Agomelatine

Contraindications

Agomelatine is contraindicated in patients with kidney or liver impairment. 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. 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.

Adverse effects

Common (1–10% incidence) adverse effects include

• Headache
• Nausea
• Dizziness
• Somnolence
• Diarrhea
• Insomnia
• Fatigue
• Back pain
• Abdominal pain
• Anxiety
• Increased ALAT and ASAT (liver enzymes), possibly greater than three times the upper limit of normal
• Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature)
• Constipation
• Vomiting
• Migraine

Uncommon (0.1–1%) adverse effects include

• Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves)
• Blurred vision
• Eczema
• Pruritus (itching)
• Urticaria
• Agitation
• Irritability
• Restlessness
• Aggression
• Nightmares
• Abnormal dreams

Rare (0.01–0.1%) adverse effects include

• Mania
• Hypomania
• Suicidal ideation
• Suicidal behaviour
• Hallucinations
• Steatohepatitis
• Increased GGT and/or alkaline phosphatase
• Liver failure
• Jaundice
• Erythematous rash
• Face oedema and angioedema
• Weight gain or loss, which tends to be less significant than with SSRIs

Excepting effects on the liver, the above adverse effects were usually mild to moderate and occurred in the first two weeks of treatment, subsiding thereafter.

36.1% of patients with elevated enzyme levels normalize on their own without discontinuing agomelatine. For those who choose to discontinue the drug, the median time to liver enzyme level recovery is 14 days. A 2019 study found no difference in rates of acute liver injury between users of citalopram and agomelatine, though this rate could be decreased due to the precautionary liver enzyme monitoring in the European Union. The EU recommends checking liver enzyme levels before treatment initiation, and then after 3, 6, 12, and 24 weeks and following a dose increase.

Agomelatine does not alter daytime vigilance and memory in healthy volunteers. Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine.

Dependence and withdrawal

No dosage tapering is needed on treatment discontinuation. Agomelatine has no abuse potential as measured in healthy volunteer studies.

Overdose

Agomelatine is expected to be relatively safe in overdose.

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. There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity.

Pharmacology

Pharmacodynamics

Agomelatine acts as a highly potent and selective melatonin MT₁ and MT₂ receptor agonist (K_i = 0.1 nM and 0.12 nM, respectively) and also as a relatively weak serotonin 5-HT_2B and 5-HT_2C receptor antagonist (K_i = 660 nM and 631 nM, respectively; ~6,000-fold lower than for the melatonin receptors). It is a silent antagonist rather than an inverse agonist of the serotonin 5-HT_2C receptor. The drug has negligible affinity for the serotonin 5-HT_2A receptor or for a variety of other targets.

By antagonizing the serotonin 5-HT_2C receptor, agomelatine has been found to disinhibit and increase norepinephrine and dopamine release in the frontal cortex in animals, although notably not in the striatum or nucleus accumbens. In contrast to agomelatine, other serotonin 5-HT_2C receptor antagonists and inverse agonists, such as SB-242084 and SB-206553, have been found to increase dopamine and norepinephrine levels in the nucleus accumbens. These differences may in part be related to constitutive activity of the serotonin 5-HT_2C receptor and resulting differences between neutral antagonists and inverse agonists of the receptor. In addition, there are multiple isoforms of the serotonin 5-HT_2C receptor with different properties. In other studies, while agomelatine alone did not affect the firing rates of ventral tegmental area (VTA) dopaminergic neurons, it abolished the inhibition of these neurons by the serotonin 5-HT_2C receptor agonist Ro60-0175. Due to the increase in norepinephrine and dopamine levels in the frontal cortex with agomelatine, the drug has sometimes been referred to as a norepinephrine–dopamine disinhibitor (NDDI).

Although agomelatine is widely claimed to act as a serotonin 5-HT_2C receptor antagonist, the clinical significance of this action has been disputed. Unlike with other serotonin 5-HT_2C receptor antagonists, therapeutic doses of agomelatine fail to acutely increase slow-wave sleep in humans. Additionally, no receptor occupancy studies of agomelatine have been conducted in humans to demonstrate significant occupancy of serotonin 5-HT_2C receptors at therapeutic doses.

Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, behavioral despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. Agomelatine has been found to resynchronize circadian rhythms in animal models of delayed sleep phase syndrome (DSPS). In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset.

In depressed patients, treatment with the drug increases slow-wave sleep without modification of REM (rapid eye movement) sleep amount or REM latency. From the first week of treatment, onset of sleep and the quality of sleep significantly improved without daytime clumsiness as assessed by patients.

Pharmacokinetics

The main route of metabolism for agomelatine is hepatic through the CYP1A2 (90%) and CYP2C9/19 (10%); co-administration of strong CYP1A2 inhibitors (e.g., fluvoxamine) is contraindicated. Agomelatine is well-absorbed with oral administration (≥80%), but it has very low oral bioavailability (~1%) due to extensive first-pass metabolism. The elimination half-life of agomelatine is 1 to 2 hours. The half-life of agomelatine does not change with repeated administration. There is no accumulation of agomelatine with continuous administration.

Chemistry

Structure

The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead.

Synthesis

History

Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union.

In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the brand names Valdoxan and Thymanax. In July 2006, the Committee for Medicinal Products for Human Use 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. In September 2007, Servier submitted a new marketing application to the EMA.

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. 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. However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.

It was authorized for medical use in the European Union in February 2009, and in Australia in August 2010.

Research

Circadian rhythm sleep disorders

Agomelatine has been investigated for its effects on sleep regulation due its actions as a melatonin receptor agonist. Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm sleep disorders. However, research is very limited (e.g., case reports) and agomelatine is not approved for use in the treatment of sleep disorders.

Seasonal affective disorder

A 2019 Cochrane review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder.