Persistent depressive symptoms, HPA-axis hyperactivity, and inflammation: the role of cognitive-affective and somatic symptoms

Abstract

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity and inflammation are thought to be prominent in the aetiology of depression. Although meta-analyses have confirmed this relationship, there is considerable variability in the effect sizes across studies. This could be attributed to a differential role of such biological systems in somatic versus cognitive-affective depressive symptoms which remains largely unexplored. Furthermore, most longitudinal research to date has focused on transient rather than persistent depressive symptoms. In the current study, we investigated the associations of hair cortisol and plasma C-reactive protein (CRP) with the longitudinal persistence and dimensions (cognitive-affective versus somatic) of depressive symptoms over a 14-year period using Trait-State-Occasion (TSO) structural equation modelling. The data came from a large sample of older adults from the English Longitudinal Study of Ageing. Depressive symptoms were assessed from wave 1 (2002-03) to wave 8 (2016-17). Hair cortisol (N = 4761) and plasma CRP (N = 5784) were measured in wave 6 (2012-13). Covariates included demographic, socioeconomic, lifestyle, chronic disease, and medication data. Our results revealed that higher cortisol and CRP levels were significantly associated with persistent depressive symptoms across the study period. Notably, both biomarkers exhibited stronger relationships with somatic than with cognitive-affective symptoms. The associations with somatic symptoms were also independent of relevant confounding factors. In contrast, their associations with cognitive-affective symptoms were weak after adjustment for all covariates. These distinct associations reveal the importance of considering symptom-specific effects in future studies on pathophysiological mechanisms. Ultimately, this will have the potential to advance the search for biomarkers of depression and facilitate more targeted treatments.

Fig. 1

Trait-State-Occasion (TSO) model of depressive symptoms. Simplified illustration, eFigure 1 in SI file for full specification model. C = cognitive-affective score. S = somatic score. Squares represent observed variables; circles represent latent factors. The overall factor measures the longitudinal persistence of depressive symptoms. The cognitive-affective and somatic factors correspond to the two symptom-specific dimensions

Fig. 2

Mean scores of somatic and cognitive-affective depressive symptoms at each wave (1–8) by hair cortisol and CRP tertiles. Data source: ELSA, waves 1–8. CRP = C-reactive protein. The trajectories of the mean scores were estimated using a smoothing function with linear regression. The grey bands represent the confidence intervals of the trajectories. The data presented in this graph are for descriptive purposes only and do not relate to the trait-state-occasion models tested in the main analysis

Fig. 3

Marginal effects of hair cortisol and C-reactive protein on persistent depressive symptoms: overall, cognitive-affective, and somatic factors. Data source: ELSA, waves 1–8. N: Cortisol = 4761, C-reactive protein = 5784. Unstandardised regression coefficients and confidence intervals. Estimator = WLSMV. Unadjusted model = Model 1 (no covariates). Fully adjusted model = Model 3 (adjusted for demographic, socioeconomic, lifestyle, chronic disease, and medication data)