Abstract
Background: Agomelatine is a melatonin agonist and 5HT antagonist developed for the treatment of major depressive disorder which also has some effects on the circadian system. Since circadian dysfunctions are thought to play a role in the pathophysiology of depression, some of the mechanism of action of this drug may relate to improvements in circadian rhythms.Objective: This proof of concept open-label study sought to determine if improvements in depressive symptoms following an adjunctive multimodal intervention including agomelatine intake are associated with the magnitude of circadian realignment. This was investigated in young people with depression, a subgroup known to have high rates of delayed circadian rhythms.Methods: Young people with depression received a psychoeducation session about sleep and circadian rhythms, were asked to progressively phase advance their wake up time, and completed an 8 weeks course of agomelatine (25–50 mg). Participants underwent semi-structured psychological assessments, ambulatory sleep-wake monitoring and measurement of melatonin circadian phase before and after the intervention.Results: Twenty-four young adults with depression (17–28 years old; 58% females) completed the study. After the intervention, depressive symptoms were significantly reduced [t(23) = 6.9, p < 0.001] and, on average, the timing of dim light melatonin onset (DLMO) shifted 3.6 h earlier [t(18) = 4.4, p < 0.001]. On average, sleep onset was phase shifted 28 min earlier [t(19) = 2.1, p = 0.047] and total sleep time increased by 24 min [t(19) = –2.6, p = 0.018]. There was no significant change in wake-up times. A strong correlation (r = 0.69, p = 0.001) was found between the relative improvements in depression severity and the degree of phase shift in DLMO.Conclusion: Although this needs to be replicated in larger randomized controlled trials, these findings suggest that the degree of antidepressant response to a multimodal intervention including psychoeducation and agomelatine intake may be associated with the degree of change in evening melatonin release in young people with depression. This offers promising avenues for targeted treatment based on the prior identification of objective individual characteristics.
Highlights
In the ongoing search for more effective depression treatments, the last decade has seen the emergence of new melatonergic agents developed to improve mood [1]
Based on a proof of concept open-label study, the present findings suggest that 8 weeks of agomelatine intake, provided with psychoeducation and behavioral advice, is accompanied by significant mood improvements in young people with depressive disorders
On average, based on established clinical thresholds, depressive symptoms dropped from moderate to mild severity during the course of the intervention. While these mood improvements were modest when averaged across the whole sample, the strongest antidepressant responses were observed in those individuals who underwent the largest phase advance in Dim Light Melatonin Onset (DLMO)
Summary
In the ongoing search for more effective depression treatments, the last decade has seen the emergence of new melatonergic agents developed to improve mood [1]. Due to its melatonergic pharmacological profile, agomelatine may be optimally suited to treat depression in individuals with prominent disruptions in circadian rhythms, a factor increasingly recognized as contributing to the onset and maintenance of depression for at least a subgroup of people with mood disorders. In order to identify when agomelatine is best indicated for the treatment of depression, a better understanding of the biological mechanisms underpinning the antidepressant effects of this drug is required. Agomelatine is a melatonin agonist and 5HT antagonist developed for the treatment of major depressive disorder which has some effects on the circadian system. Since circadian dysfunctions are thought to play a role in the pathophysiology of depression, some of the mechanism of action of this drug may relate to improvements in circadian rhythms
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