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Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment

Molecular Psychiatry volume 22, pages 1155–1163 (2017)Cite this article

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A Corrigendum to this article was published on 18 April 2017

Abstract

The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.

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Acknowledgements

The study was supported by grants of: the Swedish Brain Foundation (FO2015-0235) to MIS and MJ, The Swedish Research Council (2015-02760) to MIS and MJ; Network for European Funding for Neuroscience Research (BrainCYP) to MIS and RFT, German Research Foundation (grant FOR 2107; DA1151/5-1), Innovative Medizinische Forschung (DA120903, DA111107 and DA211012), Rolf-Dierichs-Stiftung (ZUW80037) to UD; CIHR (TMD 132557), the Campbell Family Mental Health Research Institute of CAMH, the CAMH foundation, an Endowed Chair in Psychiatry, the Canada Foundation for Innovation (#20289 and #16014) and the Ontario Ministry of Research and Innovation to RFT, Union Europea Fondo Social Europeo (FEDER) and Junta de Extremadura Consejería de Economía, Competitividad e Innovación (IB13186) to EPL. We thank Kerry Ressler, Bekh Bradley, Tanja Jovanovic and the team of the Grady Trauma project. Recruitment and Genotyping of this project was supported by R01 MH096764 and R01 MH071537 to Kerrry Ressler. We thank Claude Brodski and Catherine Bell for helpful discussion and critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden

    M M Jukić, J Ström, A Renblom, S C Sim & M Ingelman-Sundberg

  2. Department of Psychiatry, University of Münster, Münster, Germany

    N Opel & U Dannlowski

  3. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    T Carrillo-Roa & E B Binder

  4. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    S Miksys, M Novalen, A Llerena & R F Tyndale

  5. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    S Miksys, M Novalen, A Llerena & R F Tyndale

  6. Department of Pharmacology and Toxicology,

    S Miksys, M Novalen, A Llerena & R F Tyndale

  7. , University of Toronto, Toronto, ON, Canada

    S Miksys, M Novalen, A Llerena & R F Tyndale

  8. CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz, Spain

    E M Peñas-Lledó

  9. CIBERSAM, Madrid, Spain

    E M Peñas-Lledó

  10. Psychiatric Emergency and Post-Acute Care Department, CHU Montpellier, Hôpital Lapeyronie,

    P Courtet

  11. , Pole Urgence, Montpellier, France

    P Courtet

  12. Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia

    B T Baune

  13. Department of Psychology, Transfaculty Research Platform, University Psychiatric Clinics, University of Basel, Basel, Switzerland

    D J de Quervain & A Papassotiropoulos

  14. Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, Switzerland

    A Papassotiropoulos

  15. Department of Psychiatry, University of Marburg, Marburg, Germany

    U Dannlowski

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  1. M M Jukić
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  2. N Opel
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Correspondence to M Ingelman-Sundberg.

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RFT has consulted for Apotex. The remaining authors declare no conflict of interest.

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Jukić, M., Opel, N., Ström, J. et al. Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment. Mol Psychiatry 22, 1155–1163 (2017). https://doi.org/10.1038/mp.2016.204

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