Carmen MUÑOZ, PhD
Efficacy of Valdoxan, the first melatonergic antidepressant, in anxiety within depression
Anxiety and depression are highly comorbid diseases, with comorbidity particularly important as these are the most prevalent psychiatric disorders. Few therapeutic strategies address anxiety within depression, and those existing are far from being satisfactory in terms of latency of onset, tolerability, and dependence. As Valdoxan has demonstrated efficacy in depression vs placebo and comparators in several clinical trials, and has proven anxiolytic efficacy in animal models, the anxiolytic activity of Valdoxan 25-50 mg was evaluated in depressed patients, including the most anxious ones, in comparison with placebo and selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine reuptake inhibitor (SNRI). Data from 3 short-term placebo-controlled studies and 3 short-term studies vs SSRIs (fluoxetine, sertraline) and SNRI (venlafaxine) in major depressive disorder were assessed according to the anxiety subscore of the Hamilton Depression Rating scale (HAM-D, items 10+11) and the specific anxiety scale, the Hamilton Anxiety Scale (HAM-A), in the total population and in the most anxious depressed patients (anxiety subscore ≥5 in the HAM-D at inclusion). Valdoxan demonstrated antidepressant efficacy in the most anxious patients and an early anxiolytic efficacy from one week of treatment that was significantly greater vs placebo throughout the whole treatment period (6-8 weeks). This efficacy was maintained in patients not treated concomitantly with benzodiazepines. Compared with SSRIs and the SNRI venlafaxine, Valdoxan’s antidepressant and anxiolytic efficacies were greater in the highly anxious patients, by both evaluation methods. Thus, Valdoxan possesses anxiolytic efficacy in depressed patients from the first weeks of treatment, even in those with higher anxiety, and offers a needed alternative to SSRIs/SNRI for patients with comorbid conditions.
Anxiety and depression are highly comorbid disorders1 and several surveys and major studies have presented notable percentages of prevalence regarding the comorbidity of these diseases. In the STAR*D study (Sequenced Treatment Alternatives to Relieve Depression), the inclusion of 2337 consecutive participants led to a diagnosis at baseline of anxious depression in 45.1% of the subjects.2 In other studies, major depression is accompanied by significant anxiety in up to 62% of patients.3,4 In depressive patients, anxiety seems to accelerate, worsen, and lengthen the course of depression, and is associated with a poorer response to antidepressants.5 It has also been demonstrated that patients with severe depression associated with anxiety are significantly more impaired than those without anxiety; comorbid anxiety is associated with higher clinical severity, including suicidal risk and treatment resistance.2,6 Recent results demonstrated that after 6 weeks of treatment in partial responders, more severe psychological symptoms of anxiety were associated with both longer time to remission and lower rates of remission.7 In the STAR*D study, patients with anxious depression had lower remission rates (22% vs 33%), a worse side-effect profile, and a longer time to remission.8 Furthermore, anxiety is a common residual symptom. In this context, anxiety is responsible not only for relapses, but also for functional impairment.9
This comorbidity is particularly important as both pathologies are the most prevalent psychiatric diseases. According to the World Health Organization, depression was the leading cause of disability and the fourth leading contributor to the global burden of disease in 2000,10 as measured in disabilityadjusted life-years. In particular, unipolar depression is expected to become the second-ranked cause of disease burden in 2020, just behind ischemic heart disease, and will represent one-third of all worldwide disability caused by a neuropsychiatric condition. Furthermore, the new estimates of the analyses performed in the European Union confirm that depression is already the most important single contributor to the total disease burden.11 Anxiety disorders comprise different disorders such as generalized anxiety disorders, panic disorder, social phobia, obsessive-compulsive disorder and posttraumatic stress disorder, and these disorders contribute enormously to the burden of the disease.12
The high prevalence of this comorbidity raises the question of whether these clinical conditions should be considered different conditions, albeit often overlapping, or different aspects of the same condition. Thus, the future edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) will consider dimensional aspects of depression and anxiety and among the new categories has added “mixed anxiety/depression disorder” to the entity “depression.” By doing so, the classification better reflects clinical reality, in which most patients have depressed and anxious symptoms. Indeed, the average patient initiating depression treatment is a middleaged woman, with moderate depression; and 82% of these patients have anxiety symptoms (unpublished observations).
Therefore, the recognition and treatment of comorbid anxiety in major depression is a critical issue, and practitioners need clinically effective antidepressants. However, only a few therapeutic classes have been approved for the treatment of anxiety disorders, and few strategies have been proposed for the treatment of anxiety and depression. First, the adjunction of an anxiolytic agent, typically benzodiazepines, to the antidepressant reduces anxiety in the short term, but can lead to dependence and suicidal or accidental overdose. The preferred approach is to prescribe an antidepressant alone, which reduces symptoms for patients with major depression plus symptoms of anxiety or major depression with comorbid anxiety disorder. The use of monotherapy with an antidepressant in patients with a comorbid diagnosis may help treatment adherence, reduce risk of drug-drug interactions, and be better tolerated. Furthermore, prescribing an antidepressant may facilitate treatment in patients with mixed symptoms when differential diagnosis between depression and anxiety is difficult. Tricyclic antidepressants (clomipramine) have long been approved for the treatment of anxiety disorders as well as depression; however, due to their secondary effects, they are not recommended as first-line treatments. The efficacy of approved serotoninergic antidepressants (paroxetine, sertraline, escitalopram) has been questioned13 as selective serotonin reuptake inhibitors (SSRIs) were not found to be superior to other antidepressants in the treatment of anxious depression. Selective serotonin-norepinephrine reuptake inhibitors (SNRI) (venlafaxine, duloxetine) have also been approved for treatment of anxiety disorders and major depression. However, these antidepressants have some disadvantages, such as their latency of onset of action, and they are not equally tolerated by every patient, thus new compounds need to be developed.
Valdoxan, the first melatonergic antidepressant, has proven its efficacy in depression in several controlled trials vs placebo and available comparators in both the short and long term,14-21 and this efficacy has been shown to be maintained in the more severely depressed patients.22 The antidepressant efficacy of Valdoxan has been demonstrated to have a distinctive profile due to its unique mechanism of action—resynchronization of biological rhythms by the synergy of melatonergic and 5-HT2C receptors.23,24
In addition to its antidepressant efficacy, Valdoxan has proven anxiolytic-like activity in appropriate and validated animal models.25,26 This activity is also likely to be due to the synergy of melatonergic and 5-HT2C receptors.26
For the above reasons, it was of the utmost interest to explore Valdoxan’s antidepressant effects (evaluated by the Hamilton Depression Rating scale [HAM-D]) in the most anxious patients and its anxiolytic effect on anxious symptoms in depressed patients. Analyses were carried out on data taken from a pool of 3 short-term placebo-controlled studies14-16 and a pool of 3 short-term studies vs SSRIs (fluoxetine and sertraline) and the SNRI venlafaxine.18-20
These 6 studies were multicenter, double-blind, randomized trials for Valdoxan in major depressive disorder (MDD). The patient populations in these studies were similar: outpatients fulfilling DSM-IV (fourth revision of the DSM) criteria for MDD, males and females (with a higher proportion of female patients, between 60%-80%), mean age in the early forties, and having an average number of MDD episodes ranging from 2.2- 2.9. The studies included patients with HAM-D scores of 20-22 for 5 studies and HAM-D ≥25 for the study with fluoxetine. The doses of the antidepressants administered were: Valdoxan 25-50 mg (with the exception of one placebo-controlled study, where only the dose of 25 mg was evaluated), fluoxetine 20-40 mg, sertraline 50-100 mg, and venlafaxine 75-150 mg. The doctors and patients were blinded to the increase in dose.
The antidepressant and anxiolytic efficacies were evaluated in the total population and in the more severely anxious patients. The most severely anxious patients were defined as those entering the study with a score ≥5 for the items of the HAM-D scale reflecting psychic anxiety (item 10) and somatic anxiety (item 11). Antidepressant efficacy was evaluated according to total scores from the 17-item HAM-D (HAMD-17) and Clinical Global Impression (CGI) scales; anxiolytic efficacy was assessed by the score for items 10 and 11 on the HAM-D scale (for all 6 studies), and by the more specific evaluation tool for anxiety symptoms, the Hamilton Anxiety Scale (HAM-A) (for one of the studies vs placebo over 8 weeks of treatment and in the 3 studies vs comparators over a 6- to 8-week treatment period).
Analyses of variance were carried out for the 6-8 weeks of treatment using the last-observation-carried-forward method. Meta-analytic methods were used to provide an estimate of the overall treatment effect of Valdoxan as compared with placebo or SSRI/SNRI.
Figure 1. Valdoxan demonstrates antidepressant efficacy in more anxious, depressed patients early in the treatment (from week 2) and throughout the 6-8 week treatment period compared with placebo (left panel) and compared with SSRIs/SNRI (right panel).
Based on data from reference 27.
The antidepressant efficacy of Valdoxan is stronger in the most anxious patients vs placebo or comparators early in the treatment
In the 3 short-term studies vs placebo, Valdoxan’s antidepressant efficacy was demonstrated after a mandatory period of 6-8 weeks. The patients were also treated with or without concomitant benzodiazepines (only low doses of diazepam, zoplicone, or zolpidem were allowed). In the total population of these pooled studies (358 patients treated with Valdoxan and 363 patients treated with placebo), the difference in the HAM-D total score after the treatment was 2.86 (P<0.001) in favor of Valdoxan 25-50 mg.22 In the subpopulation of highly anxious patients (222 and 231 treated with Valdoxan and placebo, respectively), the difference was already significant after only 2 weeks of treatment (Δ after 2 weeks =2.25±0.54, P<0.001; Δ at end point =4.36±0.71, P<0.001) (Figure 1).27 The superiority was observed whether or not they were treated with concomitant benzodiazepines.
In the studies vs comparators, the total population included 562 depressed patients treated with agomelatine and 576 treated with SSRI/SNRI. Valdoxan demonstrated its antidepressant efficacy in this population over 6-8 weeks of treatment. The differences after treatment, based on the HAM-D and CGI score, were always in favor of Valdoxan: vs fluoxetine, the differences were 1.49 (superiority study; P<0.05) for the HAM-D and 0.18 (P=0.06) for the CGI scores; vs sertraline, the differences were 1.68 (P<0.05) for the HAM-D and 0.29 (P<0.05) for the CGI scores; and vs venlafaxine, 0.92 (P>0.05) for the HAM-D and 0.32 (P<0.05) for the CGI scores. The meta-analysis of these studies vs venlafaxine, sertraline, and fluoxetine yielded a difference of 1.35 (P<0.001) in favor of Valdoxan.28 This greater efficacy was confirmed in the patients with high anxiety from the second week of treatment (Δ=1.65; P= 0.005) and at end point (Δ=1.32; P<0.05) (Figure 1).27
Figure 2. Anxiolytic efficacy of Valdoxan in the more severely
anxious patients occurs early in the treatment.
Based on data from reference 27.
Valdoxan: demonstrated early anxiolytic efficacy within depression
Evaluation of the 3 placebo-controlled studies demonstrated that the anxiolytic efficacy of Valdoxan also appears early in the treatment of depressed patients: evaluation according to the HAM-D anxiety subscore (sum of items 10+11) shows that from the first evaluation time point (week 2), there was a significant difference in favor of Valdoxan, not only in the total population (Δ vs placebo =0.29±0.10; P=0.004), but also in the highly anxious population (Δ vs placebo =0.34±0.12; P<0.005) (Figure 2) which was sustained over the course of the treatment (weeks 6-8; P<0.001 for both populations).27 This efficacy has been demonstrated for psychic as well as somatic anxiety, even in the highly anxious population of depressed patients (Figure 3).29
This advantage remained significant in patients who did not concomitantly receive benzodiazepines.29 Over the 6-8 weeks of treatment, Valdoxan demonstrated a major anxiolytic efficacy: for the total population, Δ vs placebo =0.15±0.08 (P=0.066) and 0.21±0.08 (P=0.009) for psychic and somatic anxiety, respectively; for the patients with high anxiety at baseline, Δ vs placebo =0.29±0.11 (P=0.006) and 0.27±0.10 (P=0.007), for psychic and somatic anxiety, respectively. The anxiety symptoms within depression were also evaluated vs placebo using the HAM-A over 8 weeks of treatment in one of the placebo-controlled trials. Valdoxan 25 mg led to a significant decrease in the HAM-A scores in the total population (Δ vs placebo =3.43±1.18; P=0.011) and in the highly anxious population (Δ vs placebo =4.68±1.54; P=0.003) at the first evaluation time point (end point).27
Valdoxan: demonstrated favorable anxiolytic efficacy within depression versus SSRIs and SNRI
It is of major interest to evaluate the efficacy of Valdoxan, in comparison with available antidepressants, on anxiety symptoms in depressed patients, as SSRIs and SNRIs are far from being satisfactory in terms of effectiveness. Head-to-head trials of Valdoxan vs the more commonly used antidepressants showed an advantage of Valdoxan vs venlafaxine, fluoxetine, and sertraline.
Figure 3. Efficacy of Valdoxan vs placebo on the anxiety items of the HAM-D scale
over 6-8 weeks of treatment.
Compared with sertraline, Valdoxan, after 6 weeks of treatment, showed an anxiolytic efficacy (assessed by items 10+11 of the HAM-D) that was significantly higher (between-group differences =1.26 and 1.0 for psychic and somatic anxiety, respectively; P<0.05 for both) in the total population.19,30 The result was obtained using the HAM-A scale (P<0.05). Compared with venlafaxine, a difference in favor of Valdoxan was reported after 6 weeks of treatment, assessed by the specific HAM-A scale (HAM-A score at end point=10.3±7.4 and 11.1±7.6 for Valdoxan and venlafaxine, respectively; P=0.327), in the total population.30
Compared with fluoxetine, in the severely depressed patients (which constitute the total population of this study), the dif- ference in favor of Valdoxan was again demonstrated, as the HAM-A total score was 11.1±8.1 with Valdoxan and 12.3±10 with fluoxetine.20
Figure 4. The HAM-A total score in the most severely anxious
patients is significantly improved with Valdoxan vs SSRIs/SNRI.
reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; W, week.
Based on data from reference 27.
The meta-analysis of these studies shows a clear advantage of Valdoxan vs these comparator treatments: the comparison of HAM-D anxiety subscores was in favor of Valdoxan (Δ vs comparators =0.20±0.14; P=0.167), as was the significant difference in HAM-A scores (Δ=1.39±0.5; P=0.006) in the total population.27
These advantages persist and are even higher in the highly anxious population. The comparison of HAM-D anxiety subscores yields a difference of 0.26±0.19 (P=0.160) in favor of Valdoxan, and comparison of HAM-A scores yields adifference of 1.72±0.8 (P=0.032), also in favor of Valdoxan (Figure 4).27
These data clearly demonstrate that Valdoxan possesses anxiolytic efficacy within depression as early as the first weeks of treatment. Not only are its antidepressant properties maintained in themore anxious patients, Valdoxan also shows anxiolytic efficacy in depressed patients, even those with higher anxiety. Of particular importance are the results obtained in patients not treated with benzodiazepines, which demonstrated that even in the absence of this concomitant medication, Valdoxan alleviated anxiety. Therefore, coadministration of such anxiolytic agents with Valdoxan is unnecessary, thus providing a large number of advantages (no deterioration of daytime condition, no withdrawal syndrome, no dependence, among others).
Of great importance is the favorable effect of Valdoxan in anxiety within depression as compared with SSRIs and the SNRI venlafaxine, even in the more anxious patients, as this offers a much needed alternative for patients with comorbid conditions. As doctors have recognized that more than 80% of depressed patients have anxiety as a comorbidity—implying higher clinical severity, increased suicidal risk, treatment resistance, low rates of remission, and longer time to remission— treatmentwithValdoxan ensures optimalmanagement of these depressed patients.
Valdoxan shows a clear advantage vs available antidepressants in addressing the anxious symptoms within depression, and may have a unique position in clinical pharmacotherapy for this comorbidity as it is better tolerated and has better adherence levels than other anxiolytic medications. A recent Valdoxan review31 suggests that because of its unique mode of action—the potential to restore circadian rhythms—Valdoxan might occupy a special place in the management of patients with severe depression and other mood disorders. The results presented in this article support this suggestion and add new insights concerning the properties of Valdoxan, the first melatonergic antidepressant. _
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Keywords: anxiety within depression, comorbidity, Valdoxan