Carmen MUÑOZ, PhD
by C. Muñoz,France
Incompletely treated single depressive episodes pave the way for chronic depressive disorder, which has an even stronger negative impact on daily life functioning. Complete remission after a single episode can help prevent the transition to full-fledged chronic depressive disorder. To achieve complete remission, new antidepressants are needed that are capable of addressing all the residual symptoms after the depressive episode has resolved. Valdoxan, the first melatonergic antidepressant, is a totally new approach to depression since it is the first available antidepressant that incorporates a nonmonoaminergic mechanism in its mode of action and treats depression by resynchronizing circadian rhythms. Valdoxan has a novel and distinctive profile of antidepressant efficacy in the short- and long-term management of depression vs placebo as well as vs the most prominent comparators, with an early improvement of symptoms that increases continuously throughout the entire administration period, as described by both patients and doctors. Valdoxan addresses all of the symptoms of depression, including those against which other antidepressants are ineffective, and offers clinical advantages such as weight neutrality, preservation of sexual function, and absence of discontinuation syndrome. Furthermore, results fromrecent research suggest the absence of emotional blunting after remission. These properties result in a more sustained and complete remission than that observed with conventional antidepressants, thus ensuring better efficacy in the treatment of depression.
One of the major predicaments generated by depression is its contribution to the global burden of disease (GBD). With depression the 4th leading contributor to the GBD, the World Health Organization (WHO) estimated its burden in 2010 to be higher than that of cardiovascular disease and cancer.1 Community surveys consistently show that the prevalence of major depression is high, and that major depression is strongly associated with disability and impaired functioning and well-being. Depression is the leading cause of years lost to disability (YLDs). By the year 2020, depression is projected to reach 2nd place in the ranking of disability-adjusted life years (DALYs) calculated for all ages and both sexes, a position already achieved today by the age-group 15-44 years.
Depression has a major impact on quality of life and personal as well as work productivity, to the point where these have become the litmus test of antidepressant treatment efficacy. Unfortunately, conventional antidepressants often fail to achieve complete recovery and are associated with residual symptoms and high recurrence rates.2 Recent studies indicate that 2 out of 3 patients receiving a first-line treatment with a selective serotonin reuptake inhibitor (SSRI) will not achieve remission and are at risk for relapse.3 Incompletely treated single depressive episodes pave the way for chronic depressive disorder, which has an even higher impact on daily life functioning. This transition from single depressive episode to fullfledged chronic depressive disorder can occur even with mild depressive symptoms and subsyndromal depression. Thus, whatever the setting, functional remission often remains an elusive therapeutic goal.4
Failure of treatment to achieve complete remission of a depressive episode can be explained by a relative mismatch between therapeutics and the pathophysiology of the disorder, which is still only partially understood. The so-called monoaminergic hypothesis, based on the observation of the antidepressant properties of monoaminergic agents, has driven drug development and the treatment of depressed patients for nearly 60 years.5 However, in recent years, drug development has been taking a new direction in the wake of a greater awareness of the relevance of the core symptoms of depression. Thanks to its novel and distinctive profile of antidepressant action, the recently developed antidepressant agomelatine (Valdoxan) has ushered in a deeper understanding of the pathophysiology of depression (for a review see reference 6).
This article describes the biological basis for Valdoxan’s antidepressive efficacy and highlights its early benefits and additional properties. In particular, studies have shown the favorable antidepressant efficacy of Valdoxan versus SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), and how is differs from them clinically in terms of efficacy on the core symptoms of depression, which conventional antidepressants fail to adequately address. Management of depression with Valdoxan is thus much more effective in ensuring complete and sustained remission and preventing a depressive episode from evolving into major depressive disorder.
Valdoxan: a novel and distinctive profile of antidepressant action
Valdoxan, the first melatonergic antidepressant, is the first available antidepressant that incorporates a nonmonoaminergic mechanism in its mode of action, making it a truly novel approach to depression. Valdoxan is a melatonergic (MT1 and MT2) receptor agonist and a 5-HT2C receptor antagonist, which treats depression by resynchronizing the circadian rhythms that are profoundly disturbed in depressed patients.7
Circadian misalignment has recently been related to the severity of depression8 and altered expression of circadian rhythm genes has been observed in individuals with a history of depression.9 Circadian malfunction is a core feature of depression and disruption of circadian rhythms in depressed patients affects mood, behavior, and physiological and biological functions. Therefore, synchronization of circadian rhythms via pathways affecting the circadian clock and normalizing homeostatic functions promises acute and sustained symptom relief.
The resynchronizing and antidepressant properties of Valdoxan have been described in validated animal models, and previous preclinical research has demonstrated that its antidepressant efficacy is mediated by its action on both the MT1 and MT2 receptors and the 5-HT2C receptors.10 Behavioral studies, comparing Valdoxan’s effects with those of melatonin alone or 5 HT2C antagonists alone indicate that the efficacy of agomelatine is grounded in the synergy between the melatonergic (MT1 and MT2) and serotonergic (5-HT2C) receptors: Valdoxan, which acts on both types of receptors, is effective, while melatonin alone or 5-HT2C antagonists alone have no or only a partial effect.
Melatonergic and 5-HT2C receptors are located not only in the suprachiasmatic nucleus, but also in other areas of the brain involved in mood regulation, such as the hippocampus and frontal cortex,11 and the action of Valdoxan on both types of receptors, favoring their synergy, has recently been characterized at the synaptic and intracellular level in these areas of the brain: treatment with Valdoxan prevents the stress-induced increase in glutamate in rat frontal cortex, unlike melatonin alone and 5-HT2C antagonists alone.12 Similarly, Valdoxan increases the expression of brain-derived neurotrophic factor (BDNF) in rat frontal cortex13 and the survival of newly formed cells in the hippocampus,14 while melatonin alone and 5HT2C antagonists alone have no effect.
Furthermore, melatonergic receptor antagonists abolish the increases in BDNF and cell survival induced by Valdoxan, suggesting that the melatonergic component is necessary, but not sufficient, for the effects of Valdoxan. This synergy has also been observed in the expression of early genes and elements of the intracellular transcriptional pathways. Finally, Valdoxan increases neurogenesis in hippocampus and induces an early maturation of neurons.14
Figure 1. Mechanism of action of Valdoxan.
serotonin 5-HT2C receptors. The resynchronization of circadian rhythms resulting
from the synergistic action of these receptors explains the antidepressant efficacy
observed in preclinical models and clinical trials with Valdoxan. This synergy is
also the basis for the anxiolytic properties of Valdoxan, not addressed in this
article, and of other clinical benefits such as preservation of sexual functioning.
Modified from reference 16: de Bodinat et al. Nat Rev Drug Discov. 2010;9(8):
628-642). © 2010, Nature Publishing Group.
Valdoxan treatment therefore activates intercellular and intracellular elements of the brain that appear to cycle in a circadian manner13,15 and which are implicated in the pathophysiology of depression. An overview of the mechanism of the antidepressant action of Valdoxan is given in Figure 1,16 which highlights the resynchronization of circadian rhythms resulting from its unique profile of action—agonist at melatonergic (MT1 and MT2) receptors and antagonist at 5 HT2C receptors—acting in a synergistic manner.
Valdoxan: demonstrated favorable antidepressant efficacy in the short and long term
Valdoxan’s novel and original mechanism of action lends it a distinctive profile of antidepressant efficacy, which has been characterized and demonstrated versus placebo as well as versus modern antidepressants. Throughout Valdoxan’s development, studies have consistently evidenced a common denominator that constitutes its unique clinical signature: (i) early and continuous improvement in symptoms; (ii) improvement in all of the core symptoms of depression; (iii) favorable efficacy versus comparators after acute and chronic administration; and (iv) a range of clinical benefits that contribute to the complete and sustained remission observed under treatment.
_ Antidepressant efficacy versus placebo: first demonstration of early and continuous improvement
Valdoxan’s antidepressant efficacy has been demonstrated in several placebo-controlled studies. Three studies used Valdoxan 25 mg or a flexible dosing of 25 to 50 mg.17-19 These studies reported statistically significant differences vs placebo in 17-item Hamilton Rating Scale for Depression (HAMD17) scores both in the early phases in the treatment, and after the mandatory period of 6-8 weeks, where HAMD17 scores were 2.57, P<0.05; 2.30, P<0.05; and 3.44, P<0.001, respectively for the three studies. A meta-analysis of these studies evaluated the items of the HAMD scale separately and showed that the differences were statistically significant for all of the symptoms of depression: depressed mood; somatic and psychic anxiety; sleep and daytime functioning; and anhedonia, measured by the renewed interest of the patient in performing work and activities. These characteristics of Valdoxan were confirmed in a fourth study at the dose of 25 mg versus placebo,20 where from the first week of treatment the decrease in the HAMD score was significantly more important for Valdoxan than placebo (P=0.005) and remained significant throughout the mandatory period of 8 weeks (P=0.01) (Figure 2). Evaluation of the Maier subscale score showed the significant (P<0.05) improvement in core emotional depressive symptoms with Valdoxan. In all of these studies, Valdoxan was more effective than placebo with respect to the other parameters evaluated (response, remission) and the other scales used (CGI [Clinical Global Impression scale], MADRS [Montgomery-Åsberg Depression Rating Scale]).
Figure 2. Early onset of Valdoxan’s antidepressant action.
Rating Scale for Depression) score after treatment with Valdoxan 25 mg compared
with placebo in a randomized placebo-controlled study. The statistical
significance versus placebo was maintained along the whole mandatory treatment
period of 7 weeks. ITT (intention-to-treat) population, observed cases.
Modified from reference 20: Stahl et al. J Clin Psychiatry. 2010;71(5):616-626.
© 2010, Physicians Postgraduate Press, Inc.
Demonstration of efficacy in severely depressed patients is a key criterion for establishing the efficacy of any antidepressant. A pooled analysis of positive placebo-controlled studies, using incremental and nonoverlapping cutoffs of the HAMD scale at baseline from ≥25 up to ≥30, showed that the an- tidepressant efficacy of Valdoxan was maintained whatever the severity of depression with an effect that was clinically and statistically significant through all the degrees of severity (delta = 3.31, P=0.003 and delta = 4.45, P=0.025 for cutoffs of 26-27 and ≥30, respectively).21
Evaluation of relapse prevention with Valdoxan showed its efficacy in long-term treatment of up to 10 months, with nearly 8 out of 10 patients free of relapse (percentage of relapses with Valdoxan = 21.7% and 23.9% after 6 and 10 months of randomization, respectively, P<0.0001 vs placebo). This was further demonstration of the distinctive efficacy of Valdoxan, since the survival curve for the patients switched to placebo separated gradually from that of patients continuing on Valdoxan, thus indicating not only the absence of any withdrawal syndrome, but also underlining the different pharmacological action of Valdoxan compared with the survival curves obtained with monoaminergic antidepressants.22
_ Antidepressant efficacy versus comparators: confirmation of early improvement and favorable antidepressant efficacy
Valdoxan has been compared with the SNRI venlafaxine and with available SSRIs (sertraline fluoxetine, escitalopram) both in short-term and long-term treatment. The early improvement with Valdoxan 25-50 mg was observed already by the first week versus venlafaxine (75-150 mg) with an increase in daytime functioning resulting from an improvement in daytime alertness (P<0.001) and in the sensation of feeling good (P=0.001) as evaluated by visual analog scales.23 There was also nearly twice the number of responders with Valdoxan (19%) than with venlafaxine (11%, P=0.01).24 This favorable action over venlafaxine was sustained after 6 weeks (delta score of 0.32, P=0.016) and 6 months (delta = 0.32, P=0.025).6
With the SSRI sertraline, the early improvement was observed at the second week (first point of evaluation) with twice the number of responders as judged by the HAMD score (20% with Valdoxan 25-50 mg, versus 10.9%with sertraline 50-100 mg, P=0.027). These results in favor of Valdoxan were maintained throughout the rest of the study, with a difference in HAMD scores of 1.68, P=0.031 after 6 weeks and a greater number of responders after 6 months (76% for Valdoxan and 63.5% for sertraline, P= 0.017).25
A comparative trial with Valdoxan 25-50 mg and fluoxetine 20-40 mg was carried out in a large cohort of severely depressed patients (n=515). CGI scale scores evidenced an early improvement with Valdoxan after 2 weeks of treatment (delta versus fluoxetine = 0.17, P<0.035), which continued throughout the treatment. The main end point of the study was treatment efficacy after 8 weeks of treatment using the HAMD17 scale, which was shown to be greater with Valdoxan with a significant delta of 1.49, P=0.024 in favor of Valdoxan (Figure 3).26 This difference can be considered as clinically significant in view of the differences reported in placebo-controlled studies,27,28 and taking into account the fact that fluoxetine is an active comparator.
A similar delta was found in the study versus escitalopram, where 71 patients were randomly allocated to Valdoxan and 67 to escitalopram: after 6 weeks of treatment with Valdoxan 25-50 mg or escitalopram 10-40 mg, the difference in HAMD scores was 1.46, with a standard error of 1.03 in favor of Valdoxan. This clinically significant difference was also statistically significant in terms of noninferiority (P=0.002) with a predefined inferiority margin of +1.5.29
Figure 3. Comparative efficacy of Valdoxan and fluoxetine.
in a population of severely depressed patients, defined by a HAMD17 (17-item
Hamilton Rating Scale for Depression) score ≥25 and a CGI (Clinical Global
Impression)-severity of illness score ≥4 at inclusion. The mean of severity of the
included population was of was 28.6±2.6. The main criterion was the superiority
of Valdoxan over fluoxetine. Based on data from reference 26.
The favorable antidepressant efficacy of Valdoxan versus SSRIs and SNRI was confirmed in a pooled analysis of these studies. Over the 6/8-week period, a significant difference in favor of Valdoxan vs active comparators (sertraline, fluoxetine, venlafaxine, escitalopram) was observed, with a total HAMD17 score of 1.37 (P<0.001) and a higher percentage of responders (response was defined as decrease from baseline total score ≥50%) with Valdoxan (71.75%) than with SSRIs/SNRIs (64.52%), with a statistically significant (P=0.005) difference of 7.21% in favor of Valdoxan.30
Early and late clinical benefits of Valdoxan: paving the way for sustained and complete remission Valdoxan’s tolerability profile is similar to that of placebo, with dizziness (excluding vertigo) being the only adverse event occurring more frequently than with the placebo 6% vs 3.5%, respectively, in the short term-placebo-controlled safety set.6 Several isolated cases of reversible transaminase elevations were observed in 1.1% of patients treated with Valdoxan ver- sus 0.7% in patients on placebo.6 The difference was not statistically significant and the cases were not associated with any clinical signs. Nevertheless, transaminase determination is recommended at initiation of treatment and periodically thereafter. Even at important dosages, no changes were observed in other biochemical, cardiovascular, or hematological parameters. The number of patients withdrawn due to adverse events was more important with sertraline, fluoxetine, venlafaxine, and escitalopram (10.5% in pooled analysis) than with Valdoxan (6.3%).30 Other early benefits that ensure good tolerability of Valdoxan is the absence of withdrawal syndrome, as shown in a specific study versus paroxetine.31
Figure 4. Valdoxan and patient feedback.
that Valdoxan has a thorough action on all of the different facets of depression,
improving emotions and social and cognitive functioning.
Among the other long-term clinical benefits of Valdoxan are its weight neutrality and its absence of interference with sexual function. In a pooled analysis evaluating 6 months of treatment with Valdoxan or placebo, the change in baseline weight was 0.23 kg with Valdoxan and 0.24 kg with placebo.6 Lack of interference with sexual function was suggested by the low level of emergent sexual adverse events in the overall safety set during Valdoxan treatment. This was confirmed in a specific study in depressed remitted patients, in which Valdoxan showed a favorable sexual profile in comparison with venlafaxine.32 To avoid bias due to the disease, these results were corroborated by a specific study in healthy volunteers versus placebo and paroxetine: while no sexual dysfunction was reported with Valdoxan, this was not the case with paroxetine, which differed significantly (P<0.05) from placebo and Valdoxan as early as by the first 2 weeks of treatment.33
Figure 5. Valdoxan in naturalistic settings of daily clinical practice.
(selective serotonin reuptake inhibitors) or SNRIs (serotonin-norepinephrine reuptake
inhibitors) or other available antidepressants used in previous treatments.
The patients experience an early and continuous improvement over time of
their emotional, functional, and social symptoms of depression.
Modified from reference 35: Gorwood. J Psychopharmacol. 2010;24(2 suppl):
15-19. DOI: 10.1177/1359786810385490 /jop.sagepub.com. © 2010, The Author.
A recent study assessing emotional processing in healthy volunteers after treatment with Valdoxan 25 mg or placebo showed that Valdoxan improved positive affective memory, decreased subjective ratings of sadness, reduced recognition of sad facial expressions, and reduced the emotion-potentiated startle effect. These early effects on emotional processing in healthy volunteers, which were more specific that those seen with SSRIs, suggest lesser emotional blunting and detachment after remission of depression. This constitutes a distinctive advantage, since these effects, which are detrimental to the quality of life of the remitted depressed patient, are often reported with conventional antidepressant treatment.34
The properties of Valdoxan described in this review stem from its resynchronization effect on circadian rhythms, a novelmode of action that confers a distinctively unique clinical efficacy. This efficacy is observed throughout the duration of treatment, and is greater than that achieved by conventional monoaminergic antidepressants. Valdoxan is thus easier to administer for the minimum recommended 6-month duration of antidepressant treatment. Patient adherence to treatment with Valdoxan is stronger than that observed with SSRIs or SNRIs.6 Clinical experience with Valdoxan has confirmed this distinctive efficacy, since feedback from the patients shows they experience improvement in emotions and social and cognitive functioning (Figure 4) that increases continuously week after week (Figure 5)35 and is accompanied by early and late clinical benefits. The results from clinical studies show that Valdoxan ensures more sustained and complete remission than the currently available conventional antidepressants, a finding borne out in the naturalistic setting of clinical daily practice. _
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Keywords: depressive episode; Valdoxan (agomelatine); circadian rhythm; antidepressant; efficacy; pharmacological profile