Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.
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PMID:Agomelatine: innovative pharmacological approach in depression. 1970 23

Antidepressant pharmacotherapy forms the basis of management of major depressive disorder (MDD). In principle, the management of MDD should first elicit rapid relief of symptoms and then restore normal functioning and prevent relapse. It is recommended that treatment should continue for at least one year to minimize the risk of recurrence. Currently, most antidepressants fail to fulfill these goals, and rates of remission and long-term compliance are usually unsatisfactory. These shortcomings may be linked to tolerability and residual symptoms. Agomelatine is a novel antidepressant with an innovative mode of action characterized by agonism at the melatonergic MT(1)/MT(2) receptors and antagonism at the 5-HT(2C) receptors. As early as one week into treatment, depressive symptoms evaluated by the Clinical Global Impression Scale - Improvement (CGI-I) showed a significant improvement with agomelatine compared with venlafaxine (p < 0.0001). This rapid antidepressant efficacy was also seen at 2 weeks on the Hamilton Rating Scale for Depression (HAM-D), on which the mean total scores for agomelatine were lower than those for placebo (p < 0.05). At 6-8 weeks, evaluation on HAM-D, CGI-I and the CGI - Severity of illness (CGI-S) showed significant improvements with agomelatine versus placebo (p < 0.05). Patients treated with agomelatine also experienced greater relief of symptoms on CGI-I at 6 weeks compared with venlafaxine (p < 0.05). The antidepressant efficacy of agomelatine is maintained over the long term; almost 80% of patients remain free from relapse after 10 months of treatment. Agomelatine also significantly improves disturbed sleep and anxiety within depression, and this broad efficacy minimizes the risk of residual symptoms. The recent registration of agomelatine by the European Medicines Agency now offers the potential of fulfilling many currently unmet clinical needs throughout the time course of management of MDD.
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PMID:Agomelatine: efficacy at each phase of antidepressant treatment. 1970 25

(1) When an antidepressant is considered a necessary addition to psychological support in treating patients with depression, the first-line drug is a tricyclic such as clomipramine or a selective serotonin reuptake inhibitor (SSRI) such as paroxetine; (2) Agomelatine, a melatonin receptor agonist, is approved in the European Union for the treatment of depression; (3) Available evaluation does not include any clinical trials designed to compare the efficacy of agomelatine with that of a tricyclic or a selective serotonin reuptake inhibitor. Most data come from 7 placebo-controlled trials; (4) Agomelatine (25 mg/day) was statistically more effective (on a rating scale) than placebo in only 3 of these 7 trials. The clinical relevance of the score improvements is questionable. No data are available on the cure rate or on suicide prevention; (5) In one trial, increasing the daily dose from 25 mg to 50 mg provided no supplementary benefit; (6) A trial in 367 patients failed to show that agomelatine was any more effective than placebo in preventing new depressive episodes (29% after one year). In another trial including 339 patients, the relapse rate was statistically lower after 6 months on agomelatine (20.6%) than on placebo (41.4%); (7) Very high doeses of agomelatine are oncogenic in animals. The risk in humans is not known. Dizziness, gastrointestinal and cutaneous disorders have been observed. Agomelatine is probably hepatotoxic; (8) In summary, agomelatine has unproven efficacy and poorly documented adverse effects. It is better to continue to use older antidepressants such as tricyclics or serotonin reuptake inhibitors.
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PMID:Agomelatine: new drug. Adverse effects and no proven efficacy. 2002 May 62

Biological rhythms have always been considered to be disrupted in depression, with the predominant theory being that of hyperarousal. However, recent data suggest that it might be more appropriate to suggest that depressed patients are incapable of achieving and maintaining the particular level of internal homeostasis which permits them to function smoothly, to lower the level of arousal during sleep sufficiently so that quality of sleep is good, and to increase this level enough during the day so the person can function properly. Therefore, the transition from one state to another is somewhat problematic, delayed, incomplete and desynchronised. Thus, agents with a 'rhythm stabilising' effect could be beneficial in the treatment of mood disorders. Such an agent should have a beneficial effect on restoring and stabilising the rhythm of a physiological function while not pushing it towards a specific pole, or inducing the opposite pole; it should also allow response to internal and environmental stimuli and zeitgebers, and restore synchronisation of the various body rhythms while not inducing or worsening desynchronisation. Agomelatine could represent the first of a new class of 'rhythm stabilising antidepressants', but further research is necessary to support this theory.
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PMID:Disruption of biological rhythms as a core problem and therapeutic target in mood disorders: the emerging concept of 'rhythm regulators'. 2015 24

Agomelatine is a novel antidepressant which acts as a melatonergic (MT1/MT2) receptor agonist and serotonergic (5-HT2C) receptor antagonist. The antidepressant properties of agomelatine have been demonstrated in animal models as well as in clinical studies. Several preclinical studies reported agomelatine-induced effects on brain plasticity, mainly under basal conditions in healthy animals. Yet, it is important to unravel agomelatine-mediated changes in the brain affected by psychopathology or exposed to conditions that might predispose to mood disorders. Since stress is implicated in the etiology of depression, it is valid to investigate antidepressant-induced effects in animals subjected to chronic stress. In this context, we sought to determine changes in the brain after agomelatine treatment in chronically stressed rats. Adult male rats were subjected to footshock stress and agomelatine treatment for 21 consecutive days. Rats exposed to footshock showed a robust increase in adrenocorticotropic hormone (ACTH) and corticosterone. Chronic agomelatine treatment did not markedly influence this HPA-axis response. Whereas chronic exposure to daily footshock stress reduced c-Fos expression in the hippocampal dentate gyrus, agomelatine treatment reversed this effect and normalized neuronal activity to basal levels. Moreover, chronic agomelatine administration was associated with enhanced hippocampal cell proliferation and survival in stressed but not in control rats. Furthermore, agomelatine reversed the stress-induced decrease in doublecortin expression in the dentate gyrus. Taken together, these data show a beneficial action of agomelatine in the stress-compromised brain, where it restores stress-affected hippocampal neuronal activity and promotes adult hippocampal neurogenesis.
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PMID:The novel antidepressant agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in chronically stressed rats. 2023 41

In this 8-week double-blind multicenter trial, we evaluated the efficacy and safety of 2 fixed doses of agomelatine in patients with moderate to severe major depressive disorder. Primary efficacy variable was the change in 17-item Hamilton Depression Rating Scale (HAM-D17) total score from baseline to week 8/end of treatment. Secondary efficacy assessment compared the improvements in clinical response and remission (HAM-D17), Clinical Global Impression--Improvement Score, Clinical Global Impression--Severity Score, Hospital Anxiety and Depression (HAD), sleep (Leeds Sleep Evaluation Questionnaire), disability (Sheehan Disability Scale), and overall Quality of Life in Depression Scale between the agomelatine and placebo groups. Eligible patients (n = 511; baseline mean HAM-D17 score = 27.0) were randomized (1:1:1) to once-daily agomelatine, 25 mg; agomelatine, 50 mg; or placebo. Agomelatine 50 mg provided a statistically significant improvement in HAM-D17 score from first baseline visit through week 8 compared with placebo (week 8 treatment difference, 2.5; P = 0.004), whereas agomelatine 25 mg did not show (P = 0.505) a significant improvement. Treatment differences for all secondary efficacy variables were also statistically significant for agomelatine 50 mg versus placebo: Clinical Global Impression--Improvement (P = 0.012); Clinical Global Impression--Severity difference (P = 0.003); improvement in HAD total score, 2.2 (P = 0.014); patients' ability to get sleep (P < 0.001); quality of sleep (P = 0.002). Both doses of agomelatine were well tolerated relative to placebo. However, clinically notable transient aminotransferase elevations were observed in 4.5% of the patients in the agomelatine 50 mg group. The results showed significant antidepressant efficacy of agomelatine 50 mg/d, including a positive effect on sleep compared with placebo in outpatients with moderate to severe major depressive disorder.
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PMID:Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial. 2052 Feb 86

For many patients suffering from major depressive disorder, available treatments are unsatisfactory due to long delays before the onset of effects, low response rates, poor tolerability, and high recurrence rates. Evidence now suggests that major depressive disorder is a complex syndrome fed by multiple pathways and therefore that modulating serotonergic and noradrenergic neurotransmission, while important, is insufficient. To this effect, data have shown consistently over the last 50 years that patients suffering from depression experience a wide range of circadian rhythm disturbances, and that temporary remission of symptoms can be reached with chronotherapeutic interventions. Agomelatine, a melatonergic antidepressant with an innovative pharmacological profile, is both a melatonergic receptor agonist and a 5HT(2C) receptor antagonist. Its antidepressant activity has been demonstrated in animal models and placebo-controlled trials as well as in comparator studies. Clinically and statistically significant improvements in the core symptoms of depression, as well as a rapid onset of benefits, low relapse rates upon discontinuation, and high tolerability have been noted. It is likely that the antidepressant activity of agomelatine results, at least in part, from the resynchronization of the circadian rhythms that are disturbed in many depressed patients. In a recent study, for example, treatment with agomelatine significantly improved the amplitude of the circadian rest-activity/ sleep-wake cycle and decreased depression and anxiety symptoms compared with treatment with sertraline. Together, these data suggest that agomelatine, through its innovative mechanism of action, may result in a more complete and sustained remission for chronically depressed patients.
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PMID:Restoring circadian rhythms: a new way to successfully manage depression. 2066 4

One of the ongoing clinical challenges associated with the management of major depressive disorder is the fact that many patients do not achieve complete remission and even fewer patients remain in remission. Residual symptoms and poor treatment adherence are two of the main risk factors for relapse with current therapies. In order to face these challenges, clinicians need new treatment strategies that can provide more sustained, longer-term efficacy and adherence. Agomelatine, an innovative antidepressant, is a melatonergic MT(1)/MT(2) agonist with 5HT(2C) receptor antagonist activity. Randomized, controlled studies have shown that agomelatine reduces depression symptoms and is well tolerated during short-term and long-term treatment strategies. Low relapse rates (21.7% for agomelatine versus 46.6% for placebo after 6 months of continuation treatment; p < 0.0001) have been reported and are believed to be the result of the cumulative effect of agomelatine at all stages of depression. In particular, specific residual symptoms, such as anxiety and sleep disturbances, which increase the rate of relapse, are significantly improved with agomelatine treatment. Furthermore, quality of life during remission, which can affect adherence rates, is likely to be improved because sexual function and weight are preserved. The combination of these unique properties suggests that treatment with agomelatine will provide more sustained, longer-term remission because antidepressant efficacy is combined with fewer residual symptoms and better tolerability and adherence.
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PMID:The antidepressant agomelatine improves the quality of life of depressed patients: implications for remission. 2066 5

Agomelatine (Valdoxan - Servier) is an antidepressant licensed for treating patients with major depressive episodes. The drug company's website for agomelatine states that the drug acts simultaneously as a melatonin receptor agonist and a serotonin receptor antagonist and claims that it is a "major therapeutic advance in management of depression through the restoration of circadian rhythms". Here we consider whether agomelatine offers significant advantage for patients with major depressive episodes.
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PMID:Agomelatine for major depressive episodes. 2068

Twenty-three patients with moderate and severe nonpsychotic depressions without psychotic symptoms were treated with valdoxan during 8 weeks. Valdoxan was used in the combination with antidepressants and tranquilizers in 73.9% patients, the latter drugs were withdrawn after 3-6 weeks in 65.3% of cases. The distinct positive changes in the mental state of patients were seen on CGI-I and HADM-21 scales. To the end of the study, 69.6% of patients were practically healthy according to the CGI-S scale; 17.4% had border-line psychiatric disorder without symptoms of depression; 13% had mild depressive symptoms. No significant side-effects were observed in 91.3% of patients.
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PMID:[Treatment of patients with moderate and severe nonpsychotic depressions]. 2118 20


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