Agomelatine in the treatment of major depressive disorder. Potential for clinical effectiveness

Department of Psychiatry, University Health Network, Toronto, Ontario, Canada.
CNS Drugs (Impact Factor: 4.38). 03/2010; 24(6):479-99. DOI: 10.2165/11534420-000000000-00000
Source: PubMed

ABSTRACT To demonstrate the clinical effectiveness of an antidepressant drug requires evidence beyond short- and long-term efficacy, including a favourable adverse-effect profile and sustained treatment adherence. Under these conditions, patients should experience enhanced social and functional outcomes. The novel antidepressant agomelatine, a melatonergic MT(1)/MT(2) receptor agonist with serotonin 5-HT(2C) receptor antagonist activity, displays antidepressant efficacy with a favourable adverse-effect profile that is associated with good patient adherence. Specifically, agomelatine has demonstrated significant short-term (6-8 weeks) and sustained (6 months) antidepressant efficacy relative to placebo, as well as evidence of relapse prevention (up to 10 months). In head-to-head comparative studies with venlafaxine and sertraline, there was evidence of early (at 1-2 weeks) and sustained (at 6 months) advantages for agomelatine. In addition to evidence of early efficacy, agomelatine also restored disturbed sleep-wake patterns early in treatment. There was no evidence of antidepressant-induced sexual dysfunction, weight gain or discontinuation-emergent symptoms. Agomelatine has demonstrated a range of properties that suggest it could offer advantages over current treatments for major depressive disorder, although further comparative trials are still required, as is evidence from real-world clinical practice.

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    • "Moreover, these apparently negative attributes suggest a greater risk of breakthrough depressive symptoms than other antidepressants because of a lack of sustained binding to its neurobiological target, unless multiple daily dosing is applied. Nevertheless, as noted earlier, agomelatine has as yet not been associated with ADS (Chanrion et al., 2008; Aloyo et al., 2009), while 25–50 mg agomelatine once daily is as effective an antidepressant as comparator antidepressants (Kennedy and Rizvi, 2010). Despite the reasons already described earlier validating its low risk for inducing ADS, the latter paradox prompts further discussion on the pharmacokinetic and pharmacodynamic characteristics of agomelatine. "
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    ABSTRACT: Objective Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology.DesignThe relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS.ResultsAltered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems.Conclusions This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome. Copyright © 2014 John Wiley & Sons, Ltd.
    Human Psychopharmacology Clinical and Experimental 11/2014; 29(6). DOI:10.1002/hup.2429 · 1.85 Impact Factor
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    • "The efficacy of the antidepressant agomelatine has broadly been demonstrated both in preclinical and clinical trials (Fornaro et al. 2010; Kennedy & Emsley, 2006). Due to the small impact on other receptors, only a few side-effects and good tolerance, the rates of discontinuation of treatment are low (Kennedy & Rizvi, 2010). Agomelatine has a short plasma half-life of 1–2 h and an absolute bioavailability of 5–10 % due to its high hepatic first-pass metabolism. "
    The International Journal of Neuropsychopharmacology 07/2012; 16(2):1-3. DOI:10.1017/S1461145712000648 · 5.26 Impact Factor
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    • "Agomelatine is a novel mechanism antidepressant characterized by pharmacological activity as an agonist at melatonergic MT 1 and MT 2 receptors, and an antagonist at 5-HT 2c receptors (Millan et al., 2003; Audinot et al., 2003). There is some evidence to suggest that agomelatine is associated with early onset of improvement in MDD (Kennedy and Rizvi, 2010; Lam, 2010). Recent RCTs have shown that agomelatine statistically separated from placebo at 1 week on depressive symptoms (Stahl et al., 2010), and at 2 weeks, on depressive symptoms from placebo (Oli e and Kasper, 2007) and sertraline (Kasper et al., 2010). "
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    ABSTRACT: There is still considerable controversy about the onset and time course of improvement with antidepressants in the treatment of major depressive disorder. Previous studies suggested a delayed-onset hypothesis with therapeutic improvement taking several weeks, but recent meta-analyses have shown support for earlier onset of improvement within the first week or two of treatment. This paper briefly reviews the evidence, focused on antidepressant studies published since 2006, for early onset of improvement within the first 2 weeks of treatment. A PubMed electronic search was conducted with selection of relevant studies from 2007 to March 2012. With the caveat of methodological limitations, results from randomized clinical trials, meta-analyses and naturalistic studies consistently show that: (1) antidepressants in general have early onset of improvement, (2) some antidepressants, including the novel mechanism agent, agomelatine, are associated with early improvement in both core and specific symptoms such as anhedonia and sleep–wake disturbances, and (3) early improvement predicts sustained response and remission. Use of newer statistical methods to examine individual response trajectories may address some of the methodological limitations of previous studies. The predictive value of early improvement has important clinical relevance for antidepressant treatment. Measurement-based assessment for response should occur earlier and more frequently. A lack of improvement (defined as ≤20% reduction from baseline in scores on a depression rating scale) at 2–3 weeks after initiation of an antidepressant should prompt the clinician to consider a change in management.
    European Neuropsychopharmacology 01/2012; 22:S492–S498. DOI:10.1016/j.euroneuro.2012.07.005 · 5.40 Impact Factor
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