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Front. Psychiatry | doi: 10.3389/fpsyt.2018.00624

Parallel Changes in Mood and Melatonin Rhythm Following an Adjunctive Multimodal Chronobiological Intervention with Agomelatine in People with Depression; a Proof of Concept Open Label Study

 Rébecca Robillard1, 2*,  Joanne Carpenter3, Kristy-Lee Feilds3,  Daniel F. Hermens4,  Django White3, Sharon L. Naismith3, 5, Delwyn Bartlett6, Bradley Whitwell3, James Southan3, Elizabeth M. Scott3 and Ian B. Hickie3
  • 1Royal's Institute of Mental Health Research, University of Ottawa, Canada
  • 2University of Ottawa, Canada
  • 3Brain and Mind Centre, University of Sydney, Australia
  • 4Sunshine Coast Mind and Neuroscience Thompson Institute, University of the Sunshine Coast, Australia
  • 5Charles Perkins Centre, University of Sydney, Australia
  • 6Woolcock Institute of Medical Research, Australia

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-week 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 < .001) and, on average, the timing of dim light melatonin onset (DLMO) shifted 3.6 hours earlier (t(18) = 4.4, p < .001). On average, sleep onset was phase shifted 28 minutes earlier (t(19) = 2.1, p = .047) and total sleep time increased by 24 minutes (t(19) = -2.6, p = 0.018). There was no significant change in wake-up times. A strong correlation (r = .69, p = .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 randomised 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.

Keywords: Melatonin agonist, Agomelatine, Melatonin, Depression, circadian rhythms dysfunctions

Received: 30 Jul 2018; Accepted: 05 Nov 2018.

Edited by:

Colin T. Dourish, P1vital Limited, United Kingdom

Reviewed by:

Ivan G. Koychev, University of Oxford, United Kingdom
Paul Moser, Independent researcher  

Copyright: © 2018 Robillard, Carpenter, Feilds, Hermens, White, Naismith, Bartlett, Whitwell, Southan, Scott and Hickie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Rébecca Robillard, Royal's Institute of Mental Health Research, University of Ottawa, Ottawa, ON K1Z 7K4, Ontario, Canada, Rebecca.Robillard@theroyal.ca