Valdoxan: recovering usual functioning in depressed patients

Carmen MUÑOZ,PhD
Servier International
Suresnes, FRANCE

Valdoxan: recovering usual functioning in depressed patients

by C. Muñoz, France

It is now widely recognized that improvement in global functioning should be part of the treatment of depression. In order to achieve this improvement, novel treatment strategies are needed in our therapeutic armamentarium. Valdoxan is precisely such a strategy for the treatment of depression due to its unique mode of action (synergy between melatonergic receptor agonism and 5HT2C receptor antagonism). In this article, the antidepressant efficacy of Valdoxan is described, from symptomatic improvement to early and sustained improvement in functioning. The efficacy of Valdoxan in moderately to severely depressed patients has been confirmed by a new placebo-controlled study as well as in a meta-analysis of short- and long-term studies versus SSRIs/ SNRI. Valdoxan has also demonstrated early efficacy in restoring pleasure, interest, and positive emotions in depressive patients. These effects result in early and sustained improvement in functioning, which was observed in several clinical trials and clinical practice. Valdoxan is thus established as the only antidepressant to promptly act on these major aspects of depression, thereby demonstrating that Valdoxan possesses a comprehensive antidepressant efficacy.

Medicographia. 2014;36:501-507 (see French abstract on page 507)

It is widely recognized that major depression remains undertreated in spite of the efforts made to understand its pathophysiology and the treatments currently available to patients. This disabling disease induces significant impairments in important areas of functioning: major depressive disorder actually exerts a significant negative impact on overall functioning and quality of life (ie, employment status, stability of interpersonal relationships, financial success) and is associated with one of the highest number of days out of role at the societal level of any physical or mental disorder.1

The efficacy of antidepressants in major depressive disorder has long been assessed only by measuring symptom reduction. However, it is now being recognized that to consider remission only as a reduction in depressive symptoms is not enough since clinical remission is not necessarily accompanied by optimum functioning. A recent study conducted in 274 depressed outpatients,2 about half of whom were considered to be in remission, revealed that these patients did not feel that they were actually free from depression. Residual symptoms and cognitive dysfunction are among the remaining symptoms that were thought to induce this subjective impression.

From the patients’ perspective, remission starts with a return to positive mental health, followed by a feeling of returning to their usual normal self, a return to a usual level of functioning at work or home, feeling in emotional control, enjoying family and social relationships, and only at the bottom of the list comes the absence of symptoms of depression.3 Recovering emotions is essential to improving the functional outcome in depressive patients. Significant functional impairment, if not adequately treated, may precipitate relapses and recurrences.4

It is, therefore, increasingly recognized nowadays that the treatment of depression not only needs to achieve statistical remission— as measured by classical depression scales such as the Montgomery and Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAM-D), and Quick Inventory of Depressive Symptomatology (QIDS)—but also needs to be effective in clinical practice. To bring about a full recovery, an antidepressant needs to provide a global improvement in functioning. It is thus essential that the functional impairments associated with depression are monitored and assessed regularly, and treatments should be developed to treat them, maybe even with the use of novel strategies.5 The current trend is to consider functioning as a critical target for therapeutics.6

Functional assessments can be performed with validated tools such as scales and questionnaires filled by patients; among them, the most widely known and used is the Sheehan Disability Scale (SDS),7 a ten-point visual analog scale used by patients to auto-evaluate the disruption of their work/school, social life, and family life/home responsibilities. Other aspects of functioning can be evaluated by the Social Adjustment Scale- Self Report (SAS-SR)8 or by the clinician-rated Global Assessment of Functioning scale (GAF scale).9 Residual symptoms associated with functional impairment such as daytime sleepiness, impairment in sexual function, somatic complaints, and cognitive impairment, are also assessed by specific scales.5

A good way to informally assess psychosocial function recovery in daily practice is to ask patients at each visit a few specific questions targeting aspects such as absenteeism, level of enjoyment regarding their interactions with others, or favorite activities or interests.

As mentioned above, treatments that improve functional outcomes in depression may need to use novel strategies or novel therapeutic targets. Valdoxan is a recent antidepressant drug with a novel pharmacological profile: it is both a MT1 and MT2 receptor agonist and a 5HT2C receptor antagonist, and the synergy between both properties is responsible for the antidepressant efficacy of Valdoxan. Valdoxan has been shown to possess short- and long-term antidepressant activity in clinical trials vs placebo and vs selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs).10-12 This antidepressant activity was confirmed in daily clinical practice.13,14 As discussed previously, Valdoxan improves the core symptoms of depression, resulting in an early improvement in emotional processing.15 This can lead to an improvement in functioning and, therefore, complete recovery. This is what makes Valdoxan different from conventional antidepressants. In this article, the antidepressant efficacy of Valdoxan will be reviewed in light of its early and sustained improvement in functioning.

Valdoxan: from symptomatic improvement to
improvement in functioning

The antidepressant efficacy of Valdoxan has been evaluated in 12 short-term studies versus placebo, 7 of which had a positive outcome, 3 of which failed, and 2 of which were negative. In all positive placebo-controlled trials, efficacy was shown in severely depressed patients. A total of 7 trials were completed in which Valdoxan was compared directly with SSRIs/ SNRI; Valdoxan was shown to be superior in 2 trials, and noninferior to its comparators in 4 trials. Long-term trials have also demonstrated the antidepressant efficacy of Valdoxan versus placebo and SSRIs.

One of these studies deserves special attention since it clearly confirmed the antidepressant efficacy of Valdoxan in moderately to severely depressed patients. This study was a dose regimen study where Valdoxan was administered to moderately to severely depressed adult patients (HAM-D≥22) at fixed doses of 10 mg or 25 mg, or at a flexible dose of 25-50 mg for up to 6 weeks with the possibility of extending the treatment to 24 weeks. After 6 weeks, the decrease in HAM-D score and the percentage of responders were shown to be significantly in favor of Valdoxan for each of the dose regimens (P<0.001 for the 10 mg group and P<0.0001 for both the 25 mg or 25- 50 mg groups).16 In the subgroup of more severely depressed patients (defined as having a HAM-D score ≥25 and a Clinical Global Impression scale (CGI) score ≥5 at inclusion), the differences with placebo only reached statistical significance for the 25 mg and 25-50 mg doses of Valdoxan in terms of decrease in HAM-D score (10 mg=1.57, NS; 25 mg=5.38, P<0.0001; 25-50 mg=5.53, P<0.0001) and response rate (10 mg=35.6%, NS; 25 mg=50%, P<0.002; 25-50 mg=50.8%, P<0.002) (Figure 1).16

Figure 1
Figure 1. Antidepressant efficacy of Valdoxan in
moderately to severely depressed patients.

The data represent the treatment effect after 6 weeks of treatment
with Valdoxan 10-25 mg/day and 25-50 mg/day
Based on data from reference 16: Kennedy et al. Eur Neuropsychopharmacol.
2014;24(4): 553-563.

Two meta-analyses (short-term treatment vs SSRIs/SNRI and long-term treatment vs SSRIs) have demonstrated that Valdoxan has a significant advantage versus a pool of SSRIs (fluoxetine, sertraline, paroxetine, and escitalopram) and the SNRI venlafaxine in the short-term treatment (6-8-12 weeks) of depressed patients, with patients treated with Valdoxan showing a greater decrease in HAM-D score and a significantly greater number of responders (Figure 2).11 Moreover in the long term (24 weeks), the percentage of remitters was also greater among patients treated with Valdoxan, and fewer discontinuations due to adverse events were observed with Valdoxan than with SSRIs.12 These short- and long-term effects were even more pronounced in the most severely depressed patients.

Finally, a recent meta-analysis of all the shortterm studies (published and unpublished) performed with Valdoxan versus placebo and versus SSRIs and venlafaxine has confirmed that Valdoxan is an effective antidepressant and that it is, on the whole, better tolerated than the antidepressants to which it was compared.18

Restoration of pleasure and interest and recovery of emotions in depression
The antidepressant efficacy of Valdoxan has also been demonstrated through its improvement of anhedonia—the loss of pleasure and interest—a core symptom of depression that is not usually evaluated with available antidepressants. A specific study in depressed patients showed that Valdoxan improves anhedonia significantly earlier and more effectively than venlafaxine, and that this effect was observed early in the treatment course.19 The effect of Valdoxan on the recovery of emotions was first demonstrated in a study performed with healthy volunteers, where Valdoxan, unlike the classic SSRIs/SNRIs, demonstrated a specific reduction in the recognition of only sad facial expressions.20 This result was confirmed in a study versus escitalopram, where after 24 weeks of treatment, patients treated with Valdoxan showed less emotional detachment (P=0.06), as shown by means of a specific questionnaire on emotions.21

Figure 2
Figure 2. Meta-analysis of short-term trials (6 to 12
weeks) with Valdoxan versus SSRIs and venlafaxine.

Based on data from reference 11: Kasper et al. Int Clin
Psychopharmacol. 2013;28(1):12-19.

In clinical practice, the effect of Valdoxan on emotions has been evaluated in more than 1500 depressed patients treated with Valdoxan over 6 weeks. The specific Multidimensional Assessment of Thymic States scale (MAThyS)22 was used to evaluate emotions. MAThyS is a visual analogue scale that rates 7 emotions (sadness, anxiety, panic, irritability, anger, joy, and exaltation) and 5 dimensions (emotional reactivity, cognitive speed, motivation, psychomotor function, and sensory perception). After only 2 weeks of treatment sadness, anxiety, panic, irritability, and anger decreased significantly while joy increased and exaltation remained stable. Valdoxan also induced an improvement in all the dimensions of the scale, motivation being the most improved after 2 weeks of treatment, resulting in a global score that was significantly (P<0.001) greater compared with baseline (Figure 3). These changes were correlated with significant decreases in the QIDS and CGI scales after 2 and 6 weeks of treatment.23

Figure 3
Figure 3. Evolution of the 5 dimensions of the MAThyS scale in depressed patients
treated with Valdoxan for 6 weeks

Based on data from reference 21: Gorwood et al. Int J Neuropsychopharmacology. 2014;17(suppl 1):

Neuroimaging results from a recent study on depressed patients treated with Valdoxan 25-50 mg or placebo and healthy volunteers have shed light on the physiological correlates of this effect: compared with healthy volunteers, depressed patients showed hyperactivity at baseline in both the dorsolateral prefrontal cortex (DLPC) and ventrolateral prefrontal cortex (VLPC), the latter being considered to be the substrate of anhedonia.24 After 7 days of treatment, Valdoxan normalized the hyperactivity of the VLPC to the level of healthy volunteers. After 6 to 7 weeks of treatment with Valdoxan, the brain activation of patients with major depressive disorder was normalized, ie, there was a decrease in the excessive activation of the DLPC and an increase in ventral anterior cingulate cortex activation (vACC).25 Furthermore, after 7 days of treatment, the activity of the amygdala (the brain region implicated in emotional processing) was decreased during the processing of emotional pictures.26

Valdoxan: early and sustained improvement
in functioning

Improvement in functioning is the ultimate goal of antidepressant treatment. The efficacy of Valdoxan measured using the conventional scales of depression, the restoration of pleasure, and its specific impact on emotional processing translate into an increase in daily functioning (both social and cognitive). The effect of Valdoxan on social and cognitive functioning was evaluated using specific scales in clinical trials as well as in large studies in clinical practice.

Valdoxan improves social functioning
in patients with moderate-to-severe depression

The dose-regimen study mentioned above evaluated social functioning using the Sheehan Disability Scale after administration of Valdoxan for 6 weeks. In adult patients, the doses of 25 mg or 25-50 mg of Valdoxan significantly improved (P<0.0001) the three dimensions of the scale—namely, work, social life, and family life. This translated into a significant decrease in the number of days lost (P=0.046 and P<0.001 for the doses of 25 mg and 25-50 mg, respectively) and in the number of unproductive days (P<0.001 and P<0.0001 for the doses of 25 mg and 25-50 mg, respectively) in comparison with placebo (Figure 4).16

Figure 4
Figure 4. Improvement in working functional outcomes after 6 weeks of
treatment with Valdoxan as evaluated by number of days lost and number of
unproductive days.

Based on data from reference 16: Kennedy et al. Eur Neuropsychopharmacol. 2014;24(4):

In clinical practice, three main studies have shown an improvement in functioning with Valdoxan: VALID (VALdoxan In Depression), DIAPASON, and DAVANTAGE.

The VALID study, which included 111 depressed patients treated with Valdoxan, showed a significant improvement in depression—as measured by the MADRS scale—from the first week of treatment (decrease from baseline from 28.7 to 24.8, P<0.001) and this significant improvement continued over the 8 weeks of treatment, with a remission rate of 46.8%. CGI scores also showed a positive change: the mean CGI-S score improved as early as the first week of treatment and over the 8 weeks of the study (final score 2.2, P<0.001). In parallel, an improvement in functioning was noticed in the three dimensions of the patient-rated SDS scale (where the mean scores decreased from baseline to week 8 of treatment, with a significant decrease achieved as early as week one, P<0.001) and the physician-rated scale GAF. The mean GAF scores increased significantly (P<0.001) from the second week of treatment (first measurement) up to week 8 (from 60.5 at baseline to 80.2).27

The DIAPASON study included more than 3000 depressed patients who were administered Valdoxan and followed up during a period of 6 to 8 weeks. The QIDS and SDS scores evaluated at inclusion and at the end of treatment showed a significant improvement.28

The DAVANTAGE study was performed in more than 2000 depressed patients with relatively severe depression at baseline, as assessed by the clinician’s rating of the QIDS and CGI-S scales at inclusion (scores of 16.1 and 4.8, respectively). Assessment of functioning was performed using the Widlöcher Retardation Depressive Scale (RDS)—which evaluates different aspects of mental and motor retardation—and the SDS scale. The improvement in QIDS and CGI scores was progressive and statistically significant (P<0.001) over the treatment period. Functioning was significantly improved with a decrease in RDS score from 26.6 at inclusion to 11.4 at week 6/8 (P<0.001) There was also a significant improvement in the three dimensions (work, social life, family life) of the SDS score, with a decrease in total SDS score from 20.3 at inclusion to 10.2 (P<0.001) after 6/8 weeks of treatment with Valdoxan.29

Valdoxan improves cognitive functioning
Clinical studies using visual analog scales have shown that Valdoxan provides significant and early improvement in one of the main aspects of cognition—clear thinking—while escitalopram does not.30

In clinical practice, the observational DAVANTAGE study, which included 508 patients, used the d2 test of attention, a graphic test designed to assess selective and sustained attention by measuring accuracy, performance consistency, and number of mistakes. The different components of the test include the KL score (concentration performance index: accuracy, number of correct responses minus number of incorrect responses) and the GZ score (quantitative performance index: productivity, number of analyzed items). After 6 to 8 weeks of treatment with Valdoxan, both indexes increased: the concentration performance index changed from 105.7 to 132.8 (P<0.001) and the quantitative performance index from 318.1 to 381 (P<0.001). Furthermore, the improvement in clinical retardation observed with the RDS test was directly correlated with an improvement in cognition.29

The tolerability of Valdoxan was good in clinical trials and observational studies. However, it should be mentioned that cases of liver injury including increases in transaminase levels and, in patients with hepatic risk factors, rare cases of hepatic failure with fatal outcome or liver transplantation have been reported. Therefore, as described in Valdoxan’s Summary of Product Characteristics, Valdoxan is contraindicated in patients with hepatic impairment or transaminase levels exceeding 3 times the normal upper limit and caution should be exercised when prescribing Valdoxan for patients with hepatic injury risk factors. Liver function tests should be performed in all patients and the recommendations of the SmPC should be followed.31


The results of the studies described in this article confirm that the dose of 25 mg is the optimal daily dose for Valdoxan. The difference in effect between treatment with Valdoxan and placebo shown in the dose-regimen study is—by far—much greater than what is recommended in the guidelines for shortand long-term treatment and definitely confirms the antidepressant efficacy of Valdoxan in patients with moderate-tosevere depression. What doctors look for first in an antidepressant is that it should have an effect on depressed mood and anxiety, and Valdoxan clearly fulfills this need.

But Valdoxan has been shown to go beyond this efficacy and this is what makes it unique among all available antidepressants. What depressed patients expect from an antidepressant is that it will help them get their lives back to normal, ie, to recover the positive aspects of their lives that were lost due to depression, to recover interest and pleasure, to be able to get back to their job, family, and social activities. Valdoxan can give them these positive emotions early in the treatment course.

Valdoxan improves anhedonia, the second core symptom of depression, which is usually addressed by antidepressants only late in the treatment course. Valdoxan’s effect on functioning translates into a decrease in the number of lost and unproductive days. This effect, together with the improvement in social and cognitive functioning found in a large number of patients in clinical practice, confirms the benefits of treatment with Valdoxan. The correlation between improvement in retardation and improvement in cognition shown in the DAVANTAGE study is extremely important since improved retardation plays a major role in functional remission, even when clinical remission is observed.

Brain imaging has shown that these improvements have neurological correlates. From the very first week of treatment, Valdoxan acts on those areas of the brain that are implicated in the process of anhedonia and automatic regulation of emotions (VLPC and amygdala). Then, after 7 weeks of treatment, Valdoxan prepares the brain for further normalizations in the activity of the structures implicated in cognitive control and motivation.

In summary, the results presented in this article establish Valdoxan as the only antidepressant with early efficacy on the major symptoms of depression, such as loss of pleasure and interest and loss of motivation. Thus, Valdoxan’s comprehensive antidepressant efficacy answers the needs of both doctors and patients for a more complete recovery. ■

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Keywords: agomelatine; depression; functioning; Valdoxan