Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an
atypical antidepressant most commonly used to treat
major depressive disorder and
generalized anxiety disorder.[7] One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects.[7][8] Another review also found it was similarly effective to many other antidepressants.[9]
Common side effects include weight gain, fatigue,
liver problems, nausea, headaches, and anxiety.[10][11] Due to potential liver problems ongoing blood tests are recommended.[12] Its use is not recommended in people with
dementia or over the age of 75.[10] There is tentative evidence that it may have fewer side effects than some other antidepressants.[7] It acts by
blocking certain serotonin receptors and
activating melatonin receptors.[12]
Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010.[12] Its use is not approved in the United States and efforts to get approval were ended in 2011.[12] It was developed by the pharmaceutical company
Servier.[12]
Medical uses
Major depressive disorder
Agomelatine is used for the treatment of
major depressive episodes in adults in Europe.[13] Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in six of the ten short-term double-blind
placebo-controlled studies.[13] Two were considered "failed" trials, as comparators of established efficacy failed to differentiate from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies.[13] The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study.[13] One meta-analysis found agomelatine to be as effective as standard antidepressants, with an
effect size (
SMDTooltip standardized mean difference) of 0.24.[8][14]
In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed agomelatine to be one of the most effective and one of only two medications found to be more tolerable than placebo.[15]
A
meta-analysis found that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In people with a greater
baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points.[16] Controlled studies in humans have shown that agomelatine is at least as effective as the
SSRI antidepressants
paroxetine,
sertraline,
escitalopram, and
fluoxetine in the treatment of
major depression.[17] A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants.[9]
However, the body of research on agomelatine has been substantially affected by
publication bias, prompting analyses which take into account both published and unpublished studies.[8][18][19] These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as "marginally clinically relevant",[19] being only slightly above placebo.[18][19] According to a 2013 review, agomelatine did not seem to provide an advantage in efficacy over other antidepressants for the acute-phase treatment of major depression.[20]
It is not recommended in Europe for use in
children and
adolescents below 18 years of age due to a lack of data on
safety and
efficacy.[13] However, a recent 12 week study first reported in September 2020, and published in 2022 showed greater efficacy vs. placebo for agomelatine 25 mg per day in youth age 7–17 years and an acceptable tolerability profile with similar efficacy to
fluoxetine.[26][27] Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.[13]
Agomelatine is contraindicated in patients with kidney or
liver impairment.[13] According to information disclosed by Servier in 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the
European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decide whether to pursue the treatment or not.[28] No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate
renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.[13]
Adverse effects
Agomelatine does not alter daytime
vigilance and
memory in healthy volunteers. In depressed patients, treatment with the drug increased
slow wave sleep without modification of REM (
rapid eye movement) sleep amount or REM latency.[29] Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.[2][13]
Agomelatine appears to cause fewer
sexual side effects and discontinuation effects than paroxetine.[2]
Common (1–10% incidence) adverse effects include[2][13][30][31]
Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature)
Weight gain or loss, which tends to be less significant than with
SSRIs[32]
Dependence and withdrawal
No dosage tapering is needed on treatment discontinuation.[13] Agomelatine has no
abuse potential as measured in healthy volunteer studies.[2][13]
Overdose
Agomelatine is expected to be relatively safe in overdose.[33]
Interactions
Agomelatine is a substrate of
CYP1A2,
CYP2C9 and
CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant
fluvoxamine, reduce its clearance and can lead to an increase in agomelatine exposure, and possibly serotonin syndrome
.[2][30] There is also the potential for agomelatine to interact with
alcohol to increase the risk of
hepatotoxicity.[2][30]
Agomelatine has shown an antidepressant-like effect in
animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and
melatonin onset.[13]
In March 2005, Servier submitted agomelatine to the
European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax.[45] On 27 July 2006, the
Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about
side effects.[45] In September 2007, Servier submitted a new marketing application to the EMA.[46]
In March 2006,
Servier announced it had sold the rights to market agomelatine in the United States to
Novartis.[47] It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012.[48] However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.[49]
^
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^Montgomery SA, Kasper S (September 2007). "Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine". International Clinical Psychopharmacology. 22 (5): 283–91.
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