The preclinical discovery and development of agomelatine for the treatment of depression

ABSTRACT

Introduction

Under the treatment of commonly used antidepressants, many patients with major depressive disorder (MDD) do not achieve remission. All previous first-line treatments for depression have focused on the enhancement of monoaminergic activity. Agomelatine was the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission.

Areas covered

The aim of this case history is to describe the discovery strategy and development of agomelatine. The pharmacodynamic profile of the drug is briefly presented. The article summarizes (a) the preclinical behavioral data on agomelatine’s effects on depressive-like behavior, anxiety, and circadian rhythmicity disruptions, and (b) the results of early preclinical studies on safety, efficacy in MDD, and the risk-benefit pharmacological profile. Furthermore, the article examines findings of post-marketing research on safety, efficacy, and cost-effectiveness of the drug.

Expert opinion

There is now evidence supporting the clinical efficacy and safety profile of agomelatine in the acute-phase treatment of MDD. Agomelatine may be more effective in specific subgroups of MDD patients, those with severe anxiety symptoms or disturbed circadian profiles. Its antidepressant and anxiolytic activities are due to synergy between its melatonergic and 5-hydroxytryptaminergic effects. Since its discovery, novel compounds acting on the melatonergic system have been under investigation for the treatment of MDD.

KEYWORDS:

• Major depression
• antidepressants
• agomelatine
• melatonin
• melatonergic receptors
• circadian rhythms

Article highlights

• Agomelatine combines agonist activity at melatonergic MT1/MT2 receptors and antagonist activity at 5-HT2c receptors.

• The interplay between melatonergic agonism and the 5-HT2c antagonism may be responsible for the antidepressant effect of agomelatine.

• Preclinical studies show that agomelatine administration improves depressive-like behavior, anxiety, and disrupted circadian rhythms.

• Clinical trials have validated the efficacy and safety of agomelatine to treat depression but there is insufficient evidence regarding its use in long-term treatment.

• Agomelatine may be more effective in subgroups of patients with major depression and severe anxiety symptoms or disturbed circadian profiles.

• Liver function monitoring is needed throughout agomelatine treatment but the cessation of agomelatine leads to rapid hepatic recovery.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was not funded.