Novel melatonin-based therapies: potential advances in the treatment of major depression

Summary

Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT_2C) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.

Introduction

Major depression is a leading cause of premature death and ongoing disability.1, 2 Although the therapeutic benefits of drugs for less severe forms of depression is debatable,3, 4 the overall value that results from the wider provision of both drug and psychological treatments for patients with depression is clear. Benefits include reduced suicide rates, increased participation in the workforce, reduced secondary alcohol or other substance misuse, decreased risk of cardiovascular disease, and, through more regular and extensive use of appropriate health services, destigmatisation of depression and anxiety.5, 6

As long-term antidepressant therapy is often an essential component of treatment for individuals with severe depression, the drive to develop drugs with improved safety profiles has intensified. Although the newer antidepressant drugs have clinically important differences in efficacy and tolerability,⁷ most drug development remains focused on the moderation of the same monoamine targets (eg, serotonin, norepinephrine, or dopamine). Recently, there have been major advances in our understanding of the biology of the circadian system, the clinical significance of disrupted daily cycles, the adverse effects of many antidepressant drugs on circadian cycles and sleep architecture, and the mechanism by which lithium has profound effects on circadian biology. In view of the development of one melatonin analogue with reported antidepressant activity, agomelatine, these advances have led to a renewed focus on the potential clinical benefits that could be derived from modulation of the circadian system.8, 9, 10