Serotonergic influence on depressive symptoms and trait anxiety is mediated by negative life events and frontal activation in children and adolescents

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5 - HTT LPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents ( N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5 - HTT LPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5 - HTT LPR/rs25531 S + S/L G + S/L A + L G L A + L G L G genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5 - HTT LPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only L A L A genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5 - HTT LPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.