Agomelatine

updated

Agomelatine is authorized in the EU for major depressive episodes in adults (Valdoxan, 2009), after a 2006 refusal for insufficiently shown effectiveness, and no FDA-approved product was located on 9 October 2026. Its effect over placebo is small (SMD 0.24, about 1.5 Hamilton points) with evidence of publication bias, and the EU label requires liver monitoring. A PubMed search found no trial of cognitive enhancement in people with disrupted sleep-wake cycles.

Antidepressant

  • CHMP adopted a negative opinion on 27 July 2006 for insufficiently shown effectiveness, and the EMA page records refusal of the marketing authorization on 16 January 2007; Valdoxan was later authorized in the EU on 19 February 2009.
  • A meta-analysis including unpublished trials found a mean difference of -1.51 Hamilton depression points in favor of agomelatine and substantial publication bias; a meta-analysis of 20 trials (7,460 participants) found SMD 0.24 over placebo.
  • A 2026 meta-analysis of 25 placebo-controlled trials (6,812 participants) found no significant effect on objective total sleep time (MD -15.73 minutes) and a small gain in subjective sleep quality (SMD 0.31).
  • In 8 healthy older men given agomelatine 50 mg for 15 days, the body-temperature and cortisol rhythms advanced by nearly 2 hours and no polysomnographic sleep variable changed.
  • The EU product information requires liver function tests and contraindicates hepatic impairment and potent CYP1A2 inhibitors; a pooled analysis found transaminases above 3 times normal in 1.3% on 25 mg and 2.5% on 50 mg versus 0.5% on placebo.
  • A PubMed search on 9 October 2026 returned 25 records on agomelatine with cognition and sleep-wake terms, and none tested cognitive enhancement in people with disrupted sleep-wake cycles.

Where is agomelatine approved, and for what?

Agomelatine is authorized in the EU for major depressive episodes in adults (Valdoxan, since 19 February 2009), after an earlier refusal for insufficiently shown effectiveness. No FDA-approved agomelatine product was located.

On 27 July 2006 CHMP adopted a negative opinion on Valdoxan/Thymanax (agomelatine 25 mg) for major depressive disorder, and the EMA page records refusal of the marketing authorization on 16 January 2007. The main concern was insufficiently shown effectiveness: the long-term study did not show efficacy, and the size of the short-term effect did not allow a firm conclusion. CHMP had no special safety concerns at that time. The company later reapplied.

Valdoxan has been authorized in the EU for major depressive episodes in adults since 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier). The EU product information was last updated on 15 April 2025.

openFDA Drugs@FDA queries for agomelatine returned no application on 9 October 2026, and a DailyMed search returned no agomelatine label. This supports only a dated, US-scoped statement.

Agomelatine is C15H17NO2 (243.30 g/mol, CAS 138112-76-2), N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, a single defined molecule. Supplier material has not been compared with that record.

EMA: negative opinion 27 July 2006, refusal recorded 16 January 2007

Regulatory record

European Medicines Agency. Valdoxan/Thymanax (agomelatine 25 mg film-coated tablets), EPAR page recording the 2006 negative CHMP opinion and the 2007 refusal of marketing authorization, with the linked question-and-answer document.

On 27 July 2006 CHMP adopted a negative opinion on Valdoxan/Thymanax (agomelatine 25 mg) for major depressive disorder, and the EMA page records refusal of the marketing authorization on 16 January 2007. The linked question-and-answer document gives the main concern as insufficiently shown effectiveness: the long-term study did not show efficacy, and the size of the short-term effect did not allow a firm conclusion. CHMP had no special safety concerns at that time. The company later reapplied.

Participants / model
Adults with major depressive disorder in the submitted program
Treatment
Agomelatine 25 mg film-coated oral tablets
Follow-up
Regulatory decision, 2006 to 2007
Study design
Official EMA regulatory benefit-risk decision
Funding
not stated in the source

A refusal for insufficient efficacy, not for safety. The EU authorization of 2009 followed a new application.

Read the original source
EMA EPAR: authorized 19 February 2009, benefit possibly smaller than other antidepressants

Regulatory record

European Medicines Agency. Valdoxan EPAR summary, agomelatine, authorized in the EU on 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier).

Valdoxan has been authorized in the EU for major depressive episodes in adults since 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier). In five short-term placebo-controlled studies in 1,893 adults, agomelatine beat placebo in the two studies without an active comparator and did not differ from placebo in the three with fluoxetine or paroxetine arms, two of which also showed no effect of the comparator. In two relapse-prevention studies in 706 patients, one showed no difference and the other showed relapse in 21% (34 of 165) on agomelatine versus 41% (72 of 174) on placebo over 24 weeks. CHMP noted the benefit might be smaller than with other antidepressants and supported approval provided liver function is tested frequently.

Participants / model
Adults with major depression in the submitted studies
Treatment
Oral agomelatine 25 to 50 mg in the submitted studies
Follow-up
Short-term studies read at 6 weeks; relapse prevention over 24 weeks
Study design
Official EMA EPAR summary of submitted studies
Funding
not stated in the source

The summary reports the sponsor's submitted studies and the committee's reading of them. It is not a new trial.

Read the original source
Valdoxan EU product information, updated 15 April 2025: liver warnings, contraindications, PK

Official label

European Medicines Agency. Valdoxan EPAR product information (summary of product characteristics), agomelatine 25 mg film-coated tablets, last updated 15 April 2025.

Liver function tests are required before starting and at regular intervals during treatment; treatment is not started, or is stopped, if transaminases exceed 3 times the upper limit of normal. Contraindications are hepatic impairment (cirrhosis or active liver disease), transaminases above 3 times normal, and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Efficacy and safety are established in older patients under 75, and the product information says agomelatine should not be used at 75 and older, where no effect is documented. Post-marketing liver injury includes hepatic failure, with exceptional fatal outcomes or liver transplants in patients with hepatic risk factors. In trials, ALT or AST above 3 times normal occurred in 1.2% on 25 mg and 2.6% on 50 mg versus 0.5% on placebo. Absolute oral bioavailability is below 5% with substantial interindividual variation (higher in women and with oral contraceptives, lower in smokers), peak levels come within 1 to 2 hours, and the mean half-life is 1 to 2 hours.

Participants / model
Adults with major depressive episodes; label PK participants
Treatment
Valdoxan 25 mg film-coated oral tablets
Follow-up
Product information last updated 15 April 2025
Study design
Official EMA product information
Funding
not stated in the source

An EU label, not an FDA label. Dosing and monitoring-schedule details are left out of this page. The age limit appears in the posology section as a statement that agomelatine should not be used at 75 and older; the contraindications section does not list age.

Read the original source
openFDA, 9 October 2026: no agomelatine application or label

Regulatory record

U.S. Food and Drug Administration. openFDA Drugs@FDA queries for agomelatine by brand or generic name and by active ingredient, run on 9 October 2026, with a DailyMed label search.

openFDA Drugs@FDA queries for agomelatine, by brand or generic name and by active ingredient, returned no application on 9 October 2026, and a DailyMed search returned no agomelatine label.

Participants / model
Not a clinical population
Treatment
Drug applications
Follow-up
Search run on 9 October 2026
Study design
Dated US approval-record search
Funding
not stated in the source

This supports a dated, US-scoped statement only: no FDA-approved agomelatine product was located.

Read the original source
PubChem: agomelatine identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 82148 (agomelatine).

Agomelatine: PubChem CID 82148, C15H17NO2, 243.30 g/mol, CAS 138112-76-2, N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide. It is a single defined molecule.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only. Supplier material has not been compared with the record.

Read the original source

What did the studies behind the EU approval show?

Agomelatine beat placebo in the two short-term studies without an active comparator and did not differ from placebo in the three with fluoxetine or paroxetine arms. Relapse prevention was inconsistent across two studies.

In five short-term placebo-controlled studies in 1,893 adults, agomelatine beat placebo in the two studies without an active comparator and did not differ from placebo in the three with fluoxetine or paroxetine arms, two of which also showed no effect of the comparator.

In two relapse-prevention studies in 706 patients, one showed no difference and the other showed relapse in 21% (34 of 165) on agomelatine versus 41% (72 of 174) on placebo over 24 weeks.

CHMP noted the benefit might be smaller than with other antidepressants and supported approval provided liver function is tested frequently.

EMA EPAR: authorized 19 February 2009, benefit possibly smaller than other antidepressants

Regulatory record

European Medicines Agency. Valdoxan EPAR summary, agomelatine, authorized in the EU on 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier).

Valdoxan has been authorized in the EU for major depressive episodes in adults since 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier). In five short-term placebo-controlled studies in 1,893 adults, agomelatine beat placebo in the two studies without an active comparator and did not differ from placebo in the three with fluoxetine or paroxetine arms, two of which also showed no effect of the comparator. In two relapse-prevention studies in 706 patients, one showed no difference and the other showed relapse in 21% (34 of 165) on agomelatine versus 41% (72 of 174) on placebo over 24 weeks. CHMP noted the benefit might be smaller than with other antidepressants and supported approval provided liver function is tested frequently.

Participants / model
Adults with major depression in the submitted studies
Treatment
Oral agomelatine 25 to 50 mg in the submitted studies
Follow-up
Short-term studies read at 6 weeks; relapse prevention over 24 weeks
Study design
Official EMA EPAR summary of submitted studies
Funding
not stated in the source

The summary reports the sponsor's submitted studies and the committee's reading of them. It is not a new trial.

Read the original source

What did the depression trials find?

The effect over placebo is small: about 1.5 Hamilton points in a meta-analysis that included unpublished trials, and SMD 0.24 across 20 trials, with publication bias. A network meta-analysis found fewer dropouts than placebo.

A meta-analysis of published and unpublished placebo-controlled trials in adults with unipolar major depression (10 acute-phase and 3 relapse-prevention studies, 7 of them unpublished) found a mean difference of -1.51 Hamilton depression points in favor of agomelatine (99% CI -2.29 to -0.73, nine studies), an advantage in response but not remission, and no significant relapse prevention (RR 0.78, 99% CI 0.41 to 1.48). None of the negative trials had been published. The authors judged a clinically important difference from placebo unlikely and found substantial publication bias.

A meta-analysis of 20 double-blind randomized trials (7,460 participants), drawing on published papers, the EMA file, and the manufacturer, found agomelatine more effective than placebo (SMD 0.24, 95% CI 0.12 to 0.35; response RR 1.25, 95% CI 1.11 to 1.4) and equal to other antidepressants (SMD 0.00, 95% CI -0.09 to 0.10). Published trials were more favorable than unpublished ones. The first author reported fees and grants from Servier outside this work.

A network meta-analysis of 522 trials (116,477 participants) found all 21 antidepressants more effective than placebo. Agomelatine was one of two drugs with fewer dropouts than placebo (OR 0.84, 95% CrI 0.72 to 0.97) and, in head-to-head trials, was among the more effective and more tolerable drugs. Certainty of evidence was moderate to very low.

Meta-analysis with unpublished trials: 1.51 Hamilton points, publication bias

Systematic review and meta-analysis

Koesters M et al. Br J Psychiatry. 2013;203(3):179-87. PMID 23999482.

Across 10 acute-phase and 3 relapse-prevention studies, 7 of them unpublished, the mean difference was -1.51 Hamilton depression points in favor of agomelatine (99% CI -2.29 to -0.73, nine studies), with an advantage in response but not remission and no significant relapse prevention (RR 0.78, 99% CI 0.41 to 1.48). None of the negative trials had been published. The authors judged a clinically important difference from placebo unlikely and found substantial publication bias.

Participants / model
Adults with unipolar major depression in randomized trials
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 10 acute-phase and 3 relapse-prevention placebo-controlled studies
Funding
not stated in the source

Includes unpublished trials. Seven of the 13 studies were unpublished.

Read the original source
20 trials, 7,460 participants: SMD 0.24 over placebo, equal to other antidepressants

Systematic review and meta-analysis

Taylor D et al. BMJ. 2014;348:g1888. PMID 24647162.

Agomelatine was more effective than placebo (SMD 0.24, 95% CI 0.12 to 0.35; response RR 1.25, 95% CI 1.11 to 1.4) and equal to other antidepressants (SMD 0.00, 95% CI -0.09 to 0.10). Published trials were more favorable than unpublished ones.

Participants / model
Adults with depression in double-blind randomized trials (7,460 participants in 20 trials)
Treatment
Oral agomelatine versus placebo or comparator antidepressants
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 20 double-blind randomized trials
Funding
not stated in the source (the first author reported fees and grants from Servier outside this work)

Published trials were more favorable than unpublished ones. The first author reported fees and grants from Servier outside this work.

Read the original source
Network meta-analysis: 522 trials, agomelatine fewer dropouts than placebo (OR 0.84)

Systematic review and meta-analysis

Cipriani A et al. Lancet. 2018;391(10128):1357-1366. PMID 29477251.

All 21 antidepressants were more effective than placebo. Agomelatine was one of two drugs with fewer dropouts than placebo (OR 0.84, 95% CrI 0.72 to 0.97) and, in head-to-head trials, was among the more effective and more tolerable drugs. Certainty of evidence was moderate to very low.

Participants / model
Adults with major depressive disorder in double-blind randomized trials (522 trials, 116,477 participants)
Treatment
Oral antidepressants, including agomelatine
Follow-up
not stated in the source
Study design
Systematic review and network meta-analysis of 522 double-blind randomized trials
Funding
not stated in the source

Certainty of evidence was moderate to very low across comparisons.

Read the original source

Does agomelatine normalize sleep and circadian rhythm or enhance cognition?

Depression is supported at the EU label level, with a modest effect. Sleep benefits are mostly subjective, with no gain in objective total sleep time, and no trial found tests cognitive enhancement in people with disrupted sleep-wake cycles.

Sellers market agomelatine for sleep and circadian normalization, depression, and cognitive enhancement in people with disrupted sleep-wake cycles. Depression is the EU labeled use, covered above, with a modest effect over placebo.

A PubMed search on 9 October 2026 for agomelatine with cognition, cognitive, memory, attention, or executive and with healthy, volunteers, shift work, jet lag, or circadian in the title or abstract returned 25 records. None tested cognitive enhancement in people with disrupted sleep-wake cycles, shift work, or jet lag. The records were reviews (including jet lag), rodent, cell, and drug-interaction studies, two studies in depressed patients (a pilot attention study and an EEG biomarker study), a 7-day emotional-processing study in healthy volunteers (PMID 20660010), and a 2026 preprint, not peer reviewed, reporting effects on reinforcement learning in 128 healthy volunteers over 8 weeks (PMID 41542676).

The sleep and circadian findings are in the next section.

PubMed search, 9 October 2026: 25 records, none on cognition with disrupted sleep-wake cycles

PubMed search record

PubMed search run on 9 October 2026: agomelatine[tiab] AND (cognition OR cognitive OR memory OR attention OR executive)[tiab] AND (healthy OR volunteers OR shift work OR jet lag OR circadian)[tiab]. 25 records returned.

The search returned 25 records. None tested cognitive enhancement in people with disrupted sleep-wake cycles, shift work, or jet lag. The records were reviews (including jet lag), rodent, cell, and drug-interaction studies, two studies in depressed patients (a pilot attention study and an EEG biomarker study), a 7-day emotional-processing study in healthy volunteers (PMID 20660010), and a 2026 preprint, not peer reviewed, reporting effects on reinforcement learning in 128 healthy volunteers over 8 weeks (PMID 41542676).

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. The reinforcement-learning result is a preprint.

Read the original source
2026 sleep meta-analysis: 25 trials, no gain in objective total sleep time

Systematic review and meta-analysis

Stefanou A et al. J Sleep Res. 2026;35(3):e70231. PMID 41177901.

Across 25 placebo-controlled trials (6,812 participants), agomelatine had no significant effect on objective total sleep time (MD -15.73 minutes, 95% CI -49.68 to 18.22). It gave a small improvement in subjective sleep quality (SMD 0.31, 95% CI 0.21 to 0.40), fewer reports of insomnia (RR 0.59, 95% CI 0.39 to 0.90), more reports of somnolence (RR 1.34, 95% CI 1.02 to 1.75), and marginally more adverse effects overall (RR 1.05, 95% CI 1.00 to 1.11). The abstract does not break results down by diagnosis.

Participants / model
Participants in placebo-controlled randomized trials across populations (6,812 participants)
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 25 placebo-controlled trials
Funding
not stated in the source

The abstract does not state which diagnoses the trials covered.

Read the original source

What do the sleep and circadian-rhythm studies show?

Sleep gains are mostly subjective, with no significant change in objective total sleep time. A circadian phase advance appeared in 8 healthy older men without any sleep change, and the delayed sleep-wake phase study had no no-drug arm.

A 2026 meta-analysis of 25 placebo-controlled trials (6,812 participants) reporting sleep outcomes found no significant effect of agomelatine on objective total sleep time (MD -15.73 minutes, 95% CI -49.68 to 18.22), a small improvement in subjective sleep quality (SMD 0.31, 95% CI 0.21 to 0.40), fewer reports of insomnia (RR 0.59, 95% CI 0.39 to 0.90), more reports of somnolence (RR 1.34, 95% CI 1.02 to 1.75), and marginally more adverse effects overall (RR 1.05, 95% CI 1.00 to 1.11). The abstract does not break results down by diagnosis.

In a 6-week double-blind trial in 313 outpatients with major depressive disorder, agomelatine 25 to 50 mg (154 patients) improved the actigraphy-measured relative amplitude of the rest-activity cycle more than sertraline 50 to 100 mg (159 patients) at the end of week 1 (P = .01), with greater improvement in actigraphic sleep latency and sleep efficiency from week 1 to week 6 (both P < .001) and in depressive and anxiety symptoms (P < .05).

In 8 healthy older men given agomelatine 50 mg or placebo in the early evening for 15 days in a double-blind crossover design, agomelatine advanced the body-temperature and cortisol rhythms by nearly 2 hours but had no effect on any polysomnographic sleep variable. It also stimulated growth hormone secretion during waking and transiently raised prolactin.

In a nonblinded trial, 60 young adults (19 to 24 years) with delayed sleep-wake phase disorder all received 4 weeks of agomelatine and were randomized to cognitive behavioral therapy or no CBT. Sleep-wake timing shifted earlier in both groups (p < .001), and the groups differed on sleep duration, sleep quality, sleep difficulties, daytime sleepiness, and wellbeing. With no placebo or no-drug arm, the shift cannot be attributed to agomelatine rather than to time or expectation.

2026 sleep meta-analysis: 25 trials, no gain in objective total sleep time

Systematic review and meta-analysis

Stefanou A et al. J Sleep Res. 2026;35(3):e70231. PMID 41177901.

Across 25 placebo-controlled trials (6,812 participants), agomelatine had no significant effect on objective total sleep time (MD -15.73 minutes, 95% CI -49.68 to 18.22). It gave a small improvement in subjective sleep quality (SMD 0.31, 95% CI 0.21 to 0.40), fewer reports of insomnia (RR 0.59, 95% CI 0.39 to 0.90), more reports of somnolence (RR 1.34, 95% CI 1.02 to 1.75), and marginally more adverse effects overall (RR 1.05, 95% CI 1.00 to 1.11). The abstract does not break results down by diagnosis.

Participants / model
Participants in placebo-controlled randomized trials across populations (6,812 participants)
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 25 placebo-controlled trials
Funding
not stated in the source

The abstract does not state which diagnoses the trials covered.

Read the original source
Actigraphy trial: 313 depressed outpatients, 6 weeks, agomelatine versus sertraline

Randomized controlled trial

Kasper S et al. J Clin Psychiatry. 2010;71(2):109-20. PMID 20193645.

Agomelatine 25 to 50 mg (154 patients) improved the actigraphy-measured relative amplitude of the rest-activity cycle more than sertraline 50 to 100 mg (159 patients) at the end of week 1 (P = .01), with greater improvement in actigraphic sleep latency and sleep efficiency from week 1 to week 6 (both P < .001) and in depressive and anxiety symptoms (P < .05).

Participants / model
313 outpatients with major depressive disorder
Treatment
Oral agomelatine 25 to 50 mg versus sertraline 50 to 100 mg
Follow-up
6 weeks
Study design
Double-blind randomized trial with wrist actigraphy, HAM-D and HAM-A
Funding
not stated in the source

A comparison with sertraline, not placebo, in depressed outpatients.

Read the original source
8 healthy older men, 15 days: rhythms advanced about 2 hours, no sleep change

Randomized controlled trial

Leproult R et al. Clin Endocrinol (Oxf). 2005;63(3):298-304. PMID 16117817.

Agomelatine advanced the body-temperature and cortisol rhythms by nearly 2 hours but had no effect on any polysomnographic sleep variable. It also stimulated growth hormone secretion during waking and transiently raised prolactin.

Participants / model
8 healthy older men
Treatment
Oral agomelatine 50 mg in the early evening, or placebo, for 15 days
Follow-up
15 days
Study design
Double-blind crossover study
Funding
not stated in the source

A tiny study in healthy older men. It showed a circadian phase shift without any sleep change.

Read the original source
Delayed sleep-wake phase disorder: 60 young adults, nonblinded, no no-drug arm

Randomized controlled trial

Yu Y et al. Behav Sleep Med. 2023;21(5):529-539. PMID 36263691.

All participants received 4 weeks of agomelatine and were randomized to cognitive behavioral therapy or no CBT. Sleep-wake timing shifted earlier in both groups (p < .001), and the groups differed on sleep duration, sleep quality, sleep difficulties, daytime sleepiness, and wellbeing.

Participants / model
60 young adults (19 to 24 years) with delayed sleep-wake phase disorder
Treatment
Oral agomelatine for 4 weeks, with or without CBT
Follow-up
4 weeks
Study design
Nonblinded randomized trial; sleep diaries, PSQI, ESS, ISI, WHO-5
Funding
not stated in the source

With no placebo or no-drug arm, the shift cannot be attributed to agomelatine rather than to time or expectation.

Read the original source

How does agomelatine work, and what does the body do with it?

The sources reviewed do not describe agomelatine's receptor mechanism. Oral bioavailability is below 5%, and the mean half-life is 1 to 2 hours.

The sources reviewed do not describe agomelatine's receptor mechanism, so none is stated here. In 8 healthy older men, agomelatine advanced the body-temperature and cortisol rhythms by nearly 2 hours, stimulated growth hormone secretion during waking, and transiently raised prolactin.

Per the EU product information, absolute oral bioavailability is below 5% with substantial interindividual variation (higher in women and with oral contraceptives, lower in smokers). Peak levels come within 1 to 2 hours, and the mean half-life is 1 to 2 hours. The product information contraindicates potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin.

8 healthy older men, 15 days: rhythms advanced about 2 hours, no sleep change

Randomized controlled trial

Leproult R et al. Clin Endocrinol (Oxf). 2005;63(3):298-304. PMID 16117817.

Agomelatine advanced the body-temperature and cortisol rhythms by nearly 2 hours but had no effect on any polysomnographic sleep variable. It also stimulated growth hormone secretion during waking and transiently raised prolactin.

Participants / model
8 healthy older men
Treatment
Oral agomelatine 50 mg in the early evening, or placebo, for 15 days
Follow-up
15 days
Study design
Double-blind crossover study
Funding
not stated in the source

A tiny study in healthy older men. It showed a circadian phase shift without any sleep change.

Read the original source
Valdoxan EU product information, updated 15 April 2025: liver warnings, contraindications, PK

Official label

European Medicines Agency. Valdoxan EPAR product information (summary of product characteristics), agomelatine 25 mg film-coated tablets, last updated 15 April 2025.

Liver function tests are required before starting and at regular intervals during treatment; treatment is not started, or is stopped, if transaminases exceed 3 times the upper limit of normal. Contraindications are hepatic impairment (cirrhosis or active liver disease), transaminases above 3 times normal, and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Efficacy and safety are established in older patients under 75, and the product information says agomelatine should not be used at 75 and older, where no effect is documented. Post-marketing liver injury includes hepatic failure, with exceptional fatal outcomes or liver transplants in patients with hepatic risk factors. In trials, ALT or AST above 3 times normal occurred in 1.2% on 25 mg and 2.6% on 50 mg versus 0.5% on placebo. Absolute oral bioavailability is below 5% with substantial interindividual variation (higher in women and with oral contraceptives, lower in smokers), peak levels come within 1 to 2 hours, and the mean half-life is 1 to 2 hours.

Participants / model
Adults with major depressive episodes; label PK participants
Treatment
Valdoxan 25 mg film-coated oral tablets
Follow-up
Product information last updated 15 April 2025
Study design
Official EMA product information
Funding
not stated in the source

An EU label, not an FDA label. Dosing and monitoring-schedule details are left out of this page. The age limit appears in the posology section as a statement that agomelatine should not be used at 75 and older; the contraindications section does not list age.

Read the original source

What risks do the EU label and studies report?

The main warning is liver injury. The EU label requires liver function tests, contraindicates hepatic impairment and potent CYP1A2 inhibitors, and the 2014 safety review recommended a contraindication at 75 and older.

The EU product information requires liver function tests before starting and at regular intervals during treatment, and treatment is not started, or is stopped, if transaminases exceed 3 times the upper limit of normal. Contraindications are hepatic impairment (cirrhosis or active liver disease), transaminases above 3 times normal, and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Post-marketing liver injury includes hepatic failure, with exceptional fatal outcomes or liver transplants in patients with hepatic risk factors.

In a pooled analysis of 49 phase II and III studies (7,605 patients on agomelatine 25 or 50 mg, 1,629 on placebo), transaminases rose above 3 times the upper limit of normal in 1.3% on 25 mg and 2.5% on 50 mg versus 0.5% on placebo. Onset was before 12 weeks in 64% of cases, median recovery to 2 times normal or less was 14 days after stopping, and no acute liver failure or death occurred in the trials. Two authors were affiliated with Servier.

In September 2014 PRAC concluded a periodic safety review of severe liver reactions with Valdoxan/Thymanax. It recommended stronger warnings that liver tests be done before and regularly during treatment, a contraindication in patients aged 75 and above because of higher risk of severe liver effects and no documented benefit, and a letter to healthcare professionals. The current product information carries the age limit as a statement that agomelatine should not be used at 75 and older in its posology section; its contraindications section does not list age.

In the 2026 sleep meta-analysis, somnolence was reported more often than on placebo (RR 1.34, 95% CI 1.02 to 1.75).

Valdoxan EU product information, updated 15 April 2025: liver warnings, contraindications, PK

Official label

European Medicines Agency. Valdoxan EPAR product information (summary of product characteristics), agomelatine 25 mg film-coated tablets, last updated 15 April 2025.

Liver function tests are required before starting and at regular intervals during treatment; treatment is not started, or is stopped, if transaminases exceed 3 times the upper limit of normal. Contraindications are hepatic impairment (cirrhosis or active liver disease), transaminases above 3 times normal, and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Efficacy and safety are established in older patients under 75, and the product information says agomelatine should not be used at 75 and older, where no effect is documented. Post-marketing liver injury includes hepatic failure, with exceptional fatal outcomes or liver transplants in patients with hepatic risk factors. In trials, ALT or AST above 3 times normal occurred in 1.2% on 25 mg and 2.6% on 50 mg versus 0.5% on placebo. Absolute oral bioavailability is below 5% with substantial interindividual variation (higher in women and with oral contraceptives, lower in smokers), peak levels come within 1 to 2 hours, and the mean half-life is 1 to 2 hours.

Participants / model
Adults with major depressive episodes; label PK participants
Treatment
Valdoxan 25 mg film-coated oral tablets
Follow-up
Product information last updated 15 April 2025
Study design
Official EMA product information
Funding
not stated in the source

An EU label, not an FDA label. Dosing and monitoring-schedule details are left out of this page. The age limit appears in the posology section as a statement that agomelatine should not be used at 75 and older; the contraindications section does not list age.

Read the original source
Pooled liver analysis: 9,234 patients, transaminases above 3 times normal in 1.3% and 2.5%

Clinical trial

Perlemuter G et al. CNS Drugs. 2016;30(9):877-88. PMID 27342740.

Transaminases rose above 3 times the upper limit of normal in 1.3% on 25 mg and 2.5% on 50 mg versus 0.5% on placebo (7,605 patients on agomelatine, 1,629 on placebo). Onset was before 12 weeks in 64% of cases, median recovery to 2 times normal or less was 14 days after stopping, and no acute liver failure or death occurred in the trials.

Participants / model
9,234 patients in agomelatine phase II and III trials
Treatment
Oral agomelatine 25 or 50 mg daily versus placebo
Follow-up
not stated in the source
Study design
Pooled analysis of 49 phase II and III clinical trials
Funding
not stated in the source (two authors were affiliated with Servier)

Two authors were affiliated with Servier. The analysis covers trial patients, not post-marketing reports.

Read the original source
PRAC, September 2014: severe liver reactions, stronger warnings, age 75 and over

Regulatory record

European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC), 8 to 11 September 2014.

In September 2014 PRAC concluded a periodic safety review that examined cumulative data on severe liver reactions with Valdoxan/Thymanax. It recommended stronger warnings that liver tests be done before and regularly during treatment, a contraindication in patients aged 75 and above because of higher risk of severe liver effects and no documented benefit, and a letter to healthcare professionals, and forwarded these to CHMP.

Participants / model
Patients treated with agomelatine in post-marketing data
Treatment
Oral agomelatine
Follow-up
Periodic safety review concluded September 2014
Study design
Official EMA PRAC meeting highlights
Funding
not stated in the source

The current product information carries the age limit as a statement that agomelatine should not be used at 75 and older in its posology section; the contraindications section does not list age.

Read the original source
2026 sleep meta-analysis: 25 trials, no gain in objective total sleep time

Systematic review and meta-analysis

Stefanou A et al. J Sleep Res. 2026;35(3):e70231. PMID 41177901.

Across 25 placebo-controlled trials (6,812 participants), agomelatine had no significant effect on objective total sleep time (MD -15.73 minutes, 95% CI -49.68 to 18.22). It gave a small improvement in subjective sleep quality (SMD 0.31, 95% CI 0.21 to 0.40), fewer reports of insomnia (RR 0.59, 95% CI 0.39 to 0.90), more reports of somnolence (RR 1.34, 95% CI 1.02 to 1.75), and marginally more adverse effects overall (RR 1.05, 95% CI 1.00 to 1.11). The abstract does not break results down by diagnosis.

Participants / model
Participants in placebo-controlled randomized trials across populations (6,812 participants)
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 25 placebo-controlled trials
Funding
not stated in the source

The abstract does not state which diagnoses the trials covered.

Read the original source

Why does agomelatine sit in B tier?

An EU-authorized antidepressant with a small effect over placebo, publication bias, mandatory liver monitoring and no located US approval supports the B. The sleep, circadian and cognition claims are weaker than the depression use.

Agomelatine is an EU-authorized antidepressant, but only after a 2006 refusal for insufficient efficacy. Its effect over placebo is small (SMD 0.24, about 1.5 Hamilton points), with evidence of publication bias and inconsistent relapse prevention. Tolerability looks good in network meta-analysis, but liver monitoring is required and no US approval was located.

The supplier claim gets its own verdict. Depression is supported at the EU label level with a modest effect. Sleep benefits are mostly subjective, with no gain in objective total sleep time. Circadian phase advance is shown in 8 healthy older men without any sleep change and in an uncontrolled comparison in delayed sleep-wake phase disorder. Cognitive enhancement in people with disrupted sleep-wake cycles has no trial among the records found.

EMA: negative opinion 27 July 2006, refusal recorded 16 January 2007

Regulatory record

European Medicines Agency. Valdoxan/Thymanax (agomelatine 25 mg film-coated tablets), EPAR page recording the 2006 negative CHMP opinion and the 2007 refusal of marketing authorization, with the linked question-and-answer document.

On 27 July 2006 CHMP adopted a negative opinion on Valdoxan/Thymanax (agomelatine 25 mg) for major depressive disorder, and the EMA page records refusal of the marketing authorization on 16 January 2007. The linked question-and-answer document gives the main concern as insufficiently shown effectiveness: the long-term study did not show efficacy, and the size of the short-term effect did not allow a firm conclusion. CHMP had no special safety concerns at that time. The company later reapplied.

Participants / model
Adults with major depressive disorder in the submitted program
Treatment
Agomelatine 25 mg film-coated oral tablets
Follow-up
Regulatory decision, 2006 to 2007
Study design
Official EMA regulatory benefit-risk decision
Funding
not stated in the source

A refusal for insufficient efficacy, not for safety. The EU authorization of 2009 followed a new application.

Read the original source
EMA EPAR: authorized 19 February 2009, benefit possibly smaller than other antidepressants

Regulatory record

European Medicines Agency. Valdoxan EPAR summary, agomelatine, authorized in the EU on 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier).

Valdoxan has been authorized in the EU for major depressive episodes in adults since 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier). In five short-term placebo-controlled studies in 1,893 adults, agomelatine beat placebo in the two studies without an active comparator and did not differ from placebo in the three with fluoxetine or paroxetine arms, two of which also showed no effect of the comparator. In two relapse-prevention studies in 706 patients, one showed no difference and the other showed relapse in 21% (34 of 165) on agomelatine versus 41% (72 of 174) on placebo over 24 weeks. CHMP noted the benefit might be smaller than with other antidepressants and supported approval provided liver function is tested frequently.

Participants / model
Adults with major depression in the submitted studies
Treatment
Oral agomelatine 25 to 50 mg in the submitted studies
Follow-up
Short-term studies read at 6 weeks; relapse prevention over 24 weeks
Study design
Official EMA EPAR summary of submitted studies
Funding
not stated in the source

The summary reports the sponsor's submitted studies and the committee's reading of them. It is not a new trial.

Read the original source
Meta-analysis with unpublished trials: 1.51 Hamilton points, publication bias

Systematic review and meta-analysis

Koesters M et al. Br J Psychiatry. 2013;203(3):179-87. PMID 23999482.

Across 10 acute-phase and 3 relapse-prevention studies, 7 of them unpublished, the mean difference was -1.51 Hamilton depression points in favor of agomelatine (99% CI -2.29 to -0.73, nine studies), with an advantage in response but not remission and no significant relapse prevention (RR 0.78, 99% CI 0.41 to 1.48). None of the negative trials had been published. The authors judged a clinically important difference from placebo unlikely and found substantial publication bias.

Participants / model
Adults with unipolar major depression in randomized trials
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 10 acute-phase and 3 relapse-prevention placebo-controlled studies
Funding
not stated in the source

Includes unpublished trials. Seven of the 13 studies were unpublished.

Read the original source
20 trials, 7,460 participants: SMD 0.24 over placebo, equal to other antidepressants

Systematic review and meta-analysis

Taylor D et al. BMJ. 2014;348:g1888. PMID 24647162.

Agomelatine was more effective than placebo (SMD 0.24, 95% CI 0.12 to 0.35; response RR 1.25, 95% CI 1.11 to 1.4) and equal to other antidepressants (SMD 0.00, 95% CI -0.09 to 0.10). Published trials were more favorable than unpublished ones.

Participants / model
Adults with depression in double-blind randomized trials (7,460 participants in 20 trials)
Treatment
Oral agomelatine versus placebo or comparator antidepressants
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 20 double-blind randomized trials
Funding
not stated in the source (the first author reported fees and grants from Servier outside this work)

Published trials were more favorable than unpublished ones. The first author reported fees and grants from Servier outside this work.

Read the original source
Valdoxan EU product information, updated 15 April 2025: liver warnings, contraindications, PK

Official label

European Medicines Agency. Valdoxan EPAR product information (summary of product characteristics), agomelatine 25 mg film-coated tablets, last updated 15 April 2025.

Liver function tests are required before starting and at regular intervals during treatment; treatment is not started, or is stopped, if transaminases exceed 3 times the upper limit of normal. Contraindications are hepatic impairment (cirrhosis or active liver disease), transaminases above 3 times normal, and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Efficacy and safety are established in older patients under 75, and the product information says agomelatine should not be used at 75 and older, where no effect is documented. Post-marketing liver injury includes hepatic failure, with exceptional fatal outcomes or liver transplants in patients with hepatic risk factors. In trials, ALT or AST above 3 times normal occurred in 1.2% on 25 mg and 2.6% on 50 mg versus 0.5% on placebo. Absolute oral bioavailability is below 5% with substantial interindividual variation (higher in women and with oral contraceptives, lower in smokers), peak levels come within 1 to 2 hours, and the mean half-life is 1 to 2 hours.

Participants / model
Adults with major depressive episodes; label PK participants
Treatment
Valdoxan 25 mg film-coated oral tablets
Follow-up
Product information last updated 15 April 2025
Study design
Official EMA product information
Funding
not stated in the source

An EU label, not an FDA label. Dosing and monitoring-schedule details are left out of this page. The age limit appears in the posology section as a statement that agomelatine should not be used at 75 and older; the contraindications section does not list age.

Read the original source
openFDA, 9 October 2026: no agomelatine application or label

Regulatory record

U.S. Food and Drug Administration. openFDA Drugs@FDA queries for agomelatine by brand or generic name and by active ingredient, run on 9 October 2026, with a DailyMed label search.

openFDA Drugs@FDA queries for agomelatine, by brand or generic name and by active ingredient, returned no application on 9 October 2026, and a DailyMed search returned no agomelatine label.

Participants / model
Not a clinical population
Treatment
Drug applications
Follow-up
Search run on 9 October 2026
Study design
Dated US approval-record search
Funding
not stated in the source

This supports a dated, US-scoped statement only: no FDA-approved agomelatine product was located.

Read the original source
PubMed search, 9 October 2026: 25 records, none on cognition with disrupted sleep-wake cycles

PubMed search record

PubMed search run on 9 October 2026: agomelatine[tiab] AND (cognition OR cognitive OR memory OR attention OR executive)[tiab] AND (healthy OR volunteers OR shift work OR jet lag OR circadian)[tiab]. 25 records returned.

The search returned 25 records. None tested cognitive enhancement in people with disrupted sleep-wake cycles, shift work, or jet lag. The records were reviews (including jet lag), rodent, cell, and drug-interaction studies, two studies in depressed patients (a pilot attention study and an EEG biomarker study), a 7-day emotional-processing study in healthy volunteers (PMID 20660010), and a 2026 preprint, not peer reviewed, reporting effects on reinforcement learning in 128 healthy volunteers over 8 weeks (PMID 41542676).

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. The reinforcement-learning result is a preprint.

Read the original source

Studies and sources

EMA: negative opinion 27 July 2006, refusal recorded 16 January 2007

Regulatory record

European Medicines Agency. Valdoxan/Thymanax (agomelatine 25 mg film-coated tablets), EPAR page recording the 2006 negative CHMP opinion and the 2007 refusal of marketing authorization, with the linked question-and-answer document.

On 27 July 2006 CHMP adopted a negative opinion on Valdoxan/Thymanax (agomelatine 25 mg) for major depressive disorder, and the EMA page records refusal of the marketing authorization on 16 January 2007. The linked question-and-answer document gives the main concern as insufficiently shown effectiveness: the long-term study did not show efficacy, and the size of the short-term effect did not allow a firm conclusion. CHMP had no special safety concerns at that time. The company later reapplied.

Participants / model
Adults with major depressive disorder in the submitted program
Treatment
Agomelatine 25 mg film-coated oral tablets
Follow-up
Regulatory decision, 2006 to 2007
Study design
Official EMA regulatory benefit-risk decision
Funding
not stated in the source

A refusal for insufficient efficacy, not for safety. The EU authorization of 2009 followed a new application.

Read the original source
EMA EPAR: authorized 19 February 2009, benefit possibly smaller than other antidepressants

Regulatory record

European Medicines Agency. Valdoxan EPAR summary, agomelatine, authorized in the EU on 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier).

Valdoxan has been authorized in the EU for major depressive episodes in adults since 19 February 2009 (CHMP opinion 20 November 2008; holder Les Laboratoires Servier). In five short-term placebo-controlled studies in 1,893 adults, agomelatine beat placebo in the two studies without an active comparator and did not differ from placebo in the three with fluoxetine or paroxetine arms, two of which also showed no effect of the comparator. In two relapse-prevention studies in 706 patients, one showed no difference and the other showed relapse in 21% (34 of 165) on agomelatine versus 41% (72 of 174) on placebo over 24 weeks. CHMP noted the benefit might be smaller than with other antidepressants and supported approval provided liver function is tested frequently.

Participants / model
Adults with major depression in the submitted studies
Treatment
Oral agomelatine 25 to 50 mg in the submitted studies
Follow-up
Short-term studies read at 6 weeks; relapse prevention over 24 weeks
Study design
Official EMA EPAR summary of submitted studies
Funding
not stated in the source

The summary reports the sponsor's submitted studies and the committee's reading of them. It is not a new trial.

Read the original source
Valdoxan EU product information, updated 15 April 2025: liver warnings, contraindications, PK

Official label

European Medicines Agency. Valdoxan EPAR product information (summary of product characteristics), agomelatine 25 mg film-coated tablets, last updated 15 April 2025.

Liver function tests are required before starting and at regular intervals during treatment; treatment is not started, or is stopped, if transaminases exceed 3 times the upper limit of normal. Contraindications are hepatic impairment (cirrhosis or active liver disease), transaminases above 3 times normal, and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin. Efficacy and safety are established in older patients under 75, and the product information says agomelatine should not be used at 75 and older, where no effect is documented. Post-marketing liver injury includes hepatic failure, with exceptional fatal outcomes or liver transplants in patients with hepatic risk factors. In trials, ALT or AST above 3 times normal occurred in 1.2% on 25 mg and 2.6% on 50 mg versus 0.5% on placebo. Absolute oral bioavailability is below 5% with substantial interindividual variation (higher in women and with oral contraceptives, lower in smokers), peak levels come within 1 to 2 hours, and the mean half-life is 1 to 2 hours.

Participants / model
Adults with major depressive episodes; label PK participants
Treatment
Valdoxan 25 mg film-coated oral tablets
Follow-up
Product information last updated 15 April 2025
Study design
Official EMA product information
Funding
not stated in the source

An EU label, not an FDA label. Dosing and monitoring-schedule details are left out of this page. The age limit appears in the posology section as a statement that agomelatine should not be used at 75 and older; the contraindications section does not list age.

Read the original source
PRAC, September 2014: severe liver reactions, stronger warnings, age 75 and over

Regulatory record

European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC), 8 to 11 September 2014.

In September 2014 PRAC concluded a periodic safety review that examined cumulative data on severe liver reactions with Valdoxan/Thymanax. It recommended stronger warnings that liver tests be done before and regularly during treatment, a contraindication in patients aged 75 and above because of higher risk of severe liver effects and no documented benefit, and a letter to healthcare professionals, and forwarded these to CHMP.

Participants / model
Patients treated with agomelatine in post-marketing data
Treatment
Oral agomelatine
Follow-up
Periodic safety review concluded September 2014
Study design
Official EMA PRAC meeting highlights
Funding
not stated in the source

The current product information carries the age limit as a statement that agomelatine should not be used at 75 and older in its posology section; the contraindications section does not list age.

Read the original source
Meta-analysis with unpublished trials: 1.51 Hamilton points, publication bias

Systematic review and meta-analysis

Koesters M et al. Br J Psychiatry. 2013;203(3):179-87. PMID 23999482.

Across 10 acute-phase and 3 relapse-prevention studies, 7 of them unpublished, the mean difference was -1.51 Hamilton depression points in favor of agomelatine (99% CI -2.29 to -0.73, nine studies), with an advantage in response but not remission and no significant relapse prevention (RR 0.78, 99% CI 0.41 to 1.48). None of the negative trials had been published. The authors judged a clinically important difference from placebo unlikely and found substantial publication bias.

Participants / model
Adults with unipolar major depression in randomized trials
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 10 acute-phase and 3 relapse-prevention placebo-controlled studies
Funding
not stated in the source

Includes unpublished trials. Seven of the 13 studies were unpublished.

Read the original source
20 trials, 7,460 participants: SMD 0.24 over placebo, equal to other antidepressants

Systematic review and meta-analysis

Taylor D et al. BMJ. 2014;348:g1888. PMID 24647162.

Agomelatine was more effective than placebo (SMD 0.24, 95% CI 0.12 to 0.35; response RR 1.25, 95% CI 1.11 to 1.4) and equal to other antidepressants (SMD 0.00, 95% CI -0.09 to 0.10). Published trials were more favorable than unpublished ones.

Participants / model
Adults with depression in double-blind randomized trials (7,460 participants in 20 trials)
Treatment
Oral agomelatine versus placebo or comparator antidepressants
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 20 double-blind randomized trials
Funding
not stated in the source (the first author reported fees and grants from Servier outside this work)

Published trials were more favorable than unpublished ones. The first author reported fees and grants from Servier outside this work.

Read the original source
Network meta-analysis: 522 trials, agomelatine fewer dropouts than placebo (OR 0.84)

Systematic review and meta-analysis

Cipriani A et al. Lancet. 2018;391(10128):1357-1366. PMID 29477251.

All 21 antidepressants were more effective than placebo. Agomelatine was one of two drugs with fewer dropouts than placebo (OR 0.84, 95% CrI 0.72 to 0.97) and, in head-to-head trials, was among the more effective and more tolerable drugs. Certainty of evidence was moderate to very low.

Participants / model
Adults with major depressive disorder in double-blind randomized trials (522 trials, 116,477 participants)
Treatment
Oral antidepressants, including agomelatine
Follow-up
not stated in the source
Study design
Systematic review and network meta-analysis of 522 double-blind randomized trials
Funding
not stated in the source

Certainty of evidence was moderate to very low across comparisons.

Read the original source
2026 sleep meta-analysis: 25 trials, no gain in objective total sleep time

Systematic review and meta-analysis

Stefanou A et al. J Sleep Res. 2026;35(3):e70231. PMID 41177901.

Across 25 placebo-controlled trials (6,812 participants), agomelatine had no significant effect on objective total sleep time (MD -15.73 minutes, 95% CI -49.68 to 18.22). It gave a small improvement in subjective sleep quality (SMD 0.31, 95% CI 0.21 to 0.40), fewer reports of insomnia (RR 0.59, 95% CI 0.39 to 0.90), more reports of somnolence (RR 1.34, 95% CI 1.02 to 1.75), and marginally more adverse effects overall (RR 1.05, 95% CI 1.00 to 1.11). The abstract does not break results down by diagnosis.

Participants / model
Participants in placebo-controlled randomized trials across populations (6,812 participants)
Treatment
Oral agomelatine versus placebo
Follow-up
not stated in the source
Study design
Systematic review and meta-analysis of 25 placebo-controlled trials
Funding
not stated in the source

The abstract does not state which diagnoses the trials covered.

Read the original source
Actigraphy trial: 313 depressed outpatients, 6 weeks, agomelatine versus sertraline

Randomized controlled trial

Kasper S et al. J Clin Psychiatry. 2010;71(2):109-20. PMID 20193645.

Agomelatine 25 to 50 mg (154 patients) improved the actigraphy-measured relative amplitude of the rest-activity cycle more than sertraline 50 to 100 mg (159 patients) at the end of week 1 (P = .01), with greater improvement in actigraphic sleep latency and sleep efficiency from week 1 to week 6 (both P < .001) and in depressive and anxiety symptoms (P < .05).

Participants / model
313 outpatients with major depressive disorder
Treatment
Oral agomelatine 25 to 50 mg versus sertraline 50 to 100 mg
Follow-up
6 weeks
Study design
Double-blind randomized trial with wrist actigraphy, HAM-D and HAM-A
Funding
not stated in the source

A comparison with sertraline, not placebo, in depressed outpatients.

Read the original source
8 healthy older men, 15 days: rhythms advanced about 2 hours, no sleep change

Randomized controlled trial

Leproult R et al. Clin Endocrinol (Oxf). 2005;63(3):298-304. PMID 16117817.

Agomelatine advanced the body-temperature and cortisol rhythms by nearly 2 hours but had no effect on any polysomnographic sleep variable. It also stimulated growth hormone secretion during waking and transiently raised prolactin.

Participants / model
8 healthy older men
Treatment
Oral agomelatine 50 mg in the early evening, or placebo, for 15 days
Follow-up
15 days
Study design
Double-blind crossover study
Funding
not stated in the source

A tiny study in healthy older men. It showed a circadian phase shift without any sleep change.

Read the original source
Delayed sleep-wake phase disorder: 60 young adults, nonblinded, no no-drug arm

Randomized controlled trial

Yu Y et al. Behav Sleep Med. 2023;21(5):529-539. PMID 36263691.

All participants received 4 weeks of agomelatine and were randomized to cognitive behavioral therapy or no CBT. Sleep-wake timing shifted earlier in both groups (p < .001), and the groups differed on sleep duration, sleep quality, sleep difficulties, daytime sleepiness, and wellbeing.

Participants / model
60 young adults (19 to 24 years) with delayed sleep-wake phase disorder
Treatment
Oral agomelatine for 4 weeks, with or without CBT
Follow-up
4 weeks
Study design
Nonblinded randomized trial; sleep diaries, PSQI, ESS, ISI, WHO-5
Funding
not stated in the source

With no placebo or no-drug arm, the shift cannot be attributed to agomelatine rather than to time or expectation.

Read the original source
Pooled liver analysis: 9,234 patients, transaminases above 3 times normal in 1.3% and 2.5%

Clinical trial

Perlemuter G et al. CNS Drugs. 2016;30(9):877-88. PMID 27342740.

Transaminases rose above 3 times the upper limit of normal in 1.3% on 25 mg and 2.5% on 50 mg versus 0.5% on placebo (7,605 patients on agomelatine, 1,629 on placebo). Onset was before 12 weeks in 64% of cases, median recovery to 2 times normal or less was 14 days after stopping, and no acute liver failure or death occurred in the trials.

Participants / model
9,234 patients in agomelatine phase II and III trials
Treatment
Oral agomelatine 25 or 50 mg daily versus placebo
Follow-up
not stated in the source
Study design
Pooled analysis of 49 phase II and III clinical trials
Funding
not stated in the source (two authors were affiliated with Servier)

Two authors were affiliated with Servier. The analysis covers trial patients, not post-marketing reports.

Read the original source
PubChem: agomelatine identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 82148 (agomelatine).

Agomelatine: PubChem CID 82148, C15H17NO2, 243.30 g/mol, CAS 138112-76-2, N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide. It is a single defined molecule.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only. Supplier material has not been compared with the record.

Read the original source

Why is Agomelatine in B tier?

B fits an EU-authorized antidepressant whose effect over placebo is small, with publication bias and inconsistent relapse prevention, mandatory liver monitoring and no located US approval. Tolerability looks good in network meta-analysis. The grade covers depression, and the sleep, circadian and cognition claims rest on weaker data.