Disaggregating between- and within-person relations for depression and burnout symptoms with cumulative hair cortisol and endocannabinoid concentrations: A multilevel analysis of four annual assessment waves

Background: The endocannabinoid system (ECS) is increasingly being recognized as key regulatory system coupled with the glucocorticoid system implicated in the pathophysiology of stress-related mental disorders. However, prior studies examining the ECS in depression or burnout have been inconclusive, of small sample size or of cross-sectional nature limiting interpretations of causal inferences or time-dependent effects.Methods: In a prospective community based cohort study including 128 individuals (women: 108), depression (PHQ-9) and burnout symptoms (MBI-GS) as well as hair cortisol and endocannabinoids were measured annually over four years. Cortisol, arachidonylethanolamide (AEA) and 2-arachidonyl-sn-glycerol/1-arachidonyl-sn-glycerol (2-AG/1-AG) were extracted from 3 cm hair segments reflecting cumulative concentrations of the last 3 months prior hair sampling.Results: Cross sectional group comparisons at baseline revealed reduced cortisol and AEA levels in the group with a positive major depressive disorder screening compared to individuals with low depression symptomatology (both p < .05). Cortisol was also reduced in the group with a positive burnout screening compared to individuals with a negative screening at baseline (p < .05). Longitudinal multilevel analysis, showed for the total sample that a within-person increase in burnout symptoms was associated with a decrease in cortisol levels over time (p < .05). In the male subsample, a between-person increase in AEA levels across time was associated with a decrease in depression symptoms and vice versa. However, a within-person increase of AEA levels across time was associated with an increase in depression symptoms and vice versa (both p < .05). Further, a within-person increase in burnout symptoms lead to a significant increase in AEA levels in the male subsample (p < .05).Conclusions: While cross-sectional analyses suggest higher depression or burnout symptomatology to be associated with reduced cortisol and AEA release, longitudinal analyses disaggregating between- and within-person effects reveal a complex pattern. A within-person increase in burnout symptoms precedes a decrease in cortisol secretion suggesting an exhaustion of the HPA axis. Between-person analysis show only for men a negative association between depression symptoms and AEA levels over time. However, within-person effects, indicate an increase in depression symptoms to preced and to follow an increase in AEA levels, suggesting a dynamic counterregulatory mechanism between the EC and depression in men differing on the between- and within-person levels. These longitudinal associations further elucidate the time and sex dependent relation between depression, burnout, glucocorticoid and endocannabinoid secretion.