Valdoxan: antidepressant efficacy at all time phases of treatment

Carmen MUNOZ, PhD
Division of Medical
Servier International
Suresnes, FRANCE

Valdoxan: antidepressant
efficacy at all time phases
of treatment

by C. Munoz,France

An optimal management strategy in depression to achieve good and complete remission must take into consideration the different time phases of treatment of the disease; from acute short-term treatment, to themaintenance of efficacy phase. Conventional antidepressant treatments have not yet succeeded in achieving this optimal management. Thus, exploration of the relationship between time, rhythmicity, and depression was considered a novel approach to optimizing depression therapy. Valdoxan is amelatonergic MT1/MT2 receptor agonist and a 5-HT2C receptor antagonist, and it responds to the temporal aspects of depression on two levels: in its approach to the pathophysiology of the disease, through the restoration of circadian rhythms, and by providing clinical efficacy at all time phases of depression treatment. Clinical studies have tested the antidepressant efficacy of Valdoxan 25-50 mg at the different time phases versus placebo, selective serotonin reuptake inhibitors (fluoxetine, sertraline), and a serotonin noradrenaline reuptake inhibitor (venlafaxine). Valdoxan has shown earlier symptomimprovement compared with placebo, venlafaxine 75-150 mg, and sertraline 50-150 mg, with twice the number of responders as venlafaxine and sertraline. Three pivotal studies have evidenced Valdoxan’s efficacy versus placebo after 6 to 8 weeks on all core symptoms of depression, as well as its superiority to venlafaxine (Clinical Global Impression [CGI]), sertraline (Hamilton Rating Scale for Depression [HAM-D] and CGI), and fluoxetine 20-40 mg (HAM-D and CGI), including in severely depressed patients. After 6 to 10 months of treatment, Valdoxan has been shown to maintain its efficacy, with nearly 8 out of 10 patients free of relapse compared with placebo in a specific maintenance study (P<0.0001), and with superior efficacy to venlafaxine or sertraline. Together, these results demonstrate the early symptomatic improvement, the good efficacy rate, and the prevention of relapse with Valdoxan. Valdoxan is thus able to address the different time phases of depression with unique efficacy, thanks to its novel mechanism of action, by restoring the regulation of circadian rhythms, much altered in depression.

Medicographia. 2010;32:171-177 (see French abstract on page 177)

At the beginning of the 1950s, the exploration for mechanisms to treat depression looked simply at increasing the levels of neurotransmitters in the brain. This gave rise to the conventional monoaminergic antidepressants: monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, etc. All of these, however, address depression with varying degrees of side effects and interactions that compromise their use, as well as being characterized by delayed onset of action and incomplete remission.

Figure 1
Figure 1. Receptor profiles of antidepressant drugs.

Compared with other available antidepressants, Valdoxan has a novel pharmacological profile: it is the only antidepressant with an affinity for melatonergic receptors.
Binding studies indicate that Valdoxan has negligible affinity for α- or β-adrenergic, histaminergic, cholinergic, dopaminergic, or GABAergic (gamma-aminobutyric acid) receptors, and monoaminergic transporters. This innovative profile also accounts for the product’s efficacy and good tolerability. ACh, acetylcholine; TCA,
tricyclic antidepressant; A+, agonist; A–, antagonist; ,desensitization; +, reuptake inhibition.
Adapted from reference 16: Racagni G, Popoli M. Int Clin Psychopharmacol. In Press.

It was becoming increasingly clear that a new pharmacological approach was needed to optimize antidepressant treatment. Exploration of the relationship between depression, temporality, and rhythmicity offered a novel basis from which to approach optimization of therapy. Temporality and rhythmicity are markedly disturbed in depression, not only in terms of patient perception of time, but also in biological, physiological, and emotion events, which become erratic and desynchronized, in particular in severe depression and bipolar disorders. Positive mood components are flattened and delayed, and themood fluctuations increase with the severity of depression.1,2 There is compelling evidence that circadian rhythms are disrupted in depressed patients and that circadian factors may cause depression.3 Affective disorders have been related to circadian rhythms for decades. David Kupfer’s group at the University of Pittsburgh put forward the zeitgeber theory of depression in 1988.4 This approach is being increasingly revisited today. The recent observation of a positive correlation between sleep phase delay and depressive symptom severity has confirmed the relationship between circadian disturbances and depressive disorder in nonseasonal depression.5,6

These recent and historical findings support the hypothesis that circadian abnormalities are a core component of depression. Thus, resynchronizing rhythms via pathways involving the circadian clock and thus normalizing biological homeostasis promises to provide acute and sustained symptom relief, and prevent relapse over the long term. Valdoxan (agomelatine), the first melatonergic antidepressant, acts by regulating circadian rhythms, and its efficacy has been demonstrated versus both placebo7-9 and conventional antidepressants representing the monoamine hypothesis.10-12

A mode of action based on the resynchronization of time in depression

Valdoxan, a new pharmacological approach to depression, is an agonist at melatonergic MT1 and MT2 receptors and an antagonist at 5-HT2C receptors.13-15 It has negligible affinity for all other central receptors and transporters (Figure 1).16 It does not influence brain serotonin levels as with SSRIs, SNRIs, or TCAs. This unique receptor profile enables Valdoxan to resynchronize circadian rhythms and show antidepressant efficacy in appropriate adapted validated animal models. The ability to regulate circadian rhythms has been replicated in healthy volunteers, in whom Valdoxan phase-advances such rhythms as body temperature, cortisol, and endogenousmelatonin release,17,18 and in depressed patients, in whom it regulates the sleep-wake cycle, advances the time to minimum heart rate, and improves the rest/activity cycle.19,20

Preclinical research has shown that the antidepressant efficacy of Valdoxan involves melatonergic as well as 5-HT2C receptors. Both are key players in circadian regulation and depression. Synergy between the two types of receptors has been hypothesized as accounting for Valdoxan’s mode of action. The most recent data21-23 show that Valdoxan decreases stress-induced glutamate release in the prefrontal cortex, upregulates the expression of trophic factors (such as brainderived neurotrophic factor [BDNF]), also in the prefrontal cortex, and increases the survival of newly formed neurons in rat hippocampus. The fact that these effects are not mimicked by melatonin or 5-HT2C antagonists alone supports the hypothesis of synaptic and intracellular signaling synergy in accounting for Valdoxan’s mode of action.

Antidepressant efficacy of Valdoxan at all time phases of treatment

Any successful management strategy in depression must take into account another important temporal dimension of depression and its treatment, namely the successive phases and their specific requirements. Efficacy has to be sustained over the acute phase, which requires an early response, the continuation phase, in which the aim is to prevent relapse, and the maintenance phase, where the object is to prevent the recurrence of further episodes.24 Optimization of the management strategy to achieve efficacy in all three phases can ensure complete and sustained remission. Valdoxan not only reorganizes circadian biological rhythms in depressed patients; in doing so, it also takes into account the temporal dimension of depression and its treatment, enabling clinicians to meet the phase-specific requirements that hold the key to complete remission.

_ Acute-phase efficacy: early improvement
A major problem in treating depression is the delayed onset of antidepressant action that limits the rate of response in the acute treatment phase. Patients showing symptom improvement after treatment for 2 weeks are most likely to be responders.25,26 In other words, early improvement is a highly sensitive predictor of stable response and symptom remission. Initial assessment at the end of this 2-week period in studies with Valdoxan already shows a separation from placebo in the response to Valdoxan.7,8 But clinical improvement on Valdoxan actually starts earlier, within 1 week, significantly faster than on the comparator, venlafaxine10: Valdoxan 25-50 mg was superior in regulating the sleep-wake cycle, as shown by improvement in the ease of getting to sleep (P=0.007) and sleep quality (P=0.015); this was accompanied by an increased sense of feeling good (P<0.001) and improved daytime alertness (P<0.001). This improvement after the first week is so important that even clinicians felt patients were much better on Valdoxan than on venlafaxine: this was reflected by the response rate on the Clinical Global Impression Improvement (CGI-I) scale, which was double that of patients on venlafaxine (19% versus 9%; P<0.01); the difference in score was 0.39, and the 95% confidence interval (CI) was 0.20-0.58 (P<0.0001). A polysomnography study performed in depressed patients objectively confirmed early regulation of the sleep-wake cycle by Valdoxan, showing reorganization of slow-wave sleep during the night from the first week of treatment (P=0.009).19 In another clinical study, versus sertraline 50-100 mg, Valdoxan 25- 50 mg significantly improved the rest/activity cycle after treatment for 1 week (P=0.01). The first evaluation on the Hamilton Rating Scale for Depression (HAM-D), after treatment for 2 weeks, showed twice the number of responders among patients treated with Valdoxan than with sertraline (20% versus 10.9%, P=0.027).20 This result is especially important in light of the recent publication by Cipriani et al, which concluded that of the new-generation antidepressants, sertraline was the best choice when starting treatment for depression.27

_ Continuation-phase efficacy after the acute treatment phase
Valdoxan showed antidepressant efficacy versus placebo after 6-8 weeks on the HAM-D and CGI scales in the overall populations of three pivotal studies.7-9 A key issue in demonstrating antidepressant efficacy is the effect in patients with severe depression. Valdoxan has shown efficacy versus placebo in the severely depressed subpopulation, with a maintenance of this efficacy, regardless of symptom severity at inclusion.28 The aforementioned superiority over venlafaxine and sertraline observed in the initial treatment weeks was confirmed after the end of the acute phase of depression. In the study of Valdoxan versus venlafaxine,10 after treatment for 6 weeks, the differences in CGI-I scores were significantly in favor of Valdoxan (Δ=0.32; 95% CI, 0.06-0.58; P<0.05). In the sertraline study, again after treatment for 6 weeks, total scores on the three evaluation scales also differed significantly in favor of Valdoxan: HAM-D (Δ=1.68; 95% CI, 0.15-3.20; P=0.031), CGI-I (Δ=0.29; 95% CI, 0.04-0.54; P=0.023), and CGI Severity (CGI-S; Δ=0.28; 95% CI, 0.01-0.56; P=0.043) (Figure 2, page 174), thus demonstrating the convergence between clinical assessment and the specific measuring instruments.11,20 A specific study in more severely depressed patients showed the superiority of Valdoxan versus fluoxetine 20-40 mg, with a difference in total HAM-D scores of 1.49 (95% CI, 0.020- 2.77; P=0.024) and a trend toward a higher responder rate for Valdoxan (71.7% versus 63.8%; P=0.06).12

A meta-analysis of pooled studies versus comparators showed the significantly superior efficacy of Valdoxan after treatment for 6-8 weeks compared with venlafaxine, sertraline, and fluoxetine, with differences of 1.35 in total HAM-D scores (P<0.001) and 0.25 in CGI-I scores (P<0.001). The percentage of responders on both scales was also significantly superior with Valdoxan than with the monoaminergic antidepressants (HAM-D: 72.6% vs 65.1%; P=0.007, and CGI I: 82.2% vs 73.6%; P<0.001).29

_ Sustained efficacy of Valdoxan: the maintenance phase
Valdoxan offers stable protection in the maintenance phase, as demonstrated in a relapse prevention study in which responders to Valdoxan 25-50 mg were then randomized to remain on Valdoxan or switch to placebo. After treatment for 6 months, the relapse rate on Valdoxan was 21.7% versus 46.6% on placebo (P<0.0001) (Figure 3).30 In other words, eight out of ten patients remain relapse-free on Valdoxan, regardless of depression severity.30 Similar results were observed for patients continuing in the Valdoxan and placebo arms up to 10 months.31 Relapse rates on Valdoxan at both time points were less than half those on placebo. The Valdoxan and placebo survival curves only begin to separate at a late time point, 6 to 10 weeks after the discontinuation of Valdoxan to placebo, confirming the previously described lack of withdrawal effect after abrupt cessation of Valdoxan treatment.32

Figure 2
Figure 2. Antidepressant
efficacy of Valdoxan 25-50 mg
(n=150) compared with
sertraline 50-100 mg (n=156)

after treatment for 6 weeks.
Final scores on the three evaluation
scales used—Hamilton Rating Scale for
Depression (HAM-D), Clinical Global
Impression Improvement (CGI-I) scale,
and Clinical Global Impression Severity
(CGI-S) scale—showed significant differences
in favor of Valdoxan.
After reference 20: Kasper S, Hajak G,
Wulff K, et al. J Clin Psychiatry. In Press.

Valdoxan shows superior maintenance of efficacy to venlafaxine and sertraline.33 The 6-month extensions of the aforementioned head-to-head studies showed a significant difference in total scores on the CGI-I scale of 0.32 (95% CI, 0.04-0.60; P<0.05) versus venlafaxine, and a superior percentage of responders on the HAM-D scale than with sertraline (76% vs 63.5%; P<0.05). Overall, these results demonstrate the superiority of Valdoxan in all phases of depression management versus venlafaxine, sertraline, and fluoxetine (Figure 4).

Figure 3
Figure 3. Efficacy of Valdoxan in relapse prevention.

The cumulative relapse rate over a 6-month treatment period was significantly lower on Valdoxan than on placebo (P<0.0001; log rank test). Almost 8 out of 10 patients were relapse-free on Valdoxan. After reference 30: Goodwin GM, Emsley R, Rembry S, Rouillon F. J Clin Psychiatry. 2009;70:1128-1137. Copyright © 2009, Physicians Postgraduate Press, Inc.

Patient benefits

Adherence is essential if treatment is to be adequate. Valdoxan meets the requirements for maximizing adherence, with excellent compliance in all phases of treatment thanks to the powerful efficacy and benefits that patients can perceive at the start of treatment, during the continuation phase, and during maintenance of treatment. The key to early symptom improvement lies in a unique property that Valdoxan shares with no other available antidepressant: the ability to regulate the sleep-wake cycle with an early sense of increased wellbeing and improved daytime alertness. Furthermore, improvement is accompanied from the early to the late stages of treatment by mild to moderate side effects similar to placebo, such as headache, nausea, dizziness, somnolence, and back pain. Dizziness is the only side effect that occurs significantly more than on placebo, but it occurs in around 5% of patients. Valdoxan has shown no impact on heart rate or blood pressure in clinical studies. Isolated, reversible, and statistically nonsignificant cases of enzyme elevation have been reported (in 1.1% of patients on Valdoxan versus 0.72% on placebo). Thanks to its unique profile, Valdoxan is devoid of the emergent side effects seen with conventional antidepressants. Indeed, clinical studies have confirmed that it is better tolerated than SSRIs or SNRIs,7,10,34 with less patients withdrawn due to emergent adverse events with Valdoxan (6.5%) than with venlafaxine, sertraline, and fluoxetine (10.9%).29

Valdoxan is also free of discontinuation symptoms, as shown not only by specific in-study questionnaires, but also in a specific trial versus paroxetine using the Discontinuation Emer- gent Signs and Symptoms checklist. After 1 week of discontinuing Valdoxan, patients were free from emergent adverse events, whereas after 1 week of discontinuing paroxetine, patients experienced significantly more discontinuation symptoms than those continuing on paroxetine (P<0.001).32

Figure 4
Figure 4. Time course of
the management of major
depressive disorder and effects
of Valdoxan compared with
selective serotonin reuptake
inhibitors and serotonin norepinephrine
reuptake inhibitors.

Valdoxan provides earlier, higher,
and more sustained efficacy through
the different treatment phases.
Red broken lines = potential relapse
Abbreviations: CGI, Clinical Global Impression;
HAM-D, Hamilton Rating
Scale for Depression; SNRI, serotonin
norepinephrine reuptake inhibitor; SSRI,
selective serotonin reuptake inhibitor.

The two key side effects of conventional antidepressants that seriously compromise long-term treatment adherence are weight gain and sexual dysfunction. Most conventional antidepressants, most noticeably TCAs and mirtazapine, induce short-term weight gain.35,36 In the long term, SSRIs are associated with weight gain.37 A recent epidemiological study speculated that weight gain may be one of the factors responsible for the increased risk of diabetes associated with current antidepressant therapy.38 Valdoxan, on the other hand, has no detectable impact on body weight, as shown by the overall 6-month safety data: the mean change from baseline was 0.23 kg versus 0.24 kg on placebo.33

Sexual dysfunction is a common side effect of antidepressants, and has been cited as one of the most common reasons for premature drug discontinuation.39 Patients treated with Valdoxan, on the other hand, report few sexual side effects, and these are similar to those reported on placebo. Two studies have been conducted to evaluate the effect of Valdoxan on sexual function. In the first, Valdoxan 50 mg was found to better preserve sexual function in remitted depressed patients than venlafaxine 150 mg, both on preorgasm and orgasmmeasures.34 The second study was conducted in healthy volunteers, as the therapeutic effect of drugs on mood in depressed patients can partially mask concomitant undesirable effects on sexual function. The results of this study corroborated those of the first study: Valdoxan (25 or 50 mg) respected sexual functioning, whereas it was impaired with paroxetine 20 mg.40 The combination of superior efficacy with the absence of weight gain and sexual dysfunction with Valdoxan accounts for the higher level of adherence as assessed after 6 months: a meta-analysis of studies versus active comparators revealed that the proportion of patients completing the studies was significantly superior with Valdoxan (69.4% versus 61.5%; P<0.05).33


Valdoxan addresses the different time phases of depression with unique efficacy, superior to that of the SSRIs and SNRIs. Valdoxan offers faster improvement after 1-2 weeks, higher efficacy after 6-8 weeks, and sustained efficacy after 6 months. Its mechanism of action is unique: by acting synergistically at melatonergic and 5-HT2C receptors, Valdoxan reorganizes the disturbed circadian rhythms of depressed patients, thus ensuring homeostatic efficacy in depression. Its efficacy in depression provides the patient with early clinical benefits and ensures a better quality of remission.

Valdoxan was approved by the European Medicines Agency (EMEA) at the beginning of 2009. The EMEA has endorsed the properties of Valdoxan in the Summary of Product Characteristics, acknowledging its unique receptor profile, phaseshifting properties, and antidepressant efficacy (whether in the short term or in the maintenance phase, and in severely depressed subpopulations), together with improvement of symptoms from the first week and other clinical benefits such as the absence of weight gain or sexual dysfunction. Valdoxan is thus a first-line treatment in its approved indication: treatment of major depressive episode in adults for a first episode or a recurrent episode. _


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Keywords: circadian rhythm; unique receptor profile; melatonergic; antidepressant efficacy; superior; Valdoxan (agomelatine)