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Neocortical serotonin 2A receptor binding, neuroticism and risk of developing depression in healthy individuals

Nature Mental Health (2024)Cite this article

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Abstract

The serotonin 2A receptor (5-HT2AR) and personality trait neuroticism are implicated in the pathophysiology of depression and represent potential targets for prevention and treatment. Here we evaluate whether 5-HT2AR and neuroticism in healthy individuals are related to the risk of developing a future depressive episode by utilizing a large 5-HT2AR molecular-imaging cohort comprising 131 healthy individuals who underwent molecular brain imaging and neuroticism assessments and up to 19 years of data on future depression diagnosis from the Danish Registers. Using cause-specific Cox regression analysis, we found that neocortical 5-HT2AR binding coupled with the inward-directed facets of neuroticism elevated the risk of depression. The risk was greatest in individuals with both high 5-HT2AR binding and high neuroticism. Our data provide novel insights into the risk of depression and support the evaluation of clinical strategies that target 5-HT2AR, such as psychedelics, in conjunction with psychotherapy that addresses personality-based risk factors.

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Fig. 1: Cumulative incidence plot of the probability of developing depression in healthy individuals.
Fig. 2: Predicted risk of depression after 15 years in healthy individuals.

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Data availability

Deidentified data are available from the Cimbi database to researchers via email to cimbi@cimbi.dk. As per National Health Registry regulations, access to register data needs prior approval, and this can be obtained from Statistics Denmark’s research services (https://www.dst.dk/en/TilSalg/Forskningsservice/Dataadgang).

Code availability

To prevent breach of confidentiality, transfer of code and syntax is not allowed from Statistics Denmark. Please contact BrainDrugs Project Manager Peter Steen Jensen at peter.steen.jensen@nru.dk for more information on code availability.

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Acknowledgements

This study was supported by the Lundbeck Foundation R279-2018-1145 (Knudsen, Miskowiak, Frokjaer) and the Innovation Fund Denmark 4108-00004B (Knudsen).

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Authors and Affiliations

  1. Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Anjali Sankar, Simon C. Ziersen, Brice Ozenne, Vibeke H. Dam, Emily E. Beaman, Patrick. M. Fisher, Gitte M. Knudsen & Vibe G. Frokjaer

  2. Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark

    Simon C. Ziersen, Brice Ozenne & Esben Budtz-Jørgensen

  3. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Lars V. Kessing, Gitte M. Knudsen & Vibe G. Frokjaer

  4. Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark

    Lars V. Kessing, Kamilla W. Miskowiak & Vibe G. Frokjaer

  5. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Patrick. M. Fisher

  6. Neurocognition and Emotion in Affective Disorders Centre, Department of Psychology, University of Copenhagen, and Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark

    Kamilla W. Miskowiak

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Contributions

A.S. made substantial contributions to the analysis of data, interpretation of findings, drafting of the paper, and critical revisions for intellectual content. S.C.Z., B.O. and E.B.-J. provided statistical expertise for all analyses performed here and substantially contributed to the interpretation of findings and critical revisions of the paper. E.E.B. and V.H.D. substantially contributed to data curation and critical revisions of the paper. L.V.K., G.M.K., K.W.M. and P.M.F. substantially contributed to the interpretation of findings and critical revisions of the paper. V.G.F. made substantial contributions to the conception and design of the study, analysis of data, interpretation of findings and critical revisions of the paper.

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Correspondence to Anjali Sankar.

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Competing interests

G.M.K. has received honoraria as a speaker for Sage Therapeutics, Angelini and H. Lundbeck and as an expert advisor for Sanos, Onsero, Pangea, Pure and Gilgamesh. V.G.F. has served as a consultant for Sage therapeutics, H. Lundbeck, Janssen-Cilag and Gedeon Richter. K.W.M. has received consultancy fees from Lundbeck, Janssen and Angelini Pharma in the past 3 years. All other authors declare no conflicts of interest.

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Nature Mental Health thanks Sameer Jauhar, Julia Sacher and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Sankar, A., Ziersen, S.C., Ozenne, B. et al. Neocortical serotonin 2A receptor binding, neuroticism and risk of developing depression in healthy individuals. Nat. Mental Health (2024). https://doi.org/10.1038/s44220-024-00299-x

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