Comment développer un antidépresseur au mécanisme d’action innovant : l’exemple de l’agomélatine

Divers axes de recherche ont été suivis pour obtenir de nouveaux traitements de la dépression plus efficaces, mieux tolérés et d’action plus rapide. Parmi ces axes de recherche, la mélatonine, synchronisateur endogène des rythmes biologiques chez les mammifères, suscite un intérêt croissant dans la mesure où la désorganisation des rythmes circadiens est caractéristique d’un grand nombre de troubles de l’humeur. L’agomélatine est un antidépresseur qui se distingue par des propriétés agonistes pour les récepteurs mélatoninergiques (MT1 et MT2) ; ses propriétés agonistes ont été confirmées lors d’études in vivo, l’agomélatine améliorant les perturbations des rythmes circadiens observés dans différents modèles animaux. La propriété antidépressive de l’agomélatine a été mise en évidence dans plusieurs modèles animaux validés, dont les tests de la nage forcée, de la résignation acquise ou du stress chronique modéré. De façon tout à fait intéressante, l’activité antidépressive de l’agomélatine ne repose pas uniquement sur une action chronobiotique : en fait, l’agomélatine présente une activité antagoniste sur les récepteurs 5-HT2C, et ce aux doses antidépressives. Par ailleurs, l’absence d’affinité de l’agomélatine vis-à-vis d’un large éventail de récepteurs lui confère un excellent profil de sécurité, particulièrement avantageux par rapport aux antidépresseurs déjà sur le marché (pas de désordres gastro-intestinaux ni de perturbations de la fonction sexuelle ou du sommeil). L’agomélatine inaugure donc un nouveau concept dans le traitement de la dépression.There are now many potentials for the development of more effective, better tolerated, and more rapidly acting antidepressants acting in association and/or beyond the monoamine hypothesis. One of these possibilities is the development of antidepressant drugs with melatonin agonist property. This holds much promise since various affective disorders, including depression, are characterized by abnormal patterns of circadian rhythms. In line with this, the melatoninergic agonist properties of agomelatine, an antidepressant with proven clinical efficacy, may represent a new concept for the treatment of depression. By way of behavioral studies in rodents, it has been shown that administration of agomelatine can mimic the action of melatonin in the synchronization of circadian rhythm patterns. Interest in agomelatine has increased in recent times due to its prospective use as a novel antidepressant agent, as demonstrated in a number of animal studies using well-validated animal models of depression (including the forced swimming test, the learned helplessness, the chronic mild stress). Interestingly, the melatoninergic agonist property of agomelatine may not, alone, be sufficient to sustain its clear antidepressant-like activity. Recent results from receptor binding and in vivo studies gave support to the notion that agomelatine’s effects are also mediated via its function as a competitive antagonist at the 5-HT2C receptor. Finally, thanks to its absence of binding with a broad range of receptors and enzymes, agomelatine is particularly safe and devoid of all the deleterious effects reported with tricyclics and SSRIs

The safety of agomelatine in standard medical practice in depressed patients : a 26‐week international multicentre cohort study

© 2020 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Objective: The present observational cohort study documented the safety of agomelatine in current medical practice in out-patients suffering from major depressive disorder. Method: The 6-month evolution of agomelatine-treated patients was assessed with a focus on safety (emergent adverse events, liver acceptability), severity of depression using the Clinical Global Impression Severity (CGI-S) score, and functioning measured by the Sheehan Disability Scale (SDS). Results: A total of 8453 depressed patients from 761 centres in 6 countries were analysed (female: 67.7%; mean age: 49.1 ± 14.8 years). Adverse events reported were in accordance with the known safety profile of agomelatine. Cutaneous events were reported in 1.7% of the patients and increased hepatic transaminases values were reported in 0.9 % of the patients. The incidence of events related to suicide/self-injury was 1.0%. Two completed suicides, not related to the study drug, were reported. CGI-S total scores and SDS sub-scores improved and numbers of days lost or underproductive decreased over the treatment period. Conclusions: In standard medical practice, agomelatine treatment was associated with a low incidence of side effects. No unexpected events were reported. A decrease in the severity of the depressive episode and improved functioning were observed.info:eu-repo/semantics/publishedVersio

Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests:A model for reward pathology with effects of agomelatine

A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity

Structure-based discovery of potent and selective melatonin receptor agonists

Melatonin receptors MT1 and MT2 are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound 21 reaching EC50 of 0.36 nM. Six of these molecules displayed selectivity for MT2 over MT1 . Moreover, two most potent agonists, including 21 and a close derivative of melatonin, 28, had dramatically reduced arrestin recruitment at MT2, while compound 37 was devoid of Gi signaling at MT1, implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists. © Patel et al

L'espace est à vendre

Directeur d'« Actuel », ancien consultant chez Arthur De Little, Henri de Bodinat expose les complexités de la commercialisation publicitaire des journaux.de Bodinat Henri. L'espace est à vendre. In: Communication et langages, n°50, 3ème-4ème trimestre 1981. pp. 104-108

Construction de l'alliance initiale avec les parents dans les prises en charge ambulatoires en pédopsychiatrie d'enfants de 2 à 5 ans

Devant la complexité d'engagement de certains parents dans la prise en charge de leur enfant en pédopsychiatrie, nous avons étudié la question de l'alliance avec les parents dans ce contexte.En considérant les concepts d'alliance avec la patient adulte et les différentes théorisations de l'alliance avec les parents, surtout en psychiatrie du bébé , nous proposons un concept d'alliance avec les parents pour les enfants de 2 à 5 ans, basé sur l'alliance de travail de Bordin : double lien avec le parent et l'enfant dans le parent, partenariat avec accord sur l'objectif et les tâches. Après avoir défini les rôles de l'alliance avec les parents, nous examinons les facteurs entrant en jeu dans la construction de l'alliance initiale, les éléments à évaluer lors du premier entretien et comment le clinicien peut favoriser cette construction. Nous illustrons enfin notre propos par quatre cas cliniques décrivant la co-construction de l'alliance avec les parents en début de prise en charge.Facing the difficult involvement of some parents in their child's infant mental health care, we studied the alliance with the parents in this particular context. Considering the concept of alliance with an adult patient and the different theories on the alliance with parents, especially in infant's psychiatry, we propose a concept of alliance with parents of 2-5 years odl children, baseed on Bordin's working alliance : double link with the parent and the child int the parent, partnership with agreement on goal and tasks. After defining the alliance with parent's roles, we study the factors involved in building the initial alliance, the elements to evaluate during the first session and the ways to propmote this construction of alliance with parents at the biginning of the care process.ST QUENTIN EN YVELINES-BU (782972101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Emotional blunting with antidepressant treatments: A survey among depressed patients

Emotional blunting is regularly reported in depressed patients on antidepressant treatment but its actual frequency is poorly understood. We have previously used qualitative methods to develop an appropriate scale, the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (OQESA).Six hundred and sixty nine depressed patients on treatment and 150 recovered (formerly depressed) controls (aged ≥18 years) participated in this internet-based survey. The rate of emotional blunting in treated depressed patients was 46%, slightly more frequent in men than women (52% versus 44%) and in those with higher Hospital Anxiety and Depression (HAD) scale scores. There was no difference according to antidepressant agent, though it appeared less frequent with bupropion. Depressed patients with emotional blunting had much higher total blunting scores on OQESA than controls (42.83 ± 14.73 versus 25.73 ± 15.00, p < 0.0001) and there was a correlation between total blunting score and HAD-Depression score (r = 0.521). Thus, those with HAD-D score >7 (n = 170) had a higher total questionnaire score, 49.23±12.03, than those with HAD-D score ≤7 (n = 140), 35.07 ± 13.98, and the difference between the two groups was highly significant. However, patients with HAD-D score ≤7 (n = 140) had a higher total score (35.07 ± 13.98) than the recovered controls (n = 150) (25.73 ± 15.00), and the difference between the two groups was significant. Among the patients with emotional blunting, 37% had a negative perception of their condition and 38% positive. Men reported a more negative perception than women (p=0.008), and patients with a negative perception were more likely to have higher HAD scores. Higher levels of emotional blunting are associated with a more negative perception of it by the patient (r = -0.423).Include self-evaluation and the modest size of the sample for detection of differences between antidepressants.Emotional blunting is reported by nearly half of depressed patients on antidepressants. It appears to be common to all monoaminergic antidepressants. The OQESA scores are highly correlated with HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressants, but also as a symptom of depression. A higher degree of emotional blunting is associated with a poorer quality of remission. The OQESA scale allows the detection of this phenomenon