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

  • Katharina Kneer
  • Julia Reinhard
  • Christiane Ziegler
  • Anna Slyschak
  • Miriam Schiele
  • Melanie Vietz
  • Katharina Peters
  • Eva M. Meisenzahl
  • Paul Pauli
  • Andreas Reif
  • Jürgen Deckert
  • Marcel Romanos
  • Katharina Domschke
  • Susanne NeufangEmail author
Original Contribution


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.


fMRI Anxiety Depression Negative life events 5-HTTLPR/rs25531 



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.

Compliance with ethical standards

Conflict of interest

All authors declared no conflict of interests.

Supplementary material

787_2019_1389_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 17 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Katharina Kneer
    • 1
  • Julia Reinhard
    • 1
  • Christiane Ziegler
    • 2
  • Anna Slyschak
    • 1
  • Miriam Schiele
    • 2
  • Melanie Vietz
    • 3
  • Katharina Peters
    • 1
  • Eva M. Meisenzahl
    • 4
  • Paul Pauli
    • 5
  • Andreas Reif
    • 6
  • Jürgen Deckert
    • 3
  • Marcel Romanos
    • 1
  • Katharina Domschke
    • 2
    • 7
  • Susanne Neufang
    • 1
    • 4
    Email author
  1. 1.Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, Center of Mental HealthUniversity Hospital WürzburgWürzburgGermany
  2. 2.Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
  3. 3.Department of Psychiatry, Psychotherapy and Psychosomatics, Center of Mental HealthUniversity Hospital WürzburgWürzburgGermany
  4. 4.Department of Psychiatry and PsychotherapyMedical Faculty Heinrich-Heine UniversityDüsseldorfGermany
  5. 5.Department of Psychology, Center of Mental HealthUniversity of WürzburgWürzburgGermany
  6. 6.Department of Psychiatry, Psychosomatic Medicine and PsychotherapyUniversity Hospital FrankfurtFrankfurtGermany
  7. 7.Centre for Basics in Neuromodulation, Faculty of MedicineUniversity of FreiburgFreiburgGermany

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