Agomelatine: A novel mechanism of antidepressant ...

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European Psychiatry 23 (2008) 396e402 http://france.elsevier.com/direct/EURPSY/

Review

Agomelatine: A novel mechanism of antidepressant action involving the melatonergic and the serotonergic system Luis San a, Belen Arranz b,* b

a Department of Psychiatry, Hospital San Rafael, Barcelona, Spain Sant Joan de Deú, Serveis de Salut Mental, Antoni Pujades, 42, 08830, Sant Boi de Llobregat, Barcelona, Spain

Received 12 November 2007; received in revised form 9 April 2008; accepted 11 April 2008 Available online 25 June 2008

Abstract The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential. Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex). The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placeboecontrolled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25 mg/day, with the possibility of increasing doses to 50 mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatine’s efficacy over a longer treatment period. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: Circadian rhythms; Depression; Sleep disorders; Melatonin; Agomelatine

1. Introduction Depression accounts for 4.4% of the years lived with disability worldwide, and by 2020 is expected to be the second highest cause of morbidity [21]. The European lifetime prevalence of depressive disorders is 14%, of which 12.3% being for major depressive disorders (MDD) [1]. Depression is associated with high levels of dysfunction, and has serious consequences both for the depressed individual and for the family. Depressed patients also show poor physical health, including coronary heart disease, cerebrovascular disorders, respiratory infections and pain [54]. Despite extensive investigations, the exact neurobiological processes leading to depression and the mechanisms responsible for the therapeutic effects of antidepressant drugs are not yet completely understood. However, over the years it has * Corresponding author. E-mail address: [email protected] (B. Arranz). 0924-9338/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2008.04.002

become evident that factors beyond the monoamine deficiency/imbalance must be taken into account for the development of major depression [48]. Recently, the clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has stimulated the idea that resetting normal circadian rhythms may have antidepressant potential [55,3,56]. 2. Circadian system, melatonin and depression The circadian pacemaker or biological clock, is the site of generation of circadian rhythms and prepares the organism to anticipate the daily changes in the environment [56]. It is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus, on top of the optic chiasma. In order to remain perfectly entrained to the 24-hour cyclicity of the environment, the circadian clock uses several internal and external synchronizers that are able to modify the period and the phase

L. San, B. Arranz / European Psychiatry 23 (2008) 396e402

of circadian rhythms. The light/dark cycle is the dominant synchronizing agent for circadian rhythmicity, with light presented in the evening stimulating the human circadian pacemaker to phase-delay its rhythms, and light stimulus given in the morning producing a phase advance [28]. Circadian pacemaker regulation is also determined by neurotransmitter function and by the phase shifting effects of various chemical or pharmacological components, including melatonin (N-acetyl-5-methoxytryptamine) [4]. In most vertebrates, including humans, melatonin is synthesized primarily in the pinealocytes located in the pineal gland [29]. Secretion and action of melatonin is tightly related to seasonal cycles (longer peak in winter, shorter in summer) and to lightedark cycles (high at night, low during the day), and is thus considered to be the ‘hormone of darkness’ and the body’s chronological pacemaker or ‘Zeitgeber’ [37]. The amplitude and duration of the nocturnal melatonin peak translates photoperiodic information through activation of the MT1 and MT2 G-protein coupled melatonin receptors located in the SCN. Activation of MT1 receptors directly inhibits firing of neurons in the SCN, hence regulating the amplitude of the circadian rhythmicity, and possibly facilitating sleep promotion, whereas melatoninmediated activation of MT2 receptors is responsible for inducing phase shifts and hence involved in the entrainment of circadian rhythmicity [18]. These ‘chronobiotic’ properties of melatonin could have a significant regulatory influence over many of the body’s physiological functions [37,38]. The complex relation between the endogenous circadian pacemaker and the appearance of depressive symptoms is far from being elucidated [49]. Depression seems to be related with a disruption in the central circadian clock function and not to an alteration in a specific rhythm. In addition, the type of rhythm abnormality seems to be highly variable in depressed patients, including phase advance or phase delay of rhythms and increase or decrease in the rhythm amplitude. Circadian amplitude reduction of temperature, thyroid-stimulating hormone, norepinephrine and motor activity seems to be the most relevant chronobiological abnormality in depression [50]. A phase advance of the rhythm of cortisol, adrenocorticotropin, prolactin and growth hormone secretion have also been noted in depressed patients [51]. Literature regarding melatonin levels in depression remains controversial. Reduced blood melatonin concentrations and a trend toward a phase delay of melatonin rhythms have been reported in several affective disorders [7,39,8], suggesting that antidepressant efficacy could be related to melatonin secretion through monoaminergic mechanisms [40]. However, the lack of melatonin disturbances noted in other studies [9] would point out to the increase in melatonin being related to the pharmacological effect of antidepressants and not to the improvement of depressive symptoms. Administration of melatonin to depressed patients has been shown to generally improve sleep, with little effect on depressive symptoms, and does not substantially enhance the effect of existing antidepressant therapies in patients with treatment-resistance depression [13]. It appears then that melatonin is not sufficient on its own to achieve a robust clinical antidepressant efficacy.

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3. Agomelatine 3.1. Mechanism of action Agomelatine, a naphthalene analog of melatonin, is a newly developed selective agonist of the human cloned melatonergic MT1 (KI ¼ 0.1 nM) and MT2 (KI ¼ 0.12 nM) receptors [30]. In comparison with melatonin, agomelatine shows a longer half-life and a comparatively greater affinity for MT1 and MT2 melatonin receptors both in the SCN and in other brain areas [14]. Furthermore, when administered in the evening to rats with chronic mild stress, both agomelatine and melatonin show antidepressant-like activity, but only agomelatine exhibits antidepressant-like activity when administered in the morning [41]. Agomelatine also shows serotonin 5-HT2C (pKi ¼ 6.2 mM) receptor antagonist activity [30]. This effect on the serotonergic system, although initially regarded as unnecessary and possibly undesirable, has conferred agomelatine an additional value as anxiolytic and antidepressant. Blockade of the 5-HT2C receptors is suggested to be implicated in the antidepressant profile of agomelatine, as increased sensitivity of 5HT2C receptors have been noted in depressed patients, and a correlation between the therapeutic actions of antidepressants and a reduced number of 5-HT2C receptors has also been reported [45]. Although the role of the different receptor activities of agomelatine in relation to its antidepressant action has not been fully elucidated, it seems that this compound could act synergistically on both the melatonergic and the 5-HT2C receptors [41]. Evidence favouring this hypothesis is based on the fact that melatonergic and 5-HT2C receptors are expressed both in the SCN and in brain areas involved in the pathophysiology of depression, such as the cerebral cortex, hippocampus, amygdala and thalamus. In addition, both the MT1 and the 5-HT2C receptors show circadian fluctuations, with the MT1 melatonergic receptor being regulated by both light and the biological clock [31], and the 5-HT2C receptor being the only 5HT receptor exhibiting a circadian rhythm of expression [19]. Selective 5-HT2C antagonism has been shown to prevent the inhibitory effects of light on melatonin synthesis [22], while 5-HT2C agonists seem to inhibit melatonin production [23]. Furthermore, in vivo data indicate that agomelatine enhances the levels of dopamine and noradrenaline in frontal cortex, but not in nucleus accumbens or striatum, probably secondary to blockade of the inhibitory input of 5-HT2C receptors to cortical dopaminergic and adrenergic pathways [58]. It does not show significant affinity for muscarinic, histaminic, adrenergic, noradrenergic, dopaminergic or for any of the monoamine transporters [15]. Unlike other antidepressants, agomelatine is devoid of activity at the 5-HT1A receptor [20]. 3.2. Preclinical studies In animals, agomelatine mimics the actions of melatonin in the synchronization of circadian rhythm patterns in rodents

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[42]. It resynchronizes circadian rhythms in animal models of delayed sleep-phase syndrome [46], restores the phase shifts [52], and resynchronizes circadian rhythms in free-running rats kept in constant darkness [32]. Agomelatine also seems to influence daily patterns of locomotor activity, runningwheel activity and fluctuations in body temperature [52]. These behavioural effects of agomelatine do not seem to be associated with changes in hypothalamic-pituitary-adrenal axis activity [5]. Resynchronization of circadian rhythms in animals appears to occur following brief exposure to agomelatine, an effect that is consistent with its short half-life (1e2 h), while prolonged exposure is much less effective [42]. Agomelatine has shown anxiolytic properties in animal models of anxiety [37], including the elevated plus maze paradigm, the Vogel conflict test and social defeat, and may, therefore, be expected to have putative benefit in the treatment of anxiety disorders [33,43]. Unlike agomelatine, the anxiolytic effects were seen independently of the time of day of its administration [16]. Given that pre-treatment with a selective melatonergic antagonist blocked the anxiolytic effect of agomelatine in the evening but not in the morning, it has been postulated that this anxiolytic effect is related to both the melatonergic agonism and the 5-HT2C antagonistic property. Agomelatine has demonstrated antidepressant properties in animal models of depression, including learned helplessness, chronic mild stress, forced swimming and psychosocial stress model in tree shrews [58], with the antidepressant-like activity of agomelatine being superior to that of melatonin [41]. Agomelatine also seems to increase cell proliferation and neurogenesis in the ventral dentate gyrus of the hippocampal formation, a region implicated in the response to anxiety and emotion. 3.3. Clinical studies In a double-blind, placeboecontrolled, cross-over study in elderly healthy men, agomelatine 50 mg/day significantly phase-advanced the 24-hour profiles of body temperature, cortisol and thyroid-stimulating levels at the end of a 15-day treatment period and stimulated growth hormone secretion and prolactin levels during the wake period [25]. In polysomnographic investigations, however, normal sleep patterns were unchanged in this non-depressed study population. One of the possible explanations for this effect may lay in agomelatine antagonizing the 5-HT2C receptor, which has been involved in circadian rhythm resynchronization [53] and in mood regulation [17,57]. 4. Efficacy of agomelatine The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placeboe controlled studies [26,24,36] (Table 1). All the studies have demonstrated agomelatine to be efficacious in MDD at the standard dose of 25 mg/day, with the possibility of increasing doses to 50 mg/day in those patients with insufficient

improvement. The primary outcome for efficacy in these studies was change in the 17-item HDRS score from baseline. Secondary measures included the MADRS, the CGI-S score, number of responders and remitters, and time to first response. End-points were assessed in the intention-to-treat (ITT) population using the last observation carried forward (LOCF) analysis in the observed case population. In all these measures, there was a difference from placebo, favourable to agomelatine, including the most severely depressed patients. This difference was already evident at the second week of treatment. The most recent double-blind study [36] differed from the standard double-blind, flexible-dose study in that the criteria for insufficient response were defined centrally using a novel interactive voice response system (IVRS) protocol and not disclosed to physicians, meaning they were unaware of whether their patients had received a dose-adjustment or not, further reducing the confounding effect of physician expectation on treatment outcomes. In addition, the allocation of placebo patients to a ‘mock’ dose-adjusted arm allowed comparison between agomelatine and placebo to be made in patients not exhibiting a pronounced placebo response. Placebo-treated patients were twice as likely to meet criteria for non-response at week 2 than those patients treated with agomelatine ( p < 0.001). However, one limitation of the study by Olie´ and Kasper [36] is that no circadian marker was analyzed to investigate the contribution of the regulation of circadian rhythms to the mode of action of agomelatine. An ongoing study where actigraphy and other circadian parameters are measured after treatment with agomelatine has been recently designed to confirm this hypothetical mode of action. A recent meta-analysis with pooled data from these three studies was conducted to investigate the effectiveness of agomelatine in severe depression [34]. The study confirmed that agomelatine was effective in the most severe subgroup of depression, with a large magnitude of the agomelatinee placebo difference with increasing symptom severity. There is also preliminary evidence from an open-trial that agomelatine added to lithium or valproate rapidly reversed bipolar depression, supporting further investigation of agomelatine in bipolar disorder [10]. 5. Tolerability of agomelatine Agomelatine has been shown to have a good acceptability and safety profile [26,24,36] (Table 2). In these short-term studies, the percentage of patients treated with agomelatine 25e50 mg/day reporting at least one emergent adverse event was low, as were the number of adverse events during the treatment period, which was comparable to placebo. Treatment emergent adverse events were reported as mild to moderate, mainly occurred within the first 2 weeks, were usually transient and did not require any intervention. The most common emergent adverse events were headache, nausea and fatigue. Clinically relevant changes in body weight or serotonergic syndrome were not observed. No effect on sexual dysfunction was observed for agomelatine and its cardiovascular


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Table 1 Efficacy of agomelatine Study

Design

Comparator

Duration Clinical sample

Loô, 2002 [26]

Randomized, Agomelatine 8 weeks double-blind, (1, 5 and 25 mg/day) placeboecontrolled vs paroxetine (20 mg/day) and placebo

Age and sex

Outcome

711 MDD or bipolar 42.3 years; Primary outcome: II patients 66,5% female Agomelatine 25 mg/day more effective (HAM-D22). than placebo ( p ¼ 0.037). 33.5% severely Subgroup with HAM-D25: only patients treated with agomelatine 25 mg/day depressed (HAM-D 25) differed from placebo. Paroxetine not different from placebo. Secondary outcome: More responders in patients treated with 25 mg agomelatine (61.5%) as compared with placebo (46.3%). Remission rates better for agomelatine 25 mg (30.4%) and paroxetine (25.7%) than for placebo (15.4%). Improvements at end-point on MADRS and HAM-A with agomelatine 25 mg and paroxetine better than placebo.

Kennedy and Randomized, Agomelatine Emsley, double-blind, 25 mg/day or 2006 [24] placeboecontrolled placebo. Blind dose increased to agomelatine 50 mg/day at 2 weeks if insufficient improvement

6 weeks

212 MDD (HAM-D > 22)

42.5 years; Primary outcome: 60.2% female Patients on agomelatine 25 or 50 mg/day show a significantly lower HAM-D score at end-point compared with placebo ( p ¼ 0.026). Subgroup with HAM-D25: greater improvement in HAM-D with agomelatine than with placebo ( p ¼ 0.024). More responders to agomelatine than to placebo (48.7 vs 30.7%). Faster time to response ( p ¼ 0.006). Secondary outcome: More responders to agomelatine than to placebo (49.1% vs 34.3%; p ¼ 0.03). No differences in remission rates.

Olie´ and Kasper, 2007 [36]

6 weeks

238 MDD

45 years; Primary outcome: 73.5% female Patients on agomelatine 25 or 50 mg/day show a significantly lower HAM-D score at end-point compared with placebo ( p < 0.001). Secondary outcome: More responders to agomelatine than to placebo (54.3% vs 35.3%).

Randomized, Agomelatine double-blind, 25 mg/day or placeboecontrolled placebo. Blind dose increased to agomelatine 50 mg/day at 2 weeks if insufficient improvement

safety was comparable to placebo. Laboratory parameters did not show any evidence of liver or kidney disease. Mean heart rate and blood pressure remained unchanged. In general, the rate of discontinuation of treatment due to adverse events was similar in patients on agomelatine 25 or 50 mg/day to those receiving placebo. Discontinuation symptoms were assessed in one doubleblind, placeboecontrolled report involving 192 patients receiving either agomelatine 25 mg/day or paroxetine 20 mg/ day [35]. Discontinuation symptoms were measured 1 and 2 weeks after abruptly stopping 12 weeks of treatment. No statistically significant difference in the number of emergent discontinuation symptoms was seen 1 or 2 weeks after treatment interruption between patients discontinuing agomelatine and those continuing agomelatine. Thus, in comparison to other antidepressants, agomelatine seems to have a considerably

lower risk of discontinuation symptoms after abrupt tapering as, for example, occurs with noncompliant patients. 6. Agomelatine and sleep Sleep disturbances are among the most prevalent symptoms and physical signs of depression, as approximately 80% of hospitalized patients and 70% of outpatients with major depression report difficulties in initiating and maintaining sleep, as well as early awakening [6]. Several studies have demonstrated that sleep disturbance is one of the most important predictors of a new or remitting depressive episode, and that a stable sleepewake rhythm is essential in the prevention of relapse in remitted depressed patients [11]. The circadian system plays an important role in the control of the timing of sleep onset and offset, and the distribution of REM sleep


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Table 2 Main emergent adverse events of agomelatine with respect to placebo Study Adverse event

Loo et al. (2002) [26]

Kennedy and Emsley (2006) [24]

Olie´ and Kasper (2007) [36]

Headache Anxiety Abdominal pain Diarrhea Nausea Somnolence Depression Insomnia Palpitations Chest tightness Decreased appetite Pruritus Fatigue Dry mouth Dizziness Rhinitis Upper respiratory tract infection

¼ ¼ þ þ ¼ Not Not Not Not Not Not þ ¼

Not Not Not Not þ þ þ þ

Not Not Not Not Not Not Not Not Not Not þ þ ¼

reported reported reported reported reported reported

reported reported

reported reported

reported reported reported reported reported reported reported reported reported reported

þ: Higher frequency than the placebo group. : Lower frequency than the placebo group. ¼: Equal frequency than the placebo group.

[49]. Several polysomnographic abnormalities have been observed in depressed patients, with increased REM density apparently being the most reliable sleep marker for depression [47]. Several studies have reviewed the effects of agomelatine on human sleep and the circadian rhythm. In the first study [12], a single-dose of agomelatine (5 or 100 mg before bedtime) given to 6 healthy non-depressed men caused a significant increase in REM sleep with no effect on other stages of sleep. In the study by Loo et al., [26], somatic complaints and symptoms related to sleep disturbances substantially decreased in the agomelatine group. Leproult et al [25] performed a randomized, double-blind, placeboecontrolled study in 8 healthy non-depressed older men. Following evening administration of 50 mg agomelatine for 15 days, a phase advancement of between 1.5e2 h was noted for body temperature and cortisol secretion, together with increased growth hormone secretion during the wake period. Total sleep time and sleep stages were not significantly affected. Lopes et al. [27] reported on the effect of 42 days of treatment with agomelatine 25 mg/ day on the cyclic alternating pattern (CAP) in non-REM sleep in 15 depressed patients. A significant decrease in CAP time and CAP cycle after 7 and 42 nights of treatment with agomelatine compared with the baseline night was noted. A recent open study evaluated the effect of agomelatine on sleep architecture in patients suffering from major depressive disorder [44]. Fifteen outpatients with a baseline HAM-D score >/¼ 20 were treated with 25 mg/day agomelatine for 42 days. Polysomnographic studies were performed at baseline, day 7, day 14, and day 42. Sleep efficiency, time awake after sleep onset and the total amount of slow-wave sleep (SWS) increased at week 6. The amount of SWS decreased throughout the first four sleep cycles from day 7 and delta ratio

increased from day 14 onwards. No change in rapid eye movement (REM) latency, amount of REM or REM density were observed. In conclusion agomelatine seems to reduce sleep latency, improve sleep continuity and quality and normalizes the distribution of SWS sleep and delta power throughout the night. These effects of agomelatine on sleep and circadian rhythms have been attributed to its agonist activity at MT1 and MT2 receptors [38,58]. 7. Conclusions Agomelatine is an antidepressant with an entirely novel mechanism of action, as its activity is not based on classical mechanisms, such as inhibition of monoamine reuptake or metabolism [2]. The antidepressant activity of agomelatine is based on its agonism at melatonergic receptors and antagonism at 5-HT2C receptors and its main innovation lies in its chronobiotic effects on the circadian system. Agomelatine is an effective antidepressant, with similar response and remission rates to several other antidepressants. Increasing the dosage from 25 mg/day to 50 mg/day seems to be effective in treating patients with refractory depression. Agomelatine presents a good acceptability and safety profile. Agomelatine has a significant impact on the sleep of patients with MDD, with a positive effect on the subjective reports of sleep quality and a shortening of sleep latency. It also affects sleep architecture and improves the stability of non-REM sleep. These changes in sleep patterns seem to occur as early as the first week of treatment and precede the changes in HAM-D score. Despite the promising data provided in the double-blind studies, the current published data on agomelatine are somewhat limited. Published information on efficacy and tolerability is only available from short-term trials. Therefore, further studies are needed to examine agomelatine’s efficacy over a longer treatment period. The effectiveness of agomelatine in elderly patients and in subjects younger than 18 should also be investigated. References [1] Alonso J, Angermeyer MC, Lepine JP. The European study of the Epidemiology of mental disorders (ESEMeD) project. Acta Psychiatr Scand 2004;420:5e7. [2] Agid Y, Buzsaki G, Diamond DM, Frackowiak R, Giedd J, Girault JA, et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov 2007;6:189e201. [3] Boivin DB. Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. J Psychiatry Neurosci 2000;35:446e58. [4] Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 2002;21:6405e12. [5] Barden N, Shink E, Labbe´ M, Vacher R, Rochford J, Mocae¨r E. Antidepressant action of agomelatine (S 20098) in a transgenic mouse model. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:908e16. [6] Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders. A meta-analysis. Arch Gen Psychiatry 1992;49:651e68. [7] Claustrat B, Chazot G, Brun J, Jordan D, Sassolas G. A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression. Biol Psychiatry 1984;19:1215e28.

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