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

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Abstract

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-HTTLPR/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-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/LG + S/LA + LGLA + LGLG genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/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 LALA 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-HTTLPR/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.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—project number 44541416—TRR 58 (project C02 to KD and SN, project Z02 to KD, AR, JD, PP, and MR). This publication is part of the dissertation project of KK. We gratefully acknowledge the skillful technical assistance by Carola Gagel and Thomas Elpel.

Author information

Author notes

  1. Katharina Kneer and Julia Reinhard have contributed equally to this work and should, therefore, both be considered first authors.

  2. Marcel Romanos, Katharina Domschke, and Susanne Neufang have contributed equally to this work and should, therefore, all be considered last authors.

Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany

    Katharina Kneer, Julia Reinhard, Anna Slyschak, Katharina Peters, Marcel Romanos & Susanne Neufang

  2. Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Christiane Ziegler, Miriam Schiele & Katharina Domschke

  3. Department of Psychiatry, Psychotherapy and Psychosomatics, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany

    Melanie Vietz & Jürgen Deckert

  4. Department of Psychiatry and Psychotherapy, Medical Faculty Heinrich-Heine University, Bergische Landstraße 2, 40629, Düsseldorf, Germany

    Eva M. Meisenzahl & Susanne Neufang

  5. Department of Psychology, Center of Mental Health, University of Würzburg, Würzburg, Germany

    Paul Pauli

  6. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany

    Andreas Reif

  7. Centre for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Katharina Domschke

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  1. Katharina Kneer
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Correspondence to Susanne Neufang.

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Kneer, K., Reinhard, J., Ziegler, C. et al. Serotonergic influence on depressive symptoms and trait anxiety is mediated by negative life events and frontal activation in children and adolescents. Eur Child Adolesc Psychiatry 29, 691–706 (2020). https://doi.org/10.1007/s00787-019-01389-3

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