Differentiated Approach and Indications for Optimization of Agomelatine Therapy for Endogenous Depression

Objective: Objective of the study was to develop and substantiate differentiated indications for the use of agomelatine (valdoxan) in the treatment of typological variants of endogenous depressions with varying severity on the basis of the analysis of its therapeutic efficacy. Patients and Methods: An open-label prospective study was conducted, using the clinical-psychopathological, psychometric (The Hamilton Depression Rating Scale (HAMD-21); Udvalg for Kliniske Undersogelser Scale (UKU); the Snaith-Hamilton Pleasure Scale (SHAPS) for assessing anhedonic disorders), and statistical methods. A total of 56 patients (mean age was, 34,9 years) with moderate and severe endogenous depressions were examined within the framework of affective psychosis (n = 42) and shift-like schizophrenia (n = 14) (ICD-10 items F31.3-4; F32.1-2, and F33.1-2). For 4 8 weeks the patients received course treatment with agomelatine (valdoxan) in a daily dose of 25 50 mg in the evening. The mental status of patients was assessed in dynamics on fixed days according to reduction of Mean Total Score (MTS) of the corresponding scales as insignificant (less than 19% reduction in disorders), moderate (20 49%), good (50 69%), and significant (70% or more) effects. The effect of agomelatine was analyzed in two groups of patients. In the 1st group (n = 26) specificities of anti-depressive effect and its dynamics in endogenous depressions of different typological structure (melancholic, anxious, and adynamic depressions) were studied. The effect of agomelatine on anhedonic endogenous depressions and manifestations of anhedonia in various spheres of psychic activity (interests, social activity, emotional involvement and eating/drinking) were investigated in Group 2 (n = 30). Results and Discussion: Good tolerance and a high anti depressive activity of agomelatine were established during the treatment course for moderate and severe endogenous depressions. A significant improvement (84.4% reduction in HAMD-21 MTS) was detected in patients by the 3rd and 4th weeks of the course treatment and consistently persisted during the subsequent follow-up. Agomelatine demonstrated a good effect (a 50% or more reduction in HAMD-21 MTS) already by the 14th day of therapy. Balanced anti-depressive effect of the drug was observed, significant thymoleptic, stimulant, anxiolytic and antianhedonic activities (reductions in the MTS of depressive disorders by 90.83, 84.9, 82.39, and 78.9%, respectively) were noticed. Conclusion: The universal spectrum of anti-depressive effect of agomelatine, its good tolerability, high efficacy, and rapid improvement makes it the drug of choice in the treatment of a wide range of psychopathological endogenous depressions: melancholic, apathoadynamic, anxious, and anhedonic ones.


Introduction
The relevance of the development and optimization of anti-depressive therapy methods is due to the significant prevalence of depression. According to WHO (2017), up to 300 million people worldwide suffer from depression; cancer and cardiovascular diseases surpass depression in frequency. The burden of negative consequences of depression in the form of impaired social functioning of patients and the growing economic expenditures of the society is up to 40.5% and is 2-6 times higher than similar indicators for other mental pathologies. Depressions are an important risk factor for suicidal behavior of patients and occupy the second place among diseases, leading to disability and disablement.
All this makes it necessary to conduct studies, devoted to the increase of social adaptation of patients with depressions and improving their quality of life, also by optimization of therapeutic approaches and searching for pathogenetically substantiated treatment methods.
Since the 50-s of the twentieth century the targeted synthesis of "ideal" antidepressants has been carried out, taking into account the pathogenesis of depressive disorders. Several generations of such drugs have already been created. One of the first to be synthesized were "typical" tricyclic antidepressants (TCA), which today are the basic ones in anti-depressive therapy. Their high anti-depressive effect was established (on average in 70% of patients), however, anticholinergic side effects of TCA often complicated antidepressant therapy and led to its cancellation.
These groups of drugs were distinguished by the breadth and universality of the clinical effect, but mainly with mild and moderate depressions. Their strongside was low toxicity owing to the lack of effects on histamine, muscarinic and alpha-adrenergic receptors.
However, it was suggested, that the development of depression cannot be explained by the dysfunction of only one monoamine, since all monoamines are associated with certain links of the pathogenetic process, underlying the development of depressive disorders [1].
Currently among the progressive theories of depressive disorders occurrence chronobiological one is singled out, which is based on the concept of desynchronization of biological rhythms in such patients. According to this theory, the chronobiotic hormone melatonin, which is synthesized in the pineal gland during the night phase of the daily rhythm, plays a key role in synchronization of circadian rhythms, including the sleep-wake cycle [2]. The synthesis of melatonin is regulated in the suprachiasmatic nucleus, where it enters from the pineal gland and regulates circadian rhythms. The antidepressant properties of melatonin itself were not confirmed in the clinical trials, but served as the basis for the creation of drugs with similar effects. Thus, in "Servier" laboratory (France) a unique antidepressant drug agomelatine (valdoxane) was synthesized.
The innovative mechanism of its action is realized by influencing the melatonergic and serotonergic systems and, therefore, involves resynchronization of circadian rhythms due to agonism to MT1-and MT2-receptors and selective antagonism to 5-HT2c receptors, which leads to a specific and the indirect release in the frontal cortex of two basic neurotransmitters, norepinephrine and dopamine, which play an important role in the pathogenesis of depression [3][4][5]. A number of foreign and domestic studies, including placebo-controlled, as well as comparative ones, showed the efficacy of agomelatine in the treatment of depressive states in inpatients and outpatients [6][7][8]. BP Hasler., et al. [9] for the first time pointed out the positive effect of agomelatine in anhedonia, connecting it with the specificities of the melatonergic effect of the drug. It was noted in several comparative studies, that agomelatine led to a significant reduction in psychopathological anhedonic manifestations and positively affected the symptoms of depression in general, improving self-esteem and social functioning of patients [10][11][12][13]. The drug was recommended as a means of overcoming resistance in the treatment of apathetic depressions with severe anhedonic manifestations [14]. However, the data on the special features of the clinical action of valdoxan and its dynamics are insufficiently covered, taking into account the psychopathological structure of endogenous depressions and the degree of their severity.

Aim of the Study
The aim of the study was to develop and substantiate differentiated indications for prescription of agomelatine in typological variants of endogenous depressions of various severity, on the basis of the analysis of its therapeutic efficacy.
Exclusion criteria were the presence of medical, neurological and organic brain diseases at the stage of decompensation; the presence of suicidal behavior, substance abuse and alcohol addiction, as well as changes in indices of blood biochemical analysis, especially total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
An open-label prospective study was carried out; all the patients gave written informed consent to participate in it. The therapeutic efficacy of valdoxan was studied in dynamics on the basis of the clinical data and reduction in the mean total score (MTS) of the corresponding scales, as compared to the 0 th , or previous day of assessment, and was defined as insignificant (up to 19%), moderate (20 -49%), good (50 -69%) and significant (70% or more) effect.
Valdoxan in 25 mg tablets was prescribed once a day, in the evening, starting with a dose of 25 mg. In some patients (12.5%) this daily dose was maintained throughout the course of treatment. In most patients (77.5%) with no signs of improvement in their mental state during the first 1 -2 weeks of treatment, it was increased to 50 mg.
As concomitant therapy, moderate doses of previous antipsychotics, nootropics and normotimics were preserved, any antidepressants and tranquilizers were excluded.
The therapeutic efficacy and safety of agomelatine were analyzed in two groups of patients.  in different areas of psychic activity was also assessed according to the SHAPS points: in the sphere of interests (points 1, 2, 3, 9), social activity (7,8,13,14), emotional involvement (5,6,11,12) and food/drink (4, 10); before valdoxane prescription, this index was respec- The study was conducted in compliance with the principles of biomedical ethics. The significance of the differences among the obtained parameters was determined according to the Student t-test and Fisher's exact method for a small number of observations (according to p index).

Results
26 patients of the 1 st group fully completed a 56-day course of treatment with agomelatine. The course treatment lasted 8 weeks. The dynamics of the condition of the patients was evaluated initially (day 0) and on the 3 rd , 5 th , 7 th , 14 th , 28 th , 42 nd and 56 th days of therapy.
If by the beginning of the course therapy of MTS according to HAMD-21 in this group on the whole was equal to 24.42, by the end of the study it decreased by 84.41% (significant effect), and only in 6 (23.1%) patients residual signs of mild depression were noticed. In the remaining 20 (76.9%) patients, the HAMD-21 score ranged from 0 to 6 points, that is, no signs of depression were practically revealed, and the condition met the criteria for complete remission.
It is important, that clinical improvement (normalization of mood, the appearance of psychophysical activity, a decrease in the actuality of sad thoughts, reduction in congruent overvalued ideas of self-humiliation, low value, self-accusation) in patients of the 1 st group as a whole was already observed by the 14 th day of treatment.
By that time, MTS decreased to 12.08 (by 49.5%), that is, almost to the lower limit of good effect, and by the 21 st day it was already 9.0 (decreased by 2.7 times, or 63.15%), which was assessed as a distinct good effect. By the 42 nd day of therapy, the good effect, achieved by the 3 rd week in the group as a whole, increased to significant, while the MTS decreased by 77.17% and by the 56 th day reduced by 84.41%.
It is characteristic that after the 4 th week of course therapy, the significant effect of agomelatine remained stable, or increased insignificantly in percentage terms, which was confirmed by the assessment on the 42 nd and 56 th days of treatment.
The investigation of the spectrum of agomelatine anti-depressive effect (thymoleptic, stimulating, sedative, or anxiolytic) showed its relatively balanced impact on the symptoms of depression. The thymoleptic effect was determined by the dynamics of MTS signs 1, 2, 3 of HAMD-21 (depressive mood, ideas of guilt, suicidal intentions). Stimulating impact was defined according to a reduction in the MTS signs 7 and 8 (working efficiency and activity, retardation); anxiolytic effect was detected according to the reduction in MTS signs 9, 10, 11 (agitation, anxiety, somatic anxiety).  Already by the 14 th day of therapya decrease in MTS, reflecting the intensity of thymic, apatoadynamic, and anxiety symptoms, was 50.0; 49.30 and 45.28%, respectively, that is, it reached the level of good and borderline with its moderate effect.
By the end of the course of treatment, as mentioned above, the drug was highly active in relation to all three components of depression. As to the degree and tempo of symptoms reduction thymoleptic effect clearly predominated (reduction by 90.83%). The intensity of stimulating and anti-anxiety effects was slightly lower (reduction by 84.91 and 82.39%, respectively), but it was also defined as a significant effect.
In the 2 nd group, 30 patients with moderate and severe anhedonic endogenous depressions received agomelatine for 30 days. Evaluation of the effect was carried out before the start (day 0) and on the 7 th , 14 th and 30 th days of therapy. In patients of the 2 nd group, the special features of anti-depressive activity and the universality of the action of agomelatine on the separate components of depression, which were established in patients of the 1 st group, were revealed.
In general, in this group the degree of reduction of MTS on HAMD reached 78.9% by the 30 th day of therapy (a distinct significant improvement).
As shown in figure 2, in subgroups with moderate and severe depressive intensity good and significant effects were observed in total in 100 and 92.8% of patients, respectively, but in severe depression, good effect was noticed more often (21.4% versus 18.8% of cases).
In turn, significant improvement was registered in a larger number of cases in the subgroup with moderate depression (in 81.2% versus 71.4% of cases).  On average, in the 2 nd group, moderate improvement was fixed already by the 7 th day of treatment (22.6% of reduction in MTS according to HAMD-21), and by the 14 th day the condition of the patients already reached the limit of good effect (48.8% of reduction).

Citation
At the same time, in patients with both moderate and severe intensity of depressions the improvement indices on the evaluation days were in the same ranges; however, in the subgroup with moderate depression, the reduction in MTS on HAMD-21 was slightly higher, than in the subgroup with severe depressions, and on the 30 th day of treatment it was 81.7 and 76.8%, respectively.
The analysis of the effect of agomelatine on the separate components of anhedonic depression showed, that a decrease in the symptoms of anxiety and depressive affect on the 30 th day of treatment corresponded to significant effect (reduction of MTS on HAMD-21 by 76.9 and 82.2%, respectively), with a moderate effect for both components was already achieved by 7 th day of treatment, and good effect was reached on the 14 th day (Figure 3).
However, despite a slight prevalence of depressive mood over anxiety (1.2 times), in patients of this group the reduction in the severity of depressive mood during these treatment periods was greater than the symptoms of anxiety.
On the 30 th day of therapy, the reduction in symptoms of depression as a whole reached 83.6%, in the subgroup with moderate depression and a decrease in depressive mood and anxiety were approximately the same (by 84.4 and 82, 6%, respectively). In the subgroup with severe depression, these indices were lower, although they were also evaluated as significant effect: 76.0, respectively; 79.7 and 72.3% reduction in disorders, that is, the effect of agomelatine on depressive affect was more pronounced than on the affect of anxiety.  Significant effect in relation to anhedonic manifestations was already achieved on the 14 th day of treatment (decrease by 71%) and by the 30 th day the reduction in these disorders was observed by 91.5%, which corresponded to a significant effect, close to the state of recovery.
Equally pronounced effect of agomelatine in relation to the anhedonic component of depression was found, when studying the dynamics of its effect on separate spheres of psychic activity. Only in the sphere of interests the decrease in anhedonia was somewhat lower than in other spheres.
In the sphere of interests, significant effect only appeared by the 30 th day of therapy and in percentage terms it was significantly lower than the indices of anhedonia reduction in other spheres of psychic activity (social activity, emotional involvement): 88.2% versus 91.7 -95.2%, respectively ( Figure 4).
The analysis of weakening of anhedonia symptoms showed, that with the same dosage regimen, the result of treatment of hedonic disorders on the 30 th day in depressions with moderate severity were slightly higher than in severe depressions (reduction of MTS by 93.0 and 89.9%, respectively).  proportion of AEs, that first occurred, or became more frequent by the 7 th day of treatment as compared with the initial index could be associated with valdoxan. These were isolated autonomous symptoms (disturbance of accommodation, hypersalivation, or dry mouth), which significantly decreased and were mildly expressed throughout the entire treatment period, even with an increase in the daily dose of the drug. In no case did AEs require withdrawal of therapy. Such symptom as constipation (in 2 patients) was detected with a stable frequency and had a mild degree of severity (1 point) from the moment the study began, most likely, it could be rightly attributed to somatic symptoms of depression, and not to AE. In 2 female patients, initially suffering from obesity of the II degree, from the 7 th to the 30 th days of treatment, in addition to other AEs, an increase in body weight (by 1 -2 kg) was observed, which corresponded to 1 point according to the UKU. During the course of treatment with agomelatine, no somatic AEs were detected; blood pressure, heart rate did not change, blood biochemical parameters (total bilirubin, AST and ALT) from the start of the study until the 30th day of treatment remained within the normal limits.

Discussion
The obtained results confirm the high antidepressant activity of agomelatine during the treatment of endogenous depressions. Already However, these works dealt with the treatment of outpatients with mild to moderate severity of depressions [13], while in our study, inpatients were included not only with moderate, but also with severe depression (respectively 58, 9 and 41.1%), in whom high therapy results were achieved. The efficacy indicators of valdoxan by the end of the course of treatment (8 weeks) were ambiguous: for moderately expressed depressions, HAMD reduction in MTS ranged from 47.7% [10] to 81% and for severe depression, valdoxane was not appointed in these studies. Discussing the balanced spectrum of action of this drug, the authors mainly evaluated the separate components of its psychotropic activity (anhedonia, anxiety, stimulating effect) [10,12].
Our data significantly expand the existing understanding of the spectrum and nature of the anti-depressive effect of valdoxan and allows formulating specific recommendations for its use in various types of depression.

Conclusion
Owing to the universal spectrum of antidepressive effects, valdoxan can be used in various psychopathological types of endogenous depressions: sad (melancholic), apathoadynamic and anxious ones.
The results of our study showed, that treatment with valdoxan is preferable in anhedonic endogenous depressions; the drug has a distinct effect not only on anxiety, but also on hedonic disorders, including various spheres of psychic activity (interests, social contacts, emotional involvement, etc).
High efficacy and good tolerance serve as the basis for choosing this drug as an antidepressant and make it possible to formulate personalized indications for its prescription, taking into account the psychopathological specificities of depressions themselves and hedonic disorders in their clinical picture. At the same time it is possible to predict the best tempo and depth of the therapeutic response.

Declaration of Financial and Other Relationships
The publication of this article was supported by JSC Servier. Authors are solely responsible for providing the final version of the manuscript in print. All the authors took part in developing the concept of the article and writing the manuscript. The final version of the manuscript was approved by all authors.