IMMUNOMETABOLIC PROFILING OF DEVELOPMENTAL TRAJECTORY SUBGROUPS OF DEPRESSIVE SYMPTOMS IN ALSPAC
Authors: Tsang *Ruby , Timpson Nicholas , Khandaker Golam 
Published: February 2025

Abstract

Background
Depressive symptoms in childhood and adolescence are associated with an elevated risk of depression and other psychiatric diagnoses in adulthood. Therefore, delineating developmental trajectories of depressive symptoms can inform strategies for early identification and prevention. Depression in adults is associated with immunometabolic alterations and disease; however, the immunometabolic signature of developmental trajectories of depressive symptoms remains unknown. Examining a potentially broad biosignature of these trajectories can shed light on markers of and dysregulations in biological pathways that may be involved in disorder pathogenesis, persistence, and help identify predictive biomarkers.

Aims & Objective
This study aims to characterise developmental trajectories of depressive symptoms from adolescence to early adulthood and to identify proteomic, metabolomic and biochemical biomarkers associated with these trajectories.

Method
Depressive symptoms were assessed in the Avon Longitudinal Study of Parents and Children (ALSPAC) [1, 2] using the 13-item Short Mood and Feelings Questionnaire [3] across 10 time points between 10 and 25 years. Blood samples were collected at face-to-face examinations at 24 years of age; circulating proteins were measured using the Target 96 Inflammation panel (Olink Analysis Service, Uppsala, Sweden) and metabolites using a 1H-NMR spectroscopy-based platform (Nightingale Health, Helsinki, Finland). In addition, full blood count and blood biochemistry tests were conducted. We characterised depressive symptom trajectories in a subsample with data from at least three time points (n=7302) using latent class trajectory modelling, and then estimated posterior probabilities and trajectory class membership in the full sample (n=9595 where estimation was possible). We examined associations between trajectory class membership with 67 inflammation proteins and 71 metabolites using linear models with empirical Bayes moderation and with 28 blood count and biochemical measures using linear regressions (n=2256).

Results
We identified four distinct depressive symptom trajectories – stable-low (69.6%), adolescent-limited (13.3%), adolescent-persistent (7.0%), and adulthood-onset (10.0%). Relative to the stable-low trajectory class, distinct immunometabolic profiles were identified for the three ‘atypical’ trajectory classes, with some overlap in proteomic markers observed between the adolescent-persistent and adulthood-onset classes (fibroblast growth factor 21 [FGF-21], hepatic growth factor [HGF] and eotaxin [CCL11]). The adulthood-onset class showed widespread immunometabolic alterations, including elevated ApoB/ApoA1 ratio, insulin and neutrophils among others.

Discussion & Conclusion
We show that distinct developmental trajectories of depressive symptoms exist from adolescence to early adulthood, which are characterised by distinct immunometabolic changes. In particular, our findings suggest there are widespread immunometabolic alterations in the adulthood-onset class, including raised systemic inflammation and disruptions in glucose and lipid metabolism, which is consistent with an elevated cardiometabolic risk profile. These results provide some insights into markers of and biological pathways that may play a role in the emergence of depressive symptoms. These results may have implications on preventive and early intervention strategies.

References
1.Boyd, A., Golding, J., Macleod, J., Lawlor, D. A., Fraser, A., Henderson, J. et al. (2013). Cohort Profile: The ‘Children of the 90s’— the index offspring of the Avon Longitudinal Study of Parents and Children. International Journal of Epidemiology, 42(1), 111-127.
2.Northstone, K., Lewcock, M., Groom, A., Boyd, A., Macleod, J., Timpson, N. et al. (2019). The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019 [version 1; peer review: 2 approved]. Wellcome Open Research, 4(51).
3.Angold, A., Costello, E. J., Messer, S. C., Pickles, A. (1995). Development of a short questionnaire for use in epidemiological studies of depression in children and adolescents. International Journal of Methods in Psychiatric Research, 5(4), 237-249.