A Focus on Agomelatine – Mechanism of Action and Efficacy
Agomelatine is a novel and atypical antidepressant that acts as a melatonergic antidepressant and has a distinctly favourable side effect profile.
The majority of antidepressant research for the past three decades has focused on increasing monoamine levels in the synaptic cleft.
This can be achieved either by blocking reuptake, or blocking the breakdown, of synaptic monoamines. It is believed that monoamine-based antidepressants initiate adaptive neuronal changes through binding to monoamine receptors and/or monoamine transporters.
Popular first-choice monoamine-based antidepressant drugs include selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline reuptake inhibitors (SNRIs). These agents have replaced tricyclic antidepressant (TCA) drugs because of their improved efficacy and more favourable adverse-effect profile.
However, SSRI and SNRI drugs only have modest efficacy with response rates reported at approximately 50% .
These drugs are also associated with common treatment-emergent adverse events including nausea, sexual dysfunction, weight gain, and insomnia all of which limits tolerability.
MECHANISM OF ACTION OF AGOMELATINE
Agomelatine is a melatonin receptor agonist and a serotonin receptor antagonist with a favourable side effect profile. There is a lack of sexual dysfunction, sleep benefits, and no discontinuation symptoms – all of which confer valuable clinical benefits in the treatment of depression .
Agomelatine exerts affinity for melatonin receptor subtypes, MT1 and MT2, and serotonergic 5-HT2C receptors .
The melatonergic receptors, MT1 and MT2, are strongly associated with regulating circadian rhythms.
The majority of MT1 receptors are located in the suprachiasmatic nuclei of the hypothalamus while MT2 receptors are mainly located in the retina.
Abnormal circadian rhythms are linked to many characteristics of affective disorders, such as delayed sleep onset, early-morning wakening, and daytime fatigue .
Research has shown that circadian patterns of gene expression are significantly altered in the brains of patients with MDD .
When agomelatine interacts with M1 and M2 receptors, it activates several physiological signal transduction pathways via the release of melatonin from the pineal gland.
Agomelatine has been shown to resynchronize the disturbed sleep/wake cycle in depressed patients by delaying the sleep phase rhythm.
5-HT2C receptor antagonism:
Agomelatine has been shown to block 5-HT2C receptors within corticolimbic structures in the hippocampus.
Hyperactivity of the 5-HT2C receptors may contribute to the symptoms of MDD and agomelatine induced 5-HT2C antagonism has been shown to increase the release of dopamine and norepinephrine in the frontal cortex.
In summary, agomelatine exerts psychotropic effects through the synergistic interplay of its melatonergic agonist action (M1 and M2) and 5-HT2C receptor antagonist action.
DOSING AND PHARMACOKINETICS OF AGOMELATINE
The dose of agomelatine ranges from 25 mg to 50 mg at night time.
Agomelatine is rapidly absorbed and achieves peak plasma concentration within two hours.
It has an oral bioavailability of less than 5% of the required therapeutic dose however intake of high-fat foods may improve absorption.
This poor bioavailability is a result of the first-pass through the liver where it is metabolized mainly via the cytochrome P450 liver enzyme, CYP1A2.
CYP1A2 inhibitors such as fluvoxamine are contraindicated in concurrent use as it can increase the levels of agomelatine.
Agomelatine can be used concurrently with other antidepressants and mood stabilisers without the risk of negative pharmacological interactions.
Common adverse events after agomelatine administration are mild to moderate nausea, headache, dry mouth, fatigue and diarrhoea.
Furthermore, because it is extensively metabolized in the liver, hepatic enzymes should be regularly monitored.
Prescribers should perform liver function tests in all patients receiving agomelatine (MIMS UK):
- At initiation of treatment
- At weeks 3, 6, 12, 24 and periodically thereafter
- When increasing the dose of agomelatine (at the same time intervals as above)
- Any patient who develops increased serum transaminases should have their liver function tests repeated within 48 hours
- Agomelatine should be immediately discontinued if an increase in serum transaminases exceeds three times the upper limit of normal, or if patients present with symptoms or signs of potential liver injury
Agomelatine is contraindicated in patients with hepatic impairment.
We covered the clinical application of agomelatine in a previous case study.
In routine clinical practice, the observational CHRONOS study was designed to evaluate the antidepressant efficacy and safety of agomelatine .
By observing inpatients and outpatients with flexible dosing regimens, agomelatine was shown to reduce HAMD-17 scores from 22.5 to 4.7 in 90% of patients after 2 months of treatment.
A recent meta-analysis published in the BMJ systematically reviewed 20 clinical trials that evaluated the efficacy of agomelatine to prevent depression .
According to the authors:
The effect size for agomelatine compared with placebo is similar to that of other marketed antidepressants
Agomelatine shows similar efficacy to standard antidepressant in comparator controlled trials
Agomelatine is a valid treatment option in patients unable to tolerate adverse effects of standard antidepressants or in whom standard drugs are contraindicated
Another study compared agomelatine with sertraline on the circadian rest/activity cycle and depression and anxiety symptoms .
The authors concluded:
The favorable effect of agomelatine on the relative amplitude of the circadian rest-activity/sleep-wake cycle in depressed patients at week 1 reflects early improvement in sleep and daytime functioning.
Higher efficacy results were observed with agomelatine as compared to sertraline on both depressive and anxiety symptoms over the 6-week treatment period, together with a good tolerability profile.
Agomelatine has also shown benefits and safety when combined with other antidepressants such as escitalopram, venlafaxine, bupropion in the treatment of depression and OCD. , , 
A recent paper reviewed the studies and cases of agomelatine augmentation [Potměšil P, 2019]. According to the paper:
A successful combination of agomelatine was reported after adjunctive use of agomelatine combined with clomipramine, escitalopram, and venlafaxine in patients with major depression or obsessive–compulsive disorder. Moreover, bupropion or moclobemide augmentation with agomelatine in patients with major depressive disorder led to a significant improvement.
The positive results of agomelatine augmentation with other antidepressants should be confirmed through randomized, double-blind clinical trials.
Agomelatine 25 mg/day was also found to be an effective and well-tolerated adjunct to valproate/lithium for acute depression in Bipolar II disorder in an open-label study. . In acute bipolar I depression, however, agomelatine adjunctive therapy was not superior to placebo. 
Agomelatine ranked the best amongst 21 antidepressants for acceptability with reduced dropout rates compared to other antidepressants in the 2018 Network Meta-Analysis by Cipriani et al.
Generalised Anxiety Disorder:
- Agomelatine is a novel treatment option in GAD showing good efficacy and improvement of functioning, even in severely ill patients. [Stein et al, 2021]
- The 5-HT2C receptor antagonistic property of agomelatine is postulated as the mechanism of action in the treatment of GAD. [Wang et al, 2020]
- A systematic review and network meta-analysis of remission rates and tolerability in GAD reported only agomelatine showed better remission rates with good tolerability. Duloxetine, escitalopram, venlafaxine, paroxetine, and quetiapine were effective but with poor tolerability. [Kong et al, 2020].
- Agomelatine has now been approved by the TGA in Australia for GAD. [TGA PI]
Children and Adolescents:
A phase 3 RCT showed benefits in adolescents with depression but, not children. [Arango et al, 2021]
This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals.
Check out our CPD module which summarises mechanisms of actions and side effect profiles of all antidepressants and antipsychotics for further information.
Taylor D et al., The Maudsley Prescribing Guidelines in Psychiatry (12th Edition). Wiley Blackwell. 2015
Taylor D et al., Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ. 2014
Arango C, Buitelaar JK, Fegert JM, Olivier V, Pénélaud PF, Marx U, Chimits D, Falissard B; study investigators. Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries. Lancet Psychiatry. 2021