Conventional treatment of depression comprises serotonin-reuptake inhibitors and monoamine reuptake inhibitors. Deviating from tradition, agomelatine is a first-in-class antidepressant for major depression that acts as an agonist to the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C.

Another unique aspect of agomelatine is evidence of its ability to improve quality of sleep. This is a highly desirable effect, as individuals with depression frequently experience disturbed sleep. Trevor Norman, PhD, associate professor at the University of Melbourne, Australia, in an interview with Psychiatry Advisor said, “From a clinical point of view, the ability of the drug to re-entrain circadian rhythms may be unique in that most other antidepressants tend to interfere with sleep cycles.”

Although agomelatine has a high affinity for the MT1 and MT2 receptors, as well as the 5HT2B and 5HT2C receptors, it has a low affinity for several other receptors, such as adrenoceptors, ion channels, and dopaminergic, GABAergic, muscarinic, histamine, benzodiazepine, and sigma receptors. In addition, it produces little effect on monoamine oxidases and neurotransmitter transport molecules. The drug’s agonistic effect on the melatonin receptors and antagonistic effect on the serotonin receptors are both important to achieve an antidepressant effect.

Agomelatine has also been shown to increase the levels of brain-derived neurotrophic factor mRNA and protein in the hippocampus. This effect has been associated with increased neurogenesis, leading to a possible antidepressant effect.

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“Superior efficacy alone is not enough for an antidepressant to do well in the unforgiving world of clinical practice,” says John Donoghue, who is the director at Medicines in Mental Health Ltd., a UK-based organization that provides services and education to maximize the benefits of mental health medicines. “Acceptability is at least equally important, if not more so. Agomelatine is superior to other drugs when efficacy and tolerability are viewed together.” Indeed, the efficacy and tolerability of agomelatine has been shown to be 1 of 3 preferable drugs for depression after 8 weeks of treatment.1 The other 2 drugs were the serotonin-reuptake inhibitors escitalopram and vortioxetine.

In a recent network meta-analysis, agomelatine was found to have the highest acceptability of 21 antidepressants among patients.2 This could suggest that agomelatine might be a suitable first-line treatment for depression because it has equivalent efficacy but better tolerability compared with most antidepressants. However, Dr Norman has a disparate opinion: “My impression is that not too many psychiatrists in clinical practice would wholeheartedly agree with that assessment based on their own personal experience with the drug.” He believes that agomelatine would be more appropriate as a second-line of treatment.

Similar to most antidepressants, agomelatine appears to be effective across a broad spectrum of depressive conditions, instead of a specific type of depression. It has shown therapeutic efficacy for unipolar depression and depression comorbid with certain conditions such as Parkinson disease, type 2 diabetes, and cardiovascular disease.1

Agomelatine has been evaluated in bipolar depression on the basis of its regulatory effect on the circadian rhythm; however, it has not demonstrated significant benefit for this condition. Dr Norman explains: “Most antidepressants can ‘switch’ patients from depression to hypomania/mania. The rate of switching is between 20% to 40%, and some drugs are more likely than others to do this. Most clinical guidelines recommend treating depression in bipolar disorder with an antidepressant and a mood stabilizer, or not using antidepressants at all. Obviously, this would depend on an individual patient’s history. The evidence is that agomelatine has a lower rate of switching than most antidepressants.”

Agomelatine has been approved in Europe and Australia. However, its development has been discontinued in the United States because phase 3 trials showed negative results, and there was evidence that the drug induced liver toxicity. It has also been suggested that the assessment scales currently used to evaluate depression do not accurately represent the circadian effect of agomelatine in depression, leading to inconsistency in clinical results.1

Agomelatine is likely to be used as a second-line treatment for depression, at least in Australia, according to Dr Norman. He says, “The situation in Australia is probably somewhat artificial, as while the drug is approved by the Therapeutic Goods Administration (drug regulatory body of Australia), it is not on the Pharmaceutical Benefits Scheme. In Australia, medicines on the Pharmaceutical Benefits Scheme are subsidized by the government through our ‘universal’ healthcare system, Medicare. Not all medicines are automatically included, and agomelatine is one of the drugs that are not included.” This means that those patients who are prescribed the drug need to pay out of their own pocket. Over the course of treatment, the cost can be significant, so general practitioners are unlikely to prescribe agomelatine for many patients.

In addition to concerns regarding cost, other current limitations of agomelatine therapy include hepatoxicity, the lack of longitudinal studies, and limited evidence regarding its benefit in elderly individuals with depression. Before, during, and after therapy with agomelatine to address concerns regarding hepatotoxicity, certain guidelines have been introduced to monitor liver function. A new approach for the clinical evaluation of depression is also needed to accurately monitor depression and the effects of agomelatine on various aspects of the condition, including sleep patterns.

Despite these limitations, Donoghue believes, “Agomelatine could be a very useful treatment option for many patients, partly because of its very low burden of side-effects and partly because of its beneficial effects on sleep.” Indeed, although agomelatine has not been accepted globally for the treatment of depression, its unique attributes have led to renewed interest among the pharmaceutical and medical communities, especially given the growing need to develop novel therapeutic strategies for depression that is resistant to traditional treatments.

Disclosure: Dr Trevor Norman has received travel grants, research funds, and honoraria from Servier.

References

1. Norman TR, Olver JS, Agomelatine for depression: expanding the horizons? Expert Opin Pharmacother. 2019;20(6):647-656.

2. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366.