Valdoxan’s unique profile of antidepressant efficacy at the core of depression

Carmen MUÑOZ,PhD
Servier International
Suresnes, FRANCE

Valdoxan’s unique profile of antidepressant efficacy at the core of depression

by C. Muñoz, France

This article will review the efficacy of Valdoxan (agomelatine) at the core of depression, in other words, on main symptoms such as depressed mood and anhedonia. Sad mood and anhedonia, together with anxiety are regularly seen in depressed patients and are among the most distressing symptoms of the disorder. Valdoxan demonstrated efficacy in treatment of depressed mood and early anxiolytic efficacy even in the most anxious depressed patients, both in randomized and in observational postregistration trials. Two studies evaluating the effect on anhedonia through use of a scale specific for that symptom (the Snaith-Hamilton Pleasure Scale) showed earlier and better improvement with Valdoxan than with venlafaxine in the restoration of pleasure and interest. These effects on anhedonia were reported by doctors and patients in real-life situations and are all the more important given the scarcity of data in the literature on the effects of available antidepressants on this core symptom of depression. Taken together, Valdoxan’s effects at the core of depression lead to recovery of emotional integrity and of social and cognitive functioning in depressed patients, insuring better quality of life during and beyond depression.

Medicographia. 2013;35:327-333 (see French abstract on page 333)

To be effective, an antidepressant needs to target its antidepressant activity at the two main core symptoms of depression: depressed mood and anhedonia. Whereas most drugs have been evaluated in treatment of sad mood, there is not much data to consult in the literature about alleviation of anhedonia with antidepressants. Targeting the abatement of these symptoms is a challenge for antidepressant treatment to achieve complete recovery. Anhedonia has been defined by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as the diminished interest or pleasure in response to stimuli that were previously perceived as a reward during the premorbid state1; anhedonia results in poor outcome during major depression2 and is also found as a residual symptom.3 Its recognition and treatment are key to treatment, as it is at the core of depression.4

Apart from rodents, where anhedonia serves as an animal model of depression, most studies do not specifically look for this dimension. Some antidepressants have been studied for their effect on anhedonia, but no specific assessment tool or scale has been used. Among the antidepressants evaluated, moclobemide was found to be better than clomipramide for alleviation of anhedonia in depressed patients,5 but the evaluation was done using specific items of the Depressive Mood Scale (Échelle d’Humeur Dépressive [EHD]).6 Sertraline was evaluated for its effect on anhedonia in an 8-week, open-label study conducted in 140 depressed patients receiving sertraline treatment, using clusters of symptoms defined in the Inventory for Depressive Symptomatology (IDS). A significant improvement in hedonic function was found, but this improvement appeared late, occurring after improvement of the anxiety and depression clusters.7 Again, no specific tool assessing anhedonia was used in this study. For both studies, the use of nonspecific assessments could have led to a lack of sensitivity and specificity in anhedonia recognition.

On the other hand, conventional antidepressants have a negative impact on emotion recognition and processing. Emotional dysregulation is frequently described during conventional antidepressant treatment, after depression remission, as residual symptoms. Furthermore, these effects can be distinguished from the depressive process, as confirmed in healthy subjects, such as in a recent study comparing citalopram and reboxetine,8 in which treatment with selective serotonin reuptake inhibitor (SSRI) reduced activation both in response to the reward stimuli and to the aversive ones. These results raise the possibility of antidepressant-induced emotional blunting. However, it is difficult to differentiate residual symptoms, revealing lack of efficacy of the treatment, from emotional side effect of the drug. Emotional blunting is experienced by patients as impairment in resolving their own emotional issues, modification of their personality, or insensitivity to their environment including peers, family, and routine tasks.9 These secondary effects have a direct impact on cognition and social functioning, and lead to pervasive impairment during maintenance treatment.

Valdoxan (agomelatine) has a novel and unique pharmacological profile in the antidepressant armamentarium. It is an agonist at MT1/MT2 receptors and an antagonist at 5-HT2C receptors. These receptors act synergistically to contribute to the efficacy of Valdoxan in depression.10,11 Valdoxan’s distinctive antidepressant properties have been evaluated and reported in clinical randomized trials versus placebo and available antidepressants12 and, since its marketing authorization in 2009, several observational studies have replicated and confirmed its antidepressant efficacy in daily clinical practice.13-15

Because of its different pharmacological profile, also characterized by a lack of effect on serotonergic release in the brain, it was of interest to determine the effect of Valdoxan in the processing of emotional information which may be key for its distinctive efficacy on the core symptoms of depression. Indeed, a study with healthy volunteers demonstrated the early effects of Valdoxan on emotional processing, evidenced by the selective reduction in subjective reports of sadness, improvement in positive aspects of emotional memory, and modulation of the emotion-potentiation of startle response.16 These first results suggested that Valdoxan could have an impact on emotional processing in depression and anxiety and an earlier efficacy on positive affect in particular, therefore making the efficacy of Valdoxan different from conventional antidepressants.

This article will review the unique efficacy of Valdoxan on the core symptoms of depression that leads to improvement in emotional processing and functioning of depressed patients.

Valdoxan provides efficacy at the core of depression

The efficacy of Valdoxan in depression has been evaluated by the effects on all symptoms, with special attention to the key symptoms of depressed mood, anhedonia, and anxiety. Indeed, these symptoms are regularly seen in depressed patients and belong to the most distressing ones of the disorder.

_ Valdoxan is effective on depressed mood
The effect of Valdoxan on depressed mood has been evaluated in comparison with placebo treatment in an analysis of a pool of three placebo-controlled studies,17-19 and confirmed in two observational studies.13,14 The three placebo-controlled studies were multicenter, double-blind, randomized trials of Valdoxan for major depressive disorder (MDD) and the patient population was similar: outpatients fulfilling DSM-IV criteria for MDD, with a higher proportion of females than males (around 2/3) and a Hamilton Depression Rating Scale (HAM-D) score at inclusion of 20-22.

After 6 to 8 weeks of treatment, Valdoxan was significantly better than placebo in the exploratory analysis of item 1, depressed mood, in the HAM-D scale, and this whatever the severity of depression at inclusion. The difference with placebo in favor of Valdoxan was significant not only for the total population, but also for severely depressed patients at inclusion (Figure 1).20

Figure 1
Figure 1. Effect of 6 to 8 weeks of Valdoxan treatment on depressed
mood regardless of baseline severity.

Valdoxan’s efficacy, whatever the severity of the disorder, is demonstrated by
a significant difference from placebo for item 1 of the HAM-D scale, crucial for
the diagnosis of depression.
Abbreviations: Δ, difference in item 1 (depressed mood) of the HAM-D scale
between patients receiving placebo and those receiving Valdoxan 25-50 mg
over 6 to 8 weeks; CGI, Clinical Global Impression Scale; HAM-D, Hamilton
Depression Rating Scale; ITT, intention-to-treat.
After reference 20: Demyttenaere. Eur Neuropsychopharmacol. 2011;21(suppl
4):S703-S709. © 2011, Elsevier B. V. and ECNP.

The observational study VIVALDI (Valdoxan Improves depressiVe symptoms And normaLizes circaDIan rhythms) used the shortened version of the Montgomery-Asberg Depression Rating Scale (svMADRS) to evaluate the antidepressant efficacy of Valdoxan in 3317 depressed outpatients in Germany, of which 38.1% had neuropsychiatric comorbidity. The mean score of the svMADRS at inclusion was 30.6 (±8.7). The results showed a general decrease in the svMADRS total score to 24.2 (±9.7) already after 2 weeks of treatment and to 12.8 (±9.7) after 12 weeks. After the treatment period, the individual item representing depressed mood, “apparent sadness,” showed an improvement in 72.3% of the patients.13

Another observational study, CHRONOS (not an acronym), was performed in the Russian Federation with a total of 6276 patients included in the study. The majority of patients (80%) were treated as outpatients and 20% as inpatients in psychiatric facilities. Considering all patients, most of them (82%) suffered from moderate (according to International Classification of Disease [ICD]-10 criteria) depressive episodes, either single (44%) or recurrent (38%). The mean 17-item HAM-D total score at baseline was 22.5±6.9. Valdoxan was usually given as monotherapy and comorbidities excluded psychotic symptoms. This study showed a rapid and significant (P<0.00001) improvement in the total HAM-D score, already present at week 1 (decrease to 19.5±7.1) and continuing onwards. The final score after the 8 weeks of treatment was of 4.7±4.7 (P<0.00001). The score for the depressed mood item of the HAM-D scale decreased in the patients treated with Valdoxan early in the treatment.14

_ Valdoxan demonstrated early and continuous restoration of pleasure and interest
Anhedonia has been evaluated in two specific studies, one versus baseline and the second versus venlafaxine.21,22 These studies used a specific and validated anhedonia scale, the Snaith-Hamilton Pleasure Scale (SHAPS).23 A significant improvement in anhedonia was demonstrated with Valdoxan from the first week and over the course of treatment and was greater than with venlafaxine (Figure 2).22 Also, at the end of the study, Clinical Global Impression Scale (CGI) scores were significantly improved only in patients treated with Valdoxan. Details of the methodology and results of these two studies can be found in the article by Di Giannantonio21 in this issue.

_ Valdoxan demonstrates early anxiolytic efficacy even in more anxious depressed patients
Valdoxan’s anxiolytic efficacy in depression has been evaluated in this pool of three placebo-controlled, short-term studies and also in a pool of three short-term studies versus SSRIs (eg, fluoxetine and sertraline) and a selective serotonin-norepinephrine reuptake inhibitor (SNRI; eg, venlafaxine) over 6 to 8 weeks.24 These three studies versus comparators were also multicenter, double-blind, randomized trials of Valdoxan for MDD and the patient population was similar, suffering from moderate to severe depression, except the study with fluoxetine where the patients were severely depressed with a HAM-D score ≥25 at inclusion. The anxiolytic efficacy was assessed in the total population and in the more severely anxious patients (defined as those entering the study with a score ≥5 in the items of the HAM-D reflecting psychic [item 10] and somatic [item 11] anxiety). The evaluation tools were the items 10 and 11 of the HAM-D and the more specific scale, the Hamilton Anxiety Scale (HAM-A).

Figure 2
Figure 2. Snaith-Hamilton Pleasure Scale scores for anhedonia at baseline
and at week 1, 2, and 8 in patients treated with Valdoxan or venlafaxine.

Valdoxan improves anhedonia early in treatment and this improvement is greater than with
Abbreviations: SHAPS, Snaith-Hamilton Pleasure Scale; W, week.
Adapted from reference 22: Martinotti et al. J Clin Psychopharmacol. 2012;32:487-491.
© 2012, Lippincott Williams & Wilkins.

Valdoxan demonstrated anxiolytic efficacy in depression versus placebo early in the treatment. The evaluation of the items 10 and 11 of the HAM-D scale showed a significant difference in the total population (Δ=0.29; P=0.004) and also in the highly anxious population (Δ=0.34; P=0.005) after 2 weeks of treatment (first evaluation) and over the course of treatment in favor of Valdoxan. The anxiolytic efficacy was independent of the concomitant use of benzodiazepines.

The efficacy in anxiety in depressed patients was also significantly greater with Valdoxan when compared with SSRIs or the SNRI venlafaxine. Ameta-analysis of these studies showed that the comparison of HAM-D anxiety subscores and the decrease in the HAM-A scale was in favor of Valdoxan in the total population and even more so in the highly anxious population (Δbetween Valdoxan and comparators at the last value [HAM-A score, 6-8 week period] was 1.72; P=0.032). For more extensive details of the methodology of the evaluations and of the results, please refer to reference 25.

Valdoxan’s efficacy in the three dimensions of depression

While an effect on the core symptoms of depression is an essential element of antidepressant efficacy, it is also a prerequisite for a full and sustained recovery from depression. Such a recovery implicates the restoration of emotional capacities as well as good cognitive and social functioning.

_ Valdoxan’s efficacy in helping patients to recover their emotional integrity
Conventional antidepressants, namely SSRIs, may tend to neutralize the processing of both negative and positive emotions, and this emotional detachment that is observed during and after treatment may persist even after the clinical signs of depression have disappeared.26 The results obtained after administering Valdoxan to healthy volunteers, namely the specific reduction in recognition of only sad facial expressions, could suggest that treatment with Valdoxan may prevent the emotional detachment often seen with antidepressant treatment. To demonstrate this hypothesis, patients treated with Valdoxan 25-50 mg and escitalopram 10-20 mg were evaluated by means of the Oxford Depression Questionnaire (ODQ) after 24 weeks of treatment.27 This questionnaire investigates the prevalence of emotional side effects of antidepressants in patients with MDD.28 The patients evaluated were a subset of English-speaking patients (36 treated with Valdoxan and 30 with escitalopram) belonging to an international, multicenter, randomized, double-blind study with parallel groups (Valdoxan and escitalopram). Patients (males and females) had MDD of moderate or severe intensity with a 17-item HAM-D score at inclusion of ≥22. Statistical analysis using descriptive statistics were carried out to compare the emotional dimension of the patients treated with Valdoxan versus escitalopram.

The results demonstrated that 60% of patients treated with escitalopram felt that their emotions lacked intensity versus only 28% treated with Valdoxan (P=0.063) and that more than half of the patients treated with escitalopram (53%) felt that things that they cared about before illness did not seem important anymore versus only 16% treated with Valdoxan. This clearly demonstrated the more favorable effect of Valdoxan versus escitalopram on the emotional dimension after 6 months of treatment in the depressed.27

The German study VIVALDI corroborates in daily clinical practice the restoration of emotions induced by Valdoxan: nearly 70% of patients had improvement in their emotions after the acute treatment period (12 weeks).13

More recently, the effects of Valdoxan on emotions have been studied by functional imaging. Depressed patients show reduced attention to others with a shift of attention from others to self. This increased self-focus, which is a core feature in major depression, is associated with hyperactivity of prefrontal structures, such as the ventrolateral prefrontal cortex, the dorsolateral prefrontal cortex, and the dorsal anterior cingulate cortex. Depressed patients treated with Valdoxan 25mg (n=13) or placebo (n=12) were scanned, as were healthy volunteers (n=14), while performing self-referential processing using emotional pictures. Results demonstrate that Valdoxan has an early effect (after 1 week) in modifying functions in strategic brain areas involved in emotional processing; these changes in brain activity after only 7 days of treatment could contribute to the early clinical effects of Valdoxan.29

_ Improvement in cognitive functioning
The effects of Valdoxan in cognition were evaluated versus escitalopram in a double-blind, randomized, head-to-head study. A total of 138 outpatients with MDD received Valdoxan 25-50 mg (n=71) or escitalopram 10-20 mg (n=67) for 6 weeks followed by an optional treatment up to 24 weeks. Cognitive functioning was assessed by visual analog scales. After 6 weeks of treatment, Valdoxan induced more “clear thinking” (P=0.003) and improved the feeling of being “wide awake” (P=0.005) compared with baseline, while escitalopram did not (Figure 3).30

The study VIVALDI shows again the positive effect of Valdoxan in the cognitive functioning of depressed patients, with improvement in concentration difficulties observed in 70% of these patients at the end of the acute treatment period.13

Figure 3
Figure 3. Changes in cognitive functioning (clear thinking) as assessed
by visual analog scale after 2 and 6 weeks of treatment
with Valdoxan or escitalopram.

Valdoxan improves cognitive functioning better than escitalopram.
Abbreviation: W, week.
After reference 30: Quera-Salva et al. Int Clin Psychopharmacol. 2011;26:252-
262. © 2011, Wolters Kluwer Health/Lippincott Williams & Wilkins.

_ Improvement in social functioning
Randomized studies have demonstrated the improvement in social functioning with Valdoxan, evidenced by reduction in items 7 and 8 (“work and activities” and “psychomotor retardation,” respectively). The pooled analysis of three placebo controlled studies20 with 358 depressed patients treated with Valdoxan and 363 with placebo for 6 to 8 weeks, showed a difference in favor of Valdoxan of 0.32 (P<0.001) in item 7 and of 0.2 (P<0.005) in item 8. This advantage of Valdoxan has been confirmed in the observational study VALID (VALdoxan In Depression), performed in a population of 111 depressed patients (28 were men). The study was multicenter, open, and lasted 8 weeks. The mean MADRS total score at baseline was 28.7 points and decreased statistically from the first week (24.7; P<0.001) and over the 8 weeks (9.8; P<0.001) of treatment. Patients were assessed with a specific scale, the Sheehan Disability Scale (SDS), and it was demonstrated that from the first week of treatment, the three subscores of the scale, “work/school activities,” “social life,” and “family life” were significantly improved (P<0.001). At the end of the treatment, the 3 subscores had decreased from a baseline of 7.3, 7.7, and 6.9 to 2.5, 2.4, and 2.1, respectively.15

The tolerability and safety of Valdoxan is good. Liver transaminase increases have been reported in 1.4% of patients treated with 25 mg and 2.5% on 50 mg; when Valdoxan was discontinued in these patients, the serum transaminases usually returned to normal levels. Valdoxan is contraindicated in patients with hepatic impairment. Liver function tests should be performed in all patients to ensure appropriate hepatic monitoring as recommended in Valdoxan’s summary of product characteristics.31


These data clearly demonstrate that Valdoxan has powerful antidepressant efficacy with an early impact on depressed mood, anhedonia, and anxiety. This specific efficacy on core symptoms of depression contributes to a more complete recovery of emotional integrity and of both cognitive and social functioning.

Particularly interesting is the demonstrated improvement in anhedonia with Valdoxan, as anhedonia is a core, but difficult to treat, symptom which is curiously absent from the major scales that assess depression. Valdoxan’s efficacy in reducing anhedonia occurs early in the treatment and is greater than what is seen with venlafaxine. This has been repeatedly reported by doctors and patients in real-life situations with a particular regain of interest in pleasurable activities from the first days of treatment with Valdoxan. Furthermore, CGI-scale results are more favorable for Valdoxan than venlafaxine, suggesting the importance of the improvement in anhedonia. The recent functional magnetic resonance imaging (fMRI) study sheds light on how Valdoxan regulates automatic control during self-processing of emotions, suggesting the early set-up of the brain for long-term response and depression remission. The quality of recovery achieved with Valdoxan is the result of this efficacy and represents a unique aspect of Valdoxan. This recovery, first observed in randomized controlled trials, has been confirmed by consistent data from daily medical practice (Figure 4, page 331).13

Figure 4
Figure 4. Change in individual items of the svMADRS at week 12 of Valdoxan treatment.

In the noninterventional study VIVALDI, 7-8 out of 10 patients experience improvement at the core of depression and in the different dimensions of depression, thus confirming in clinical practice the results of the randomized studies.
Abbreviations: svMADRS, shortened version of the Montgomery-Asberg Depression Rating Scale.
After reference 13: Laux et al. Pharmacopsychiatry. 2012;45:284-291. © 2012, Georg Thieme Verlag KG Stuttgart New York.

The results presented in this article support the difference between Valdoxan and conventional antidepressants in terms of efficacy, where Valdoxan not only gives the patients the possibility to begin to enjoy life and to connect with their emotions early in the treatment, but also leads to recovery of social and cognitive functioning, which ensures a better quality of life during and even beyond depression. _

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Keywords: anhedonia; depression; emotions; functioning; Valdoxan