With only 30-40% of patients receiving antidepressants able to achieve full remission of symptoms, it is evident that there is a continuous need for new treatments for depression. Valdoxan® (agomelatine) is the first melatonergic antidepressant and has shown superior efficacy at every step of treatment in all depressed patients, as well as a good tolerability profile. It is approved by the TGA for the treatment of major depression in adults including prevention of relapse.

Hormones are released in the brain, which regulate body functions such as, appetite, energy and sleep, to a 24 hour cycle known as circadian rhythms. In particular, melatonin, a hormone which can induce sleep, is usually produced when the sun goes down. Disruption to the circadian rhythms from factors such as; lack of sleep, stress, trauma and shift work can result in hormones being produced at the wrong times and may increase the chance of depression.

Agomelatine is a melatonergic (MT1 and MT2) receptor agonist and serotonin (5HT2C) receptor antagonist. The release of noradrenaline and dopamine in the frontal cortex is increased by agomelatine but the extracellular level of serotonin is not affected. Agomelatine resynchronises circadian rhythms inducing a phase advance of sleep, body temperature decline and melatonin onset.

The recommended dose of agomelatine is one 25mg tablet at bedtime, without regard to food. It is rapidly and well absorbed after oral administration (>80%), however bioavailability is low due to first-pass metabolism in the liver, and peak plasma concentration is reached within one to two hours. Agomelatine is rapidly metabolised, mainly by the cytochrome P450 enzyme (CYP1A2) primarily found in the liver. The mean plasma half-life is between one to two hours and excretion is 80% urinary.

Due to hepatic metabolism by CYP1A2, other medications which interact with these enzymes may alter the bioavailability of agomelatine, in particular; fluvoxamine, cimetidine and ciprofloxacin.

Agomelatine is not recommended in patients under 18 years of age or over 65 years due to lack of data. No dose recommendations are advised in renal impairment; however it is contraindicated in hepatic impairment. All patients should receive liver function tests (LFT’s) on initiation of treatment, after three, six, twelve and twenty-four weeks and then whenever clinically required. If serum transaminases are greater than three times the normal limit then therapy should be ceased and LFT’s monitored until they return to baseline.

The side effect profile is promising and in particular, agomelatine does not cause any of the anticholinergic side effects associated with the tricyclic antidepressants, or cause any hypotension or cardiac arrhythmias. Nausea and dizziness are the most common adverse reactions; they are usually transient and don’t generally lead to cessation of therapy.

Sexual dysfunction such as impotence, loss of libido and ejaculatory failure are common with the majority of antidepressants available. Agomelatine has a lower incidence of these symptoms compared to others. It is thought that sexual dysfunction is due to increased levels of serotonin at the synaptic cleft and as agomelatine does not affect serotonin levels, it therefore reduces the incidence of this.

Sleep disturbance is often a common symptom in depression and, as expected due to the relationship with melatonin, agomelatine was found to significantly improve sleep quality over sertraline and venlafaxine. The reduction in some of these common complaints should improve compliance with this medication.

Discontinuation symptoms are not associated with the abrupt withdrawal of agomelatine, therefore no dosage tapering is required when discontinuing.

In conclusion, the risk of hepatotoxicity is a cause for concern however careful monitoring would control this. The other issue is that long-term effects are not fully known as the duration of the longest study for the 50mg dose was 12 months and only included a small group of patients. However, agomelatine is a very promising agent showing fewer side effects when compared to other antidepressants and should be considered when choosing treatment for depression, including preventing relapse, especially in patients who cannot tolerate, or have had inadequate response to, other antidepressants.

References:

  1. Les Laboratories Servier. Agomelatine (Valdoxan/Thymanax): New contraindication for use and a reminder of the importance of liver function monitoring. Les Laboratories Servier; 2013.
  2. Les Laboratories Servier. Liver function monitoring scheme with Valdoxan. Les Laboratories Servier; 2013.
  3. Servier Laboratories Ltd. Summary of Product Characteristics: Valdoxan. Leatherhead, Surrey: electronic Medicines Compendium (eMC); 2013.
  4. Therapeutic Goods Administration. Australian Public Assessment Report for Agomelatine. Canberra: Therapeutic Goods Administration; 2010.

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