Background Individuals with mood disorders are at increased risk of metabolic diseases such as Type 2 diabetes. Circadian (and linked 24 hour rest-activity) disturbances are highly prevalent among this population and have also been linked to immune-metabolic dysfunction. Currently there is limited understanding of the extent to which these pathophysiological processes co-occur across the various clinical stages of major mood disorders.

Methods 225 young people (67% female; aged 23.65 ± 5.73 years) recruited from early intervention mental health services were assigned clinically to either Stage 1a or 1b (subthreshold disorders) or Stage 2+ (full threshold disorder) of illness according to the transdiagnostic staging model. We explored relationships between immune-metabolic risk factors (BMI, fasting glucose and insulin, insulin resistance, and CRP) and rest-activity parameters from actigraphy (24 hour ambulatory motor activity monitoring) using pairwise correlations, multiple linear regression interaction effects and subgroup analyses.

Results For all participants, higher intradaily variability (greater rest-activity fragmentation) was associated with higher BMI (r=0.187, p=0.043), fasting insulin (r=0.180, p=0.031), HOMA2-IR (r=0.187, p=0.043), and CRP (r=0.178, p=0.032) across all stages of illness. Lower relative amplitude of rest-activity patterns indicating dampened circadian rhythmicity, was associated with higher BMI (β=-33.149, p=0.013) and CRP (β=-22.042, p=0.053), only for those in stage 2+ of illness. It was also associated with fasting insulin during stage 1b (β=-10.299, p=0.044) and stage 2 (β=-10.411, p=0.037), and with HOMA2-IR at stage 1b (β=-1.133, p=0.040). Finally, increased moderate-to-vigorous physical activity (MVPA) was associated with lower BMI only for those at Stage 2+ (β=-0.056, p=0.001).

Conclusions Objective measures of blunted and fragmented 24 hour rest-activity (circadian) rhythms were associated with adverse immune-metabolic outcomes. Stabilisation and amplitude-boosting of rest-activity rhythms may be particularly valuable targets for indicated prevention and early intervention of major mood disorders.

The authors have declared no competing interest.

EMS is Principal Research Fellow at the Brain and Mind Centre, The University of Sydney. She is Discipline Leader of Adult Mental Health, School of Medicine, University of Notre Dame, and a Consultant Psychiatrist. She was the Medical Director, Young Adult Mental Health Unit, St Vincents Hospital Darlinghurst until January 2021. She has received honoraria for educational seminars related to the clinical management of depressive disorders supported by Servier, Janssen and Eli-Lilly Pharmaceuticals. She has participated in a national advisory board for the antidepressant compound Pristiq, manufactured by Pfizer. She was the national coordinator of an antidepressant trial sponsored by Servier. IBH has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) projects focused on the identification and better management of anxiety and depression. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30M Australian Government-funded Project Synergy (2017-20) and to lead transformation of mental health services internationally through the use of innovative technologies.

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The research was approved by the University of Sydney Human Research Ethics Committee (2012/1631) and the Human Research Ethics Committee of the Sydney Local Health District (2020/ETH01272), and all participants gave written informed consent, with parental/guardian consent obtained for participants younger than 16 years.

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