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)

Sleep disturbances are often associated with depression and mood disorders, and certain manipulations of the sleep-wake cycle are effective as therapeutic interventions in the treatment of depression. Dysregulated circadian rhythms are thereby considered as causal. Circadian rhythms in mammals are mainly regulated by a core biological clock, located in the hypothalamic suprachiasmatic nucleus; its pacemaker activity is regulated by light and nonphotic modulatory pathways, and the driving mechanisms are serotonergic input from the raphe and the hormone melatonin originating from the pineal gland. In line, the concentration of brain serotonin and the levels of 5-HT2C receptors are high and highly expressed there. Agomelatine, a novel antidepressant drug with proven clinical efficacy in major depressive disorder, has a unique mechanism of action; it acts as an agonist at melatonergic MT1 and MT2 receptors and as an antagonist at 5-HT2C receptors. In animals, agomelatine was shown to increase noradrenaline and dopamine (but not serotonin) in the frontal cortex, to resynchronize the sleep-wake cycle in models with disrupted circadian rhythms, and to exhibit a clear antidepressant effect in various animal models of depression. On the basis of the functional relationship between melatonergic and serotonergic signaling in the suprachiasmatic nucleus, and given agomelatine's affinity at melatonergic and 5-HT2C receptors, the therapeutic efficacy of the drug may be due to the potential synergy of its action at these different receptors.
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PMID:The interaction between the internal clock and antidepressant efficacy. 1791 64

This article reviews the novel atypical antidepressant drug agomelatine (Valdoxan), which is currently being actively investigated in the United States for the treatment of depression but is not yet approved by the U.S. Food and Drug Administration. Agomelatine is a synthetic analog of the hormone melatonin and has unique pharmacological properties that distinguish it from other currently available antidepressant drugs. Agomelatine is efficacious, safe, and well tolerated but does not appear to have major efficacy advantages compared with other antidepressant drugs. Because of its unique pharmacology and relatively benign tolerability profile, however, it may be a more effective alternative for patients who do not respond to or cannot tolerate currently available antidepressant drugs.
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PMID:Agomelatine: a novel atypical antidepressant. 1824 59

Novartis and Servier are developing agomelatine for the treatment of depression. Agomelatine is a specific melatonin (MT1 and MT2) receptor agonist that also has antagonistic activities at serotonin-(2C) (5-HT(2C)) receptors. Novartis believes agomelatine is comparable to current standard therapies for depression with improved tolerability, including a low propensity to cause sexual dysfunction and weight gain. Clinical development is being conducted in the US for the treatment of depression; approval for this indication was declined in the EU, apparently due to insufficient data. Servier has also conducted a trial of the agent in patients with generalized anxiety disorder in France, South Africa and Finland, and a phase II trial in sleep disorders in France. In March 2006, Servier and Novartis signed a licensing agreement for agomelatine. Novartis obtained the exclusive rights for the development and marketing of agomelatine in the US and several other countries. Servier retained the rights to the product in the rest of the world. The clinical development plan for agomelatine includes phase III trials being conducted under the parAGOn clinical trial programme. One US-based trial that began in March 2007 (NCT00463242) is recruiting 490 patients with depression who will receive placebo or agomelatine 25 or 50 mg for 8 weeks and will then receive open-label agomelatine for 52 weeks. Novartis is also conducting an 8-week phase III trial (NCT00411099) comparing the safety and efficacy of agomelatine 25 and 50 mg in patients with major depressive disorder. A follow-up, 52-week open-label extension study (CAGO178A2301E) will also be conducted. Another phase III study underway is NCT00411242, which has the same design and is also followed by a 52-week open-label extension study (CAGO178A2302E). These studies are all expected to be completed by January 2009. In July 2006, the Committee for Medicinal Products for Human Use recommended the refusal of marketing authorisation for agomelatine for the treatment of depression. Servier had applied for a re-examination of the finding but withdrew the request in November 2006. Servier's MAA was not supported due to insufficient data and no recent development has been reported in this indication in the EU. Agomelatine prevented relapse in patients with depression compared with placebo and was well tolerated in an international phase III trial.
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PMID:Agomelatine: AGO 178, AGO178, S 20098. 1845 70

The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential. Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex). The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placebo-controlled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25mg/day, with the possibility of increasing doses to 50mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatine's efficacy over a longer treatment period.
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PMID:Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. 1858 4

Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT(2C) receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.
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PMID:The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats. 1870 30

Desynchronisation of normal circadian rhythms, including the sleep-wake rhythm, is common in major depressive disorder (MDD). The association between sleep disturbances and depression has long been recognised. Disturbed sleep is a diagnostic criterion for MDD, and insomnia commonly precedes the onset of symptomatic mood disorders. Disruptions of the sleep-wake cycle (sleep architecture and timing) are residual symptoms that may prevent the attainment of high-quality remission and delay recovery from MDD. Therefore, early recognition and treatment of sleep disturbances may be important for the treatment and prevention of recurrent depression. Evidence suggests that melatonergic (MT(1) and MT(2)) and the 5-HT(2C) serotonergic receptor subtypes are important modulators of circadian rhythmicity. Agomelatine is the first melatonergic antidepressant; an agonist of melatonin MT(1) and MT(2) receptors, with additional antagonist properties at the 5-HT(2C) receptors. Agomelatine combines antidepressant efficacy including quality and efficiency of sleep, with a more favourable side-effect profile than current antidepressant treatments, including neutral effects on sexual function, bodyweight and the absence of discontinuation symptoms. These positive features provide a novel approach to the treatment of depression and the attainment of high-quality remission in MDD.
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PMID:Addressing circadian rhythm disturbances in depressed patients. 1875 78

Major depressive disorder (MDD) is a prevalent condition with substantial heterogeneity in terms of clinical symptom profiles, overlapping syndromes and degree of severity. The challenge for any new antidepressant is to demonstrate efficacy across the spectrum of patient subpopulations with a diagnosis of MDD. The anxious depressed patient historically has a lower rate of response to traditional antidepressants and high pretreatment anxiety symptoms have also been shown to increase the risk of recurrence. In addition, severity based on standard antidepressant rating scale scores influences treatment outcomes. Some antidepressants display greater placebo separation at higher levels of severity while others fail to separate from placebo in more severe populations. Gender differences in antidepressant response have also been reported in several studies. In particular, women appear to experience a greater side-effect burden with current antidepressants. This is also important in treating late-life depression, where elderly patients are more prone to experiencing side effects and drug interactions. Despite the improved tolerability with SSRIs and other novel antidepressants, restoration of healthy sleep patterns has frequently been lacking. Finally, antidepressant efficacy must include demonstrated relapse prevention during placebo-controlled drug discontinuation trials. As a novel antidepressant with melatonin receptor agonist and 5HT(2C) antagonist properties, agomelatine has demonstrated efficacy in randomized placebo-controlled trials. Additional analyses support the benefits of agomelatine in anxious depression, increasing efficacy with greater baseline severity, including severe late-life depression. Agomelatine has also demonstrated favourable tolerability and efficacy in separate analyses of women and men and displays successful relapse prevention at doses 25 and 50 mg. Both subjective and polysomnographic measures of sleep support increased sleep efficiency and decreased awakenings during agomelatine treatment. Combining these efficacy data with favourable effects on sexual function, CNS and GI systems, there are grounds to endorse the view that agomelatine is a well-tolerated and efficacious antidepressant for a diverse range of depressed populations.
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PMID:Treating each and every depressed patient. 1875 79

There are many potentials for the development of more effective, better tolerated, and more rapidly acting antidepressants. As there is large prevalence of circadian dysfunction in various affective disorders, including depression, one of the approaches is the development of antidepressant drugs with melatonergic agonist properties. Agomelatine, with its melatonergic agonistic (at both MT(1) an MT(2) receptors) and 5-HT(2C) antagonistic properties, represents a new concept for the treatment of depression. The antidepressant action of agomelatine has been initially demonstrated in animal models of depression, such as the forced swim - the learned helplessness - and the chronic mild stress paradigms. Subsequent studies demonstrated that the antidepressant activity of agomelatine does not solely depend on its agonistic action at melatonergic receptors, but also on its antagonistic activity at 5-HT(2C) receptors. Agomelatine also exhibits anxiolytic properties that bear a striking resemblance to those of selective 5-HT(2C) receptor antagonists. In patients with major depressive disorder, agomelatine had efficacy at least comparable to that seen with available antidepressants. Interestingly, agomelatine demonstrated antidepressant efficacy not only in patients with a moderate depressive episode but also in a more severe depressed subpopulation of patients. The treatment effect increased with the severity of the disease. Agomelatine also rapidly regulates the sleep-wake cycle without causing sedation and improves daytime condition. Agomelatine has an excellent safety profile, is weight neutral, does not affect sexual functioning and does not cause discontinuation syndrome. Collectively, its efficacy, together with its excellent tolerability, makes agomelatine an especially promising antidepressant for the near future.
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PMID:Beyond the monoaminergic hypothesis: agomelatine, a new antidepressant with an innovative mechanism of action. 1925 35

Despite advances in understanding potential disease mechanisms and in developing novel therapeutic approaches to the treatment of major depressive disorder, the disease continues to carry an enormous personal, social, and economic burden. Agomelatine represents an important opportunity to advance the treatment of depression. It is a melatonergic (MT(1) and MT(2)) agonist and serotonergic (5HT(2C)) antagonist. Evidence from animal models of depression, complements emerging clinical data. In a dose range of 25-50 mg daily, agomelatine is an effective antidepressant with a very favorable side-effect profile. In particular, sleep restorative action in the absence of sedation and minimal effect on sexual function suggests that agomelatine represents a worthwhile treatment alternative for patients with major depressive disorder.
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PMID:Agomelatine and its therapeutic potential in the depressed patient. 1930 May 71

Agomelatine markedly differs from other classes of antidepressant drugs: its primary molecular targets in vivo are the melatonin MT(1) and MT(2) receptors, where it acts as a potent agonist, and the 5-HT(2C) receptors, where it exerts clear-cut antagonist properties. Agomelatine across a wide range of clinical trials suggests that agomelatine offers an important alternative for the treatment of depression, combining efficacy, even in the most severely depressed patients, with a favorable side-effect profile. It will be of interest to see if agomelatine expands the spectrum of treatment for unipolar depression. It shows efficacy in acute phase and in of maintenance treatment compared to reference antidepressants as paroxetine and venlafaxine.
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PMID:Melatonin receptor agonist agomelatine: a new drug for treating unipolar depression. 1944 80


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