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Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy

Molecular Psychiatry volume 27, pages 3417–3424 (2022)Cite this article

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Abstract

Serotonin transporter (5-HTT) binding deficits are reported in major depressive disorder (MDD). However, most studies have not considered serotonin system anatomy when parcellating brain regions of interest (ROIs). We now investigate 5-HTT binding in MDD in two novel ways: (1) use of a 5-HTT tract-based analysis examining binding along serotonergic axons; and (2) using the Copenhagen University Hospital Neurobiology Research Unit (NRU) 5-HT Atlas, based on brain-wide binding patterns of multiple serotonin receptor types. [11C]DASB 5-HTT PET scans were obtained in 60 unmedicated participants with MDD in a current depressive episode and 31 healthy volunteers (HVs). Binding potential (BPP) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [11C]DASB tract, the MDD group showed significantly lower BPP compared with HVs (p = 0.02). This BPP diagnosis difference also significantly varied by tract location (p = 0.02), with the strongest MDD binding deficit most proximal to brainstem raphe nuclei. NRU 5-HT Atlas ROIs showed a BPP diagnosis difference that varied by region (p < 0.001). BPP was lower in MDD in 3/10 regions (p-values < 0.05). Neither [11C]DASB tract or NRU 5-HT Atlas BPP correlated with depression severity, suicidal ideation, suicide attempt history, or antidepressant medication exposure. Future studies are needed to determine the causes of this deficit in 5-HTT binding being more pronounced in proximal axon segments and in only a subset of ROIs for the pathogenesis of MDD. Such regional specificity may have implications for targeting antidepressant treatment, and may extend to other serotonin-related disorders.

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Fig. 1: Visualizing the 5-HTT serotonin axonal tract.
Fig. 2: Visualizing 5-HTT binding potential by diagnostic group.
Fig. 3: Serotonin axonal tract diagnostic group difference results.
Fig. 4: NRU 5-HT atlas diagnostic group difference results.

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Acknowledgements

This work was supported by the National Institute of Mental health (P50MH090964, PI: J John Mann, MD and 5R01MH040695, PI: J John Mann, MD).

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Authors and Affiliations

  1. Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA

    Elizabeth A. Bartlett, Francesca Zanderigo, Jeffrey Miller, Patrick Hurley, Harry Rubin-Falcone, M. Elizabeth Sublette, R. Todd Ogden & J. John Mann

  2. Department of Psychiatry, Columbia University Medical Center, New York, NY, USA

    Elizabeth A. Bartlett, Francesca Zanderigo, Denise Shieh, Jeffrey Miller, Patrick Hurley, M. Elizabeth Sublette, R. Todd Ogden & J. John Mann

  3. Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA

    Denise Shieh & R. Todd Ogden

  4. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Maria A. Oquendo

  5. Department of Radiology, Columbia University Medical Center, New York, NY, USA

    J. John Mann

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  1. Elizabeth A. Bartlett
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Contributions

EAB: methodology, software, formal analysis, validation, writing – original draft, and visualization; FZ: conceptualization, methodology, writing – review and editing, and supervision; DS: formal analysis, data curation, validation, visualization, and writing – review and editing; JM: conceptualization, data curation, investigation, supervision, project administration, and writing – review and editing; PH: methodology and writing – review and editing; HRF: methodology, software, validation, formal analysis, data curation, and writing – original draft; MAO: conceptualization, supervision, and writing – review and editing; MES: conceptualization, supervision, writing – review and editing, investigation, and project administration; RTO: conceptualization, methodology, validation, formal analysis, supervision, writing – review and editing; JJM: conceptualization, investigation, resources, supervision, project administration, funding acquisition, and writing – review and editing.

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Correspondence to Elizabeth A. Bartlett.

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Conflict of interest

EAB, FZ, JM, PH, MES, TO, DS, and HRF declare no conflict of interest. MAO and JJM receive royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. MAO serves as an advisor to Alkermes, Otsuka, ATAI, St. George’s University and Fundacion Jimenez Diaz. Her family owns stock in Bristol Myers Squibb.

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Bartlett, E.A., Zanderigo, F., Shieh, D. et al. Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy. Mol Psychiatry 27, 3417–3424 (2022). https://doi.org/10.1038/s41380-022-01578-8

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