Agomelatine Review: The Truth about Agomelatine Use in Affective Disorders

What is Agomelatine?

Do you think agomelatine is a solid antidepressant? How do you think it compares to other more typical antidepressants like Prozac?

Agomelatine's unique pharmacology and favorable side effect profile make it a boon for depressed patients, especially those who have not responded to conventional antidepressants.

Here's a quick and dirty fact sheet that will get you oriented if you don't know anything about agomelatine.

  • Though agomelatine was approved in Europe for the treatment of depression in 2009, it's unavailable in the United States
  • Agomelatine blocks some serotonin receptor subtypes (5-HT2B and 5-HT2C) and activates melatonin receptors (MT1/MT2)
  • Agomelatine alleviates depression in part by normalizing circadian rhythym
  • Agomelatine has many advantages over contentional antidepressants (e.g., SSRIs)
  • Agomelatine has some nootropic and neuroprotective effects.

Agomelatine is a melatoninergic antidepressant developed by Servier and marketed under the trade names Valdoxan, Melitor, and Thymanax.

Unlike most conventional antidepressants, agomelatine's mechanism does not hinge on boosting monoamines (e.g., serotonin). Rather, its antidepressant effect is attributed to restoring abnormal circadian rhythm in depressed individuals and promoting dopamine/norepinephrine release.

Agomelatine may have advantages over conventional antidepressants like SSRIs in terms of both efficacy and tolerability. Agomelatine has also shown therapeutic potential as a treatment for other affective disorders and even dementia. Let's see what the most updated reviews have to say about agomelatine.

Agomelatine Dosage

Agomelatine is available as 25 mg tablets. Physicians typically prescribe one tablet to be taken at bedtime. In some instances, physicians may prescribe 50 mg (2x tablets). Agomelatine is not recommended at doses above 50 mg/night.

The Molecular Properties of Agomelatine

Agomelatine interacts with two distinct receptor systems:

  • Serotonin (5-HT) System. Agomelatine is an antagonist at 5-HT2B and 5-HT2C receptors 1.
  • Melatonin System. Agomelatine is a partial agonist of the melatonin receptors MT1 and MT22

Physiological Consequences of Agomelatine Use:

Agomelatine's action on the serotonin and melatonin system has the following physiological effects:

  • It disinhibits/increases noradrenaline and dopamine release in the frontal cortex, without affecting serotonin levels. This effect is mediated via inhibition of 5-HT2C receptor activity1.
  • It normalizes circadian rhythm (biological clock) by modulating melatonin receptors3.

Agomelatine, Sleep, And Depression

Circadian rhythm dysregulation is strongly linked to mood disorders4. There's also a link between depression and abnormal sleep architecture.
Depression is associated with:

  • decreased slow wave sleep (SWS)
  • increased REM sleep density
  • increased REM sleep duration
  • shortened REM sleep latency

Slow wave sleep is the restorative, indispensable part of sleep. REM sleep coincides with dreaming and, as the name implies, is characterized by rapid eye movements.

There's evidence that these sleep architecture alterations precede the development of depression. Riemann argues that "REM sleep alterations have been recently considered not only as biological "scars" but as true endophenotypes of depression."18

This may explain why sleep deprivation has an antidepressant effect5. The picture is muddied by the fact that insomnia is a common bedfellow to depression. A classic signs of depression is early morning awakenings (e.g., waking up at 4 am and being unable to fall asleep). Since sleep deprivation itself has an antidepressant effect, researchers have proposed that early morning awakenings in depressed patients reflect a compensatory response to help reduce depression.

Some researchers have gone so far as to say that depression is primarily a sleep disorder.

Most antidepressants, independent of class, profoundly suppress rapid eye movement (REM) sleep. For example, tricyclic antidepressants and SSRIs robustly reduce REM sleep. This implies that REM sleep is dispensable (you can live without it). REM suppression is not necessarily an unwanted side effect; it contributes to the antidepressant effect of drugs like SSRIs and tricyclic antidepressants.

Further reading: REM sleep dysregulation in depression: state of the art

Agomelatine inhibits 5-HT2C serotonin receptors, increasing noradrenaline and dopamine. But the primary antidepressant effect of agomelatine is by normalizing circadian rhythm. Agomelatine binds and activates melatonin receptors2 which is a key player in the biological clock.

Agomelatine Reviews

I scoured the internet for agomelatine reviews and experience reports. Here are some notable reviews:

Posted by odspot on Reddit:

I just stopped it two nights ago. I found it pretty good for getting to sleep, which was a blessing, and waking up earlier. It was pretty mentally stimulating (and potentiated other stimulants)... too much so at 25/50mg, so I cut back to 12.5mg. However, the dealbreaker was that it would render me completely exhausted/fatigued the next day. I was pretty jacked up and alert, but could barely get around. I read on psychonauts that the side-effect supposedly passes once sleep normalizes after 2-3 weeks, but I just couldn't take it (especially because changing the dose supposedly resets the adjustment period). That said, I do have a lot of baseline fatigue, so take that all with a grain of salt.

Posted by Cosmicrush on Reddit:

Yes it's awesome. I sublingual 3-5mg and I get mixed state between dazed and this paranoid empathy type state. It only shows when I socialized for the simulation and empathy. If I'm alone I go hypnogogic and get vivid hallucinations if I suddenly open my eyes after holding them shut for while.

It seems to be iffy on sleep quality. I sleep faster but the effects are short and I wake up after a couple hours.

It seems good for creative thinking. It will make you socially introverted somewhat. This might not be true. Or maybe this is only true at higher dosages.

It causes paresthesia on tongue if you sublingual. The effects aren't felt that much but it changes your state of mind. I notice the closer I am to sleep I get happy and euphoric but then I'll snap out of it and feel kind of anxious but not bad anxiety. It's hard to notice the feeling at first though.

The medication it feels like is Mirtazapine. But much more lightweight and less sedating. Mirtazapine can be annoying with side effects sometimes.

Posted by nachos420 on Reddit:

if you take it ~10-30mg sublingually you can feel the 5ht2c antagonism decently strong. I can't use it though, even at the recommended 25mg oral dose, because, like melatonin, it makes me much more likely to feel depressed the next day for no reason when normally I'm never depressed. It's odd especially because melatonin will make colors brighter the next day and such yet somehow my mind still reacts to it(at any dose) with short lived 1-2 day depression. I think the depression is a secondary side-effect from it tiring/slowing my mind/body into the next day even at low mcg doses.

Posted by an_thr:

I was prescribed 25mg per day, then 50mg per day after that stopped working. Have recently come off it entirely due to exacerbated anhedonia/amotivation at 50mg. It is expensive and you are required to have regular liver function tests, so it no longer seems worth it.

I had tried perhaps six SSRIs/SNRIs before Valdoxan and it worked better than most with few side effects. Beyond mood, the best effect for me was on sleep. Normally I wake up and feel like I have been hit by a train, but on agomelatine I would get out of bed immediately upon waking and feel fine. My sleep time was reduced from ~10 hours to ~6 hours, and I was able to fall asleep every night.

I wouldn't bother with it for mild depression in the absence of sleep problems.

I suspect any nootropic effects are due to improved sleep architecture and alleviation of depression.

Is Agomelatine An Effective Antidepressant?

A large number of studies have investigated the efficacy of agomelatine for depression.

David Taylor19 and colleagues published a meta-analysis of agomelatine efficacy for depression. He included 20 studies and nearly 7500 participants. There are a few takeaways from the meta-analysis:

  • Agomelatine was significantly more effective than placebo
  • Agomelatine efficacy was comparable to other antidepressants

One study reported that 25-50mg/day agomelatine resulted in a potent antidepressant effect as assessed by the Montgomery and Kasper diagnostic manual. Patient response was similar (if not higher) to other antidepressants6.

In addition, to its antidepressant properties, agomelatine (25mg/day) restored sleep architecture in depressed individuals by improving sleep quality6.

Agomelatine-induced sleep enhancement does not lead to daytime sedation (a common side effect of hypnotic antidepressants like Remeron)6. Finally, agomelatine may benefit more severe forms of depression, in which most if not all antidepressants fail; these forms are atypical7, melancholic 7, and anxious depression8. However, this observation may be a moot point since all antidepressant response is much higher in severely depressed patients, irrespective of the particular antidepressant.

Adverse Effects

In sharp contrast to most other clinically available antidepressant agomelatine (25-50mg/day) is not associated with9:

  • Sexual Dysfunction
  • Cardiovascular Toxicity
  • Weight Gain
  • Nausea
  • Discontinuation Syndrome
  • Gastrointestinal Disorders
  • Serotonin Syndrome
  • Insomnia
  • Excessive daytime sleepiness

Agomelatine For Other Affective Disorders

Anxiety Spectrum-Disorders

In animal models, agomelatine has anxiolytic effects.10 Agomelatine potentiates GABAergic neurons (via melatonin receptor agonist) and by antagonizing 5-HT2C receptors.

Due to its anxiolytic properties agomelatine has been investigated for use in both social anxiety disorder and generalized anxiety disorder, were 25-50mg/day of agomelatine has been superior to placebo at alleviating symptoms.

Obsessive-Compulsive Disorder

In a small study 50mg/day agomelatine was effective at reducing symptoms associated with OCD11 and also showed profound superiority when compared to SSRIs which are the standard course of treatment for OCD.

Seasonal Affective-Disorder

In one study with 37 seasonal affective disorder (SAD) patients12, 25mg/day of agomelatine for 14 weeks was proven to be efficacious and safe for the treatment seasonal depression.


In a small study13 involving 26 patients suffering from bipolar disorder, agomelatine (25mg/day) was effective and well-tolerated adjunct with mood stabilizers for bipolar depression.

Agomelatine For Other Conditions

Agomelatine could be of benefit in preventing the progression on two neurodegenerative disorders that are frequently co-morbid with depression and therefore, agomelatine could also be use in these disorders for its mood-enhancing properties.

Alzheimer’s Disease

Due to its melatonin mimetic effects, agomelatine could potentially be used in Alzheimer's disease14.

That's because melatonin has a protective effect against beta-amyloid protein. Melatonin inhibits aggregation of amyloid beta into neurotoxic aggregates. Interestingly, agomelatine has been associated with enhancement of spatial visual memory15.

Dopamine-Related Motor Disorders

Due to its melatonin mimicking effects, agomelatine could also be beneficial in motor disorders such as Parkinson’s disease.

Melatonin inhibits dopamine release from the striatum16. Parkinson's disease is caused by the neurodegeneration of dopaminergic neurons.

In Parkinson's disease, one might think
that melatonin would exacerbate symptoms since melatonin inhibits dopamine release.
However, melatonin (and melatonin-mimetics) have a neuroprotective effect that may benefit Parkinson's patients17.

The Verdict on Agomelatine

Taking into account the information provided above it is safe to assume that agomelatine is a unique and an effective tool against the battle with depression. It shows superiority to most clinically available antidepressants in terms of tolerability, in sleep improvement and for the treatment of drug-resistant forms of depression. Moreover, its use is not limited only to depression but other affective disorders were it is associated with significantly reduced symptomatology were it also shows some superiority to other antidepressants used.

Overall, agomelatine is completely justified for use in the clinic for affective disorders and possible not only!


[^1] Millan, M.J., Gobert, A., Lejeune, F., Dekeyne, A., NewmanTancredi, A., Pasteau, V., Rivet J.M., Cussac, D. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5- hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J. Pharmacol. Exp. Ther., 2003, 306(3), 954-64.

  1. Masson-Pevet, M., Recio, J., Guerrero, H.Y., Mocaer, E, Delagrange, P., Guardiola-Lemaitre, B., Pevet, P. Effects of two melatonin analogues, S-20098 and S-20928, on melatonin receptors in the pars tuberalis of the rat. J. Pineal. Res., 1998, 25(3), 172-6.

  2. Olie, J., Kasper, P.S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int.. J. Neuropsychopharmacol., 2000, 10(5), 661-73.

  3. Srinivasan, V., Pandi-Perumal, S.R., Trakht, I., Spence, D.W., Hardeland, R., Poeggeler, B. Cardinali. D.P. Pathophysiology of depression: Role of sleep and the melatonergic system. Psychiatry Res., 2009, 165(3), 201-14.

  4. Svestka, J. Sleep deprivation therapy. Neuro Endocrinol. Lett., 2008, 29(Suppl1), 65-92.

  5. Montgomery, S., Kasper, A.S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int. Clin. Psychopharmacol., 2007, 22(5), 283-91.

  6. Avedisova, A; Marachev, M (2013). "2639 – The effectiveness of agomelatine (valdoxan) in the treatment of atypical depression". European Psychiatry. 28 

  7. Heun, R; Coral, RM; Ahokas, A; Nicolini, H; Teixeira, JM; Dehelean, P (2013). "1643 – Efficacy of agomelatine in more anxious elderly depressed patients. A randomized, double-blind study vs placebo". European Psychiatry. 28

  8. Fornaro M, Prestia D, Colicchio S, Perugi G. A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation.Curr Neuropharmacol. 2010 Sep;8(3):287-304.

  9. De Berardis, D; Conti, CM; Marini, S; Ferri, F; Iasevoli, F; Valchera, A; Fornaro, M; Cavuto, M; Srinivasan, V; Perna, G; Carano, A; Piersanti, M; Martinotti, G; Di Giannantonio, M (2013). "Is there a role for agomelatine in the treatment of anxiety disorders? a review of published data". International Journal of Immunopathology and Pharmacology. 26 (2): 299–304. 

  10. Fornaro, M (February 2011). "Switching from serotonin reuptake inhibitors to agomelatine in patients with refractory obsessive-compulsive disorder: a 3 month follow-up case series". Annals of General Psychiatry. 10 (1): 5.

  11. Pjrek, E; Winkler, D; Konstantinidis, A; Willeit, M; Praschak-Rieder, N; Kasper, S (March 2007). "Agomelatine in the treatment of seasonal affective disorder". Psychopharmacology. 190 (4): 575–579. 

  12. Fornaro, M; McCarthy, MJ; De Berardis, D; De Pasquale, C; Tabaton, M; Martino, M; Colicchio, S; Cattaneo, CI; D'Angelo, E; Fornaro, P (2013). "Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study". Neuropsychiatric Disease and Treatment.

  13. Pappolla, M.A., Sos, M., Omar, R.A., Bick, R.J., Hickson-Bick, D.L., Reiter, R.J., Efthimiopoulos, S., Robakis, N.K. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J. Neurosci., 1997, 17(5), 1683-90.

  14. Conboy, L., Tanrikut, C., Zoladz, P.R., Campbell, A.M., Park, C.R., Gabriel, C., Mocaer, E., Sandi, C. Diamond, D.M. 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. Int. J. Neuropsychopharmacol., 2009, 12(3), 329-41.

  15. Tenn, C.C., Niles, L.P. The antidopaminergic action of S-20098 is mediated by benzodiazepine/GABA(A) receptors in the striatum. Brain Res., 1997, 756(1-2), 293-6.

  16. Zisapel, N.; Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol. Neurobiol., 2001, 21(6), 605-16.


  18. Taylor D, Sparshatt A, Varma S, Olofinjana O. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 2014; 348: g1888

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Xavier Kent

I'm interested in nutrition, nootropics, and javascript. I'm a firm believer in getting really good at one thing.


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