J. C. melatonin receptor sites revealed by autoradiography. sleep-phase syndrome. Pharmacol. Biochem. Behav. & Shelton, R. C. Are antidepressant drugs that Brain Res. 435, 359–362 (1987). 46, 45–49 (1993). combine serotonergic and noradrenergic mechanisms 29. Reppert, S. M., Weaver, D. R. & Godson, C. In vivo study demonstrating that agomelatine of action more effective than the selective serotonin Melatonin receptors step into the light: cloning can effectively modify circadian rhythms. reuptake inhibitors in treating major depressive and classification of subtypes. Trends Pharmacol. Sci. 47. Wirz-Justice, A. et al. Chronotherapeutics (light and disorder? A meta-analysis of studies of newer agents. 17, 100–102 (1996). wake therapy) in affective disorders. Psychol. Med. Biol. Psychiatry 62, 1217–1227 (2007). 30. Morgan, P. J., Barrett, P., Howell, H. E. & Helliwell, R. 35, 939–944 (2005). 10. Montgomery, S. A. et al. Which antidepressants have Melatonin receptors: localization, molecular 48. Emens, J., Lewy, A., Kinzie, J. M., Arntz, D. & demonstrated superior efficacy? A review of the pharmacology and physiological significance. Rough, J. Circadian misalignment in major depressive evidence. Int. Clin. Psychopharmacol. 22, 323–329 Neurochem. Int. 24, 101–146 (1994). disorder. Psychiatry Res. 168, 259-261 (2009). (2007). 31. Macchi, M. M. & Bruce, J. N. Human pineal physiology 49. Van Reeth, O. et al. Melatonin or a melatonin agonist 11. Morilak, D. A. & Frazer, A. Antidepressants and brain and functional significance of melatonin. Front. corrects age-related changes in circadian response to monoaminergic systems: a dimensional approach to Neuroendocrinol. 25, 177–195 (2004). an environmental stimulus. Am. J. Physiol. 280, understanding their behavioural effects in depression 32. Racagni, G., Riva, M. A. & Popoli, M. The interaction 1582–1591 (2001). and anxiety disorders. Int. J. Neuropsychopharmacol. between the internal clock and antidepressant 50. Koster-van Hoffen, G. C. et al. Effects of a novel 7, 193–218 (2007). efficacy. Int. Clin. Psychopharmacol. 22, S9–S14 melatonin analog on circadian rhythms of body 12. McIntyre, M. & Moral, M. A. Augmentation in (2007). temperature and activity in young, middle-aged, treatment-resistant depression. Drugs Future 31, 33. Guardiola-Lemaitre, B. in Advances in Pineal and old rats. Neurobiol. Aging 14, 565–569 1069–1081 (2006). Research. (eds Foldes, A. & Reiter, R. J.) 351–363 (1993). 13. Wong, E. H., Nikam, S. S. & Shahid, M. Multi- and (John Libbey, London, 1991). 51. Grassi-Zucconi, G., Semprevivo, M., Mocaër, E., single-target agents for major psychiatric diseases: 34. Guardiola-Lemaitre, B. & Delagrange, P. Melatonin Kristensson, K. & Bentivoglio, M. Melatonin and its therapeutic opportunities and challenges. Curr. Opin. analogues: from pharmacology to clinical application. new agonist, S20098 restore synchronised sleep Investig. Drugs 9, 28–36 (2008). Eur. J. Med. Chem. 30, S643–S651 (1995). fragmented by experimental trypanosome infection in

14. Kehne, J. H. The CRF1 receptor, a novel target for the 35. Adam, G. et al. New naphthalenic ligands of the rat. Brain Research Bull. 39, 63–68 (1996). treatment of depression, anxiety, and stress-related melatoninergic receptors J. Pharm. Belg. 47, 52. Van Reeth, O., Olivares, E., Turek, F. W., Granjon, L. disorders. CNS Neurol. Disord. Drug Targets 6, 374–380 (1992). & Mocaër, E. Resynchronisation of a diurnal rodent 163–182 (2007). 36. Yous, S. et al. Novel naphthalenic ligands with high circadian clock accelerated by a melatonin agonist. 15. Ebner, K., Sartori, S. B. & Singewald, N. Tachykinin affinity for the melatonin receptor. J. Med. Chem. Neuroreport 9, 1901–1905 (1998). receptors as therapeutic targets in stress-related 35, 1484–1485 (1992). 53. Wirz-Justice, A. et al. Early evening melatonin and, disorders. Curr. Pharm. Des. 154, 1647–1674 Identification of agomelatine as a high potency S20098 advance circadian phase and nocturnal (2009). ligand of melatonin receptors. regulation of core body temperature. Am. J. Physiol. 16. Kramer, M. S. et al. Demonstration of the efficacy 37. Van Reeth, O. et al. Comparative effects of a melatonin 272, R1178–R1188 (1997). and safety of a novel substance P (NK1) receptor agonist on the circadian system in mice and syrian 54. Redman, J. R. & Francis, A. J. Entrainment of rat antagonist in major depression. hamsters. Brain Res. 762, 185–194 (1997). circadian rhythms by the melatonin agonist, S20098 Neuropsychopharmacology 29, 385–392 (2004). 38. Ying, S. W. et al. Melatonin analogues as agonists requires intact suprachiasmatic nuclei but not the 17. Binneman, B. et al. A 6-week randomized, placebo- and antagonists in the circadian system and other pineal. J. Biol. Rhythms 13, 39–51 (1998).

controlled trial of CP-316,311 (a selective CRH1 brain areas. Eur. J. Pharmacol. 296, 33–42 (1996). 55. Pitrosky, B., Kirsch, R., Malan, A., Mocaër, E. & antagonist) in the treatment of major depression. Demonstration that agomelatine possesses Pevet, P. Organization of rat circadian rhythms during Am. J. Psychiatry 165, 617–620 (2008). agonist properties at a crucial population of daily infusion of melatonin or, S20098, a melatonin 18. Preskorn, S. H. et al. An innovative design to melatonin receptors in the suprachiasmatic agonist. Am. J. Physiol. Regul. Integr. Comp. Physiol. establish proof of concept of the antidepressant nucleus. 277, 812–828 (1999). effects of the NR2B subunit selective, N-methyl-d- 39. Audinot, V. et al. New selective ligands of human 56. Jockers, R., Maurice, P., Boutin, J. A. & Delagrange, P.

aspartate antagonist, CP-101,606, in patients with cloned melatonin MT1 and MT2 receptors. Naunyn Melatonin receptors, heterodimerization, signal treatment-refractory major depressive disorder. Schmeidebergs Arch. Pharmacol. 36, 553–561 transduction and binding sites: what’s new? J. Clin. Psychopharmacol. 28, 631–637 (2008). (2003). Br. J. Pharmacol. 154, 1182–1195 (2008).

57. Cajochen, C., Kräuchi, K., Möri, D., Graw, P. & 76. Bourin, M., Mocaër, E. & Porsolt, R. Antidepressant- 95. Leuchter, A. F. et al. Pretreatment neurophysiological Wirz-Justice, A. Melatonin and S20098 increase REM like activity of S20098 (agomelatine) in the forced and clinical characteristics of placebo responders and wake-up propensity without modifying NREM swimming test in rodents: involvement of melatonin in treatment trials for major depression. sleep homeostasis. Am. J. Physiol. Regul. Integrative and serotonin receptors. J. Psychiatry Neurosci. 29, Psychopharmacology 177, 15–22 (2004). Comp. Physiol. 272, R1189–R1196 (1997). 126–133 (2004). 96. Berk, M. & Dodd, S. Antidepressants and the placebo 58. Kräuchi, K., Cajochen, C., Möri, D., Graw, P. & 77. Alex, K. D. & Pehek, E. A. Pharmacological response. Hum. Psychopharmacol. Clin. Exp. 20, Wirz-Justice, A. Early evening melatonin and S20098 mechanisms of serotonergic regulation of dopamine 305–307 (2005). advance circadian phase and nocturnal regulation of neurotransmission. Pharmacol. Ther. 113, 296–320 97. Kennedy, S. H. & Emsley, R. Placebo-controlled trial core body temperature. Am. J. Physiol. Regul. (2007). of agomelatine in the treatment of major depressive Integrative Comp. Physiol. 272, R1178–R1188 78. Banasr, M., Hery, M., Mocaër, E. & Daszuta, A. disorder. Eur. Neuropsychopharmacol. 16, 93–100 (1997). Agomelatine, a new antidepressant drug, increases (2006). Study showing that in human volunteers, evening cell proliferation, maturation and survival of newly 98. Lemoine, P., Guilleminault, C. & Alvarez, E. administration of agomelatine has a significant generated granule cells in adult hippocampus. Improvement in subjective sleep in major depressive and sustained influence on circadian rhythms over Biol. Psychiatry 59, 1087–1096 (2006). disorder with a novel antidepressant, agomelatine: 24 hours. Long-term treatment with agomelatine enhances randomized, double blind comparison with venlafaxine.

59. Burns, C. M. et al. Regulation of serotonin2C receptor, cellular proliferation and neurogenesis in the J. Clin. Psychiatry 68, 1723–1732 (2007). G-protein coupling by RNA editing. Nature 387, hippocampus, a mechanism common to other 99. Kasper, S. et al. Efficacy of the novel antidepressant 303–308 (1997). classes of antidepressant and implicated in agomelatine on the circadian and anxiety symptoms 60. Millan, M. J., Marin, P., Bockaert, J. & la Cour, C. M. the improvement of mood. in patients with major depressive disorder: Signaling at G-protein-coupled serotonin receptors: 79. Soumier, A. et al. Mechanisms contributing to the a randomized, double-blind comparison with recent advances and future research directions. phase-dependent regulation of neurogenesis by sertraline. J. Clin. Psychiatry 71, 109–120 (2010). Trends Pharmacol. Sci. 29, 454–464 (2008). the novel antidepressant, agomelatine, in the adult 100. Kennedy, S. H., Rizvi, S., Fulton, K. & Rasmussen, J. 61. Aloyo, V. J., Berg, K. A., Spampinato, U., Clarke, W. P. rat hippocampus. Neuropsychopharmacology 34, A double-blind comparison of sexual functioning, & Harvey, J. A. Current status of inverse agonism at 2390–2403 (2009). antidepressant efficacy, and tolerability between

serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol. 80. Barden, N. et al. Antidepressant action of agomelatine and venlafaxine XR. J. Clin. Ther. 121, 160–173 (2009). agomelatine (S20098) in a transgenic mouse model. Psychopharmacol. 28, 329–333 (2008). 62. Chanrion, B. et al. Inverse agonist and neutral Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 101. Srinivasan, V. et al. Pathophysiology of depression: antagonist actions of antidepressants at recombinant 908–916 (2005). role of sleep and the melatonergic system. Psychiatry

and native 5-hydroxytryptamine2C receptors: 81. Norman, T. R., Cranston, I. & Irons, J. Effect of the Res. 165, 201–214 (2009). differential modulation of cell surface expression and novel antidepressant agomelatine in the olfactory 102. Goodwin, G. M., Emsley, R., Rembry, S., Rouillon, F. signal transduction. Mol. Pharmacol. 73, 748–757 bulbectomised rat. Int. J. Neuropsychopharmacol. & Agomelatine Study Group. Agomelatine prevents (2008). 7, S461 (2004). relapse in patients with major depressive disorder

63. Berg, K. A. et al. Effector pathway-dependent relative 82. Dekeyne, A. et al. S32006, a novel 5-HT2C receptor without evidence of a discontinuation syndrome: a efficacy at serotonin type 2A and 2C receptors: antagonist displaying broad-based antidepressant 24-week randomized, double-blind, placebo-controlled evidence for agonist-directed trafficking of receptor and anxiolytic properties in rodent models. trial. J. Clin. Psychiatry 70, 1128–1137 (2009). stimulus. Mol. Pharmacol. 54, 94–104 (1998). Psychopharmacology 199, 549–568 (2008). The antidepressant properties of agomelatine are 64. Millan, M. J. et al. The novel melatonin agonist 83. Bertaina-Anglade, V., la Rochelle, C. D., Boyer, P. A. & maintained upon sustained 6 months of treatment agomelatine (S20098) is an antagonist at Mocaër, E. Antidepressant-like effects of agomelatine and it is effective in preventing relapse.

5-hydroxytryptamine2C receptors, blockade of which (S20098) in the learned helplessness model. Behav. 103. Goodwin, G., Rouillon, F. & Emsley, R. Long-term enhances the activity of frontocortical dopaminergic Pharmacol. 17, 703–713 (2006). treatment with agomelatine: prevention of relapse in and adrenergic pathways. J. Pharmacol. Exp. Ther. 84. Corbach, S., Schmelting, B., Fuchs, E. & Mocaër, E. patients with major depressive disorder over 10 months. 306, 954–964 (2003). Comparison of agomelatine and melatonin for effects Eur. Neuropsychopharmacol. 18, S338 (2009). Demonstration that agomelatine behaves as an in chronically stressed tree shrews, an animal model of 104. Montgomery, S. A., Kennedy, S. H., Burrows, G. D., antagonist at cloned, human and native, cerebral depression. Eur. Neuropsychopharmacol. 17, S364 Lejoyeux, M. & Hindmarch, I. Absence of

populations of 5-HT2C receptor. (2007). discontinuation symptoms with agomelatine and

65. Giorgetti, M. & Tecott, L. H. Contributions of 5-HT2C 85. Corbach-Söhle, S. et al. Effects of agomelatine and occurrence of discontinuation symptoms with

receptors to multiple actions of central serotonin S32006, a selective 5-HT2C receptor antagonist, paroxetine: a randomized, double-blind, placebo- systems. Eur. J. Pharmacol. 488, 1–9 (2004). in chronically-stressed tree shrews. Eur. controlled discontinuation study. Int. Clin.

66. Millan, M. J. Serotonin 5-HT2C receptors as a target Neuropsychopharmacol. 18, S348 (2008). Psychopharmacol. 19, 271–280 (2004). for the treatment of depressive and anxious states: 86. Overstreet, D. H., Pucilowski, O., Rettori, M. C., Demonstration that discontinuation of agomelatine focus on novel therapeutic strategies. Thérapie 60, Delagrange, P. & Guardiola-Lemaitre, B. Effects of treatment in major depression is not associated 441–460 (2005). melatonin receptor ligands on swim test immobility. with symptoms of withdrawal in contrast to the

67. Kennaway, D. J. & Moyer, R. W. Serotonin 5-HT2C Neuroreport 29, 249–253 (1998). SSRI paroxetine. agonists mimic the effect of light pulses on circadian 87. Weil, Z. M., Hotchkiss, A. K., Gatien, M. L., Pieke- 105. Baldwin, D. S., Montgomery, S. A., Nil, R. & Lader, M. rhythms. Brain Res. 806, 257–270 (1998). Dahl, S. & Nelson, R. J. Melatonin receptor (MT1) Discontinuation symptoms in depression and anxiety 68. Barassin, S. et al. Circadian tryptophan hydroxylase knockout mice display depression-like behaviours and disorders. Int. J. Neuropsychopharmacol. 10, 73–84 levels and serotonin release in the suprachiasmatic deficits in sensorimotor gating. Brain Res. Bull. 68, (2007). nucleus of the rat. Eur. J. Neurosci. 15, 833–840 425–429 (2006). 106. Aronne, L. J. & Segal, K. R. Weight gain in the (2002). 88. Olié, J. P. & Kasper, S. Efficacy of agomelatine, treatment of mood disorders. J. Clin. Psychiatry.

69. Varcoe, T. J. & Kennaway, D. J. Activation of 5-HT2C a MT1/MT2 receptor agonist with 5-HT2C antagonistic 64 (Suppl. 8), 22–29 (2003). receptors acutely induces Per1 gene expression properties, in major depressive disorder. 107. Serretti, A. & Chiesa, A. Treatment-emergent sexual in the rat SCN in vitro. Brain Res. 1209, 19–28 Int. J. Neuropsychopharmacol. 10, 661–673 (2007). dysfunction related to antidepressants: a meta-analysis. (2008). 89. Descamps, A. et al. Influence of the novel J. Clin. Psychopharmacol. 29, 259–266 (2009).

70. Cuesta, M., Clesse, D., Pévet, P. & Challet, E. New antidepressant and melatonin agonist/serotonin2C 108. Drago, F. & Busa, L. Acute low doses of melatonin light on the serotonergic paradox in the rat circadian receptor antagonist, agomelatine, on the rat sleep– restore full sexual activity in impotent male rats. system. J. Neurochem. 110, 231–243 (2009). wake cycle architecture. Psychopharmacology 205, Brain Res. 878, 98–104 (2000).

71. Gannon, R. L. & Millan, M. J. Serotonin1A 93–106 (2009). 109. Brotto, L. A., Gorzalka, B. B. & LaMarre, A. K. autoreceptor activation by, S15535 enhances 90. Quera-Salva, M. A. et al. Major depressive disorder, Melatonin protects against the effects of chronic circadian activity rhythms in hamsters: evaluation of sleep EEG and agomelatine: an open-label study. stress on sexual behaviour in male rats. Neuroreport

potential interactions with serotonin2A and serotonin2C Int. J. Neuropsychopharmacol. 10, 691–696 (2007). 12, 3465–3469 (2001). receptors. Neuroscience 137, 287–299 (2006). 91. Wilson, S. & Argyropoulos, S. Antidepressants and 110. Hull, E. M., Muschamp, J. W. & Sato, S. Dopamine 72. Stahl, S. M., Grady, M. M., Moret, C. & Briley, M. sleep: a qualitative review of the literature. Drugs 65, and serotonin influences on male sexual behaviour. SNRIs: their pharmacology, clinical efficacy, and 927–947 (2005). Physiol. Behav. 83, 291–307 (2004). tolerability in comparison with other classes of 92. Leproult, R., Van Onderbergen, A., L’Hermite- 111. Montejo, A. et al. Better sexual acceptability of antidepressants. CNS Spectr. 10, 732–747 (2005). Baleriaux, M., Van Cauter, E. & Copinschi, G. Phase- agomelatine (25 and 50 mg) compared with paroxetine 73. Kasper, S. & Hamon, M. Beyond the monoaminergic shifts of 24h rhythms of hormonal release and body (20 mg) in healthy male volunteers. An 8-week, hypothesis: agomelatine, a new antidepressant with temperature following early evening administration of placebo-controlled study using the PRSEXDQ-SALSEX an innovative mechanism of action. World J. Biol. the melatonin agonist agomelatine in healthy older scale. J. Psychopharmacol. 24, 111–120 (2009). Psychiatry 10, 117–126 (2009). men. Clin. Endocrinol. 63, 298–304 (2005). 112. Musazzi, L. et al. Stress increases depolarization- 74. Linnik, I. V. et al. The novel antidepressant, 93. Kennedy, S. J. & Rizvi, S. J. Agomelatine in the evoked glutamate release in the rat prefrontal/frontal

agomelatine, blocks cerebral 5-HT2C receptors treatment of major depressive disorder: potential cortex: the dampening action of antidepressants. in vivo: a phMRI challenge study in rats. for clinical effectiveness. CNS Drugs 24, 479–499 PLoS One 5, e8566 (2010). Eur. Neuropsychopharmacol. 19, S259 (2009). (2010). 113. Walker, M. P. & Stickgold, R. Sleep, memory, and 75. Papp, M., Gruca, P., Boyer, P. A. & Mocaër, E. 94. Loo, H., Hale, A. & D’haenen, H. Determination of the plasticity. Annu. Rev. Psychol. 57, 139–166 (2006). Effect of agomelatine in the chronic mild stress model dose of agomelatine, a melatonergic agonist and 114. Bruel-Jungerman, E., Rampon, C. & Laroche, S.

of depression in the rat. Neuropsychopharmacology selective 5-HT2C antagonist, in the treatment of major Adult hippocampal neurogenesis, synaptic plasticity 28, 694–703 (2003). depressive disorder: a placebo-controlled dose range and memory: facts and hypotheses. Rev. Neurosci. Using a model of anhedonia, the first evidence study. Int. Clin. Psychopharmacol. 17, 239–247 18, 93–114 (2007). that agomelatine possesses robust antidepressant (2002). 115. Eckel-Mahan, K. L. & Storm, D. R. Circadian rhythms properties that are expressed by a mechanism Pivotal study demonstrating the clinical utility of and memory: not so simple as cogs and gears.

involving both melatonergic and 5-HT2C receptors. agomelatine in the treatment of major depression. EMBO Rep. 10, 584–591 (2009).

116. Austin, M. P., Mitchell, P. & Goodwin, G. M. Cognitive 123. Heisler, L. K., Zhou, L., Bajwa, P., Hsu, J. & Tecott, L. H. Acknowledgements

deficits in depression: possible implications for functional Serotonin 5-HT2C receptors regulate anxiety-like We would like to thank J.-M. Rivet, C. Mannoury la Cour and neuropathology. Br. J. Psychiatry 178, 200–206 behaviour. Genes Brain Behav. 6, 491–496 (2007). A. Gobert for expert help with graphics; M. Soubeyran (2001). 124. Millan, M. J., Brocco, M., Gobert, A. & Dekeyne, A. and A. Dekeyne for excellent logistical assistance; L. Alliot, E. 117. Conboy, L. et al. The antidepressant agomelatine blocks Anxiolytic properties of agomelatine, and Canet, P. Delagrange and B. Renaud for helpful comments on the adverse effects of stress on memory and enables antidepressant with melatonergic and serotonergic the manuscript; and, in particular, our many, many colleagues

spatial learning to rapidly increase neural cell adhesion properties: role of 5-HT2C receptor blockade. for their efforts, dedication and skill in bringing this project molecule (NCAM) expression in the hippocampus of rats. Psychopharmacology 177, 448–458 (2005). to fruition. Int. J. Neuropsychopharmacol. 12, 329–341 (2009). 125. Papp, M., Litwa, E., Gruca, P. & Mocaër, E. 118. Castro-Costa, E. et al. Prevalence of depressive Anxiolytic-like activity of agomelatine and melatonin Competing interests statement symptoms and syndromes in later life in ten European in three animal models of anxiety. Behav. Pharmacol. The authors declare competing financial interests: see web countries, the SHARE study. Br. J. Psychiatry 191, 17, 9–18 (2006). version for details. 393–401 (2007). 126. Stein, D. J., Ahokas, A. A. & de Bodinat, C. Efficacy 119. Magnusson, A. & Partonen, T. The diagnosis, of agomelatine in generalized anxiety disorder: symptomatology, and epidemiology of seasonal affective a randomized, double-blind, placebo-controlled study. DataBases disorder. CNS Spectr. 10, 625–634 (2005). J. Clin. Psychopharmacol. 28, 561–566 (2008). OMIM: 120. Pjrek, E. et al. Agomelatine in the treatment of seasonal First demonstration of the clinical efficacy of http://www.ncbi.nlm.nih.gov/omim affective disorder. Psychopharmacology 190, 575–579 agomelatine in treating generalized anxiety Depression (2007). disorder. IUPHAR Database of Receptors and Ion Channels: 121. Schoevers, R. A., Van, H. L., Koppelmans, V., Kool, S. 127. Boivin, D. B. Influence of sleep–wake and circadian http://www.iuphar-db.org

& Dekker, J. J. Managing the patient with co-morbid rhythm disturbance in psychiatric disorders. 5-HT2C | MT1 | MT2 depression and an anxiety disorder. Drugs 68, J. Psychiatry Neurosci. 25, 446–458 (2000). 1621–1634 (2008). 128. Srinivasan, V. et al. Melatonin in mood disorders. FUrther iNForMatioN 122. Tuma, J., Strubbe, J. H., Mocaër, E. & Koolhaas, J. M. World J. Biol. Psychiatry 7, 138–151 (2006). European Public Assessment Report — Valdoxan: Anxiolytic-like action of the antidepressant agomelatine 129. Luo, A. H. & Aston-Jones, G. Circuit projection from http://www.emea.europa.eu/humandocs/PDFs/EPAR/ (S20098) after a social defeat requires the integrity of suprachiasmatic nucleus to ventral tegmental area: valdoxan/H-915-en6.pdf the SCN. Eur. Neuropsychopharmacol. 15, 545–555 a novel circadian output pathway. Eur. J. Neurosci. All links Are AcTive in THe online pDf (2005). 29, 748–760 (2009).