Objective: Depressive symptoms and cardio-metabolic risk factors often co-occur. However, our understanding of the potential mechanisms and temporal dynamics underlying their co-development remains elusive. Method: This population-based cohort study examined bidirectional longitudinal associations between depressive symptoms and cardio-metabolic risk factors from age 10 to 25 years, using prospective data from the ALSPAC Study. Participants with at least one (of six) follow-up measurement for each outcome were included in the analyses. We measured depressive symptoms through self- as well as parent-reports, and assessed several cardio-metabolic risk factors (including adiposity measures, lipid profiles and inflammation). Results: Among our 7970 (47% male) participants, we found bidirectional, within-person associations between self-reported depressive symptoms and adiposity (i.e., fat/lean mass index, but not body mass index), across the study period. Adiposity was more stable over time (β [range] = 0.75 [0.54; 0.84]), compared to depressive symptoms (0.26 [0.12; 0.38]), and it had a stronger prospective (i.e., cross-lagged) association with future depressive symptoms (0.07 [0.03, 0.13]) compared to that between depressive symptom and future adiposity (0.04 [0.03, 0.06]). The magnitude of these associations reached its peak between 14 and 16 years. We did not find evidence of cross-lagged associations in either direction between depressive symptoms and waist circumference, insulin, triglycerides, LDL cholesterol or C-reactive protein. Conclusions: These findings suggest a bidirectional relationship between depressive symptoms and cardio-metabolic risk factors, particularly adiposity (i.e., fat/lean mass). Adiposity showed a stronger prospective association with future depressive symptoms, than vice versa, however their relationship revealed more reciprocal than previously thought.

The authors have declared no competing interest.

This project received funding from the European Union's Horizon 2020 research and innovation programme (grant reference: 848158, EarlyCause). E.W. also received funding from the UK Research and Innovation (UKRI) under the UK government's Horizon Europe / ERC Frontier Research Guarantee [BrainHealth, grant number EP/Y015037/1] and from the National Institute of Mental Health of the National Institutes of Health (award number R01MH113930). The work of H.T. was supported by the Netherlands Organization for Health Research and Development ZonMw Vici Grant (016.VICI.170.200). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and E.W. and S.D. will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); This research was specifically funded by the Wellcome Trust and MRC (core) (Grant refs: 076467/Z/05/Z; 084632/Z/08/Z; 092731), and the John Templeton Foundation (Grant ref: 61917).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ALSPAC Ethics and Law Committee gave ethical approval for this study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The dataset used in this study is available upon request and subject to ALSPAC executive data access procedures. To apply for access to the ALSPAC data: 1) Please read the ALSPAC access policy which describes the process of accessing the data and samples in detail, and outlines the costs associated with doing so (http://www.bristol.ac.uk/media-library/sites/alspac/documents/researchers/data-access/ALSPAC_Access_Policy.pdf); 2) You may also browse our fully searchable research proposals database, which lists all research projects that have been approved since April 2011 (https://proposals.epi.bristol.ac.uk/?q=proposalSummaries); 3) Please submit your research proposal for consideration by the ALSPAC Executive Committee (https://proposals.epi.bristol.ac.uk/). All scripts employed in the data processing, analyses and in the generation of study metadata are publicly available (https://github.com/SereDef/comorb-longit-project).