Citation

Bartlett EA, Zanderigo F, Shieh D, Miller J, Hurley P, Rubin-Falcone H, Oquendo MA, Sublette ME, Ogden RT, Mann JJ. Mol. Psychiatry 2022; ePub(ePub): ePub.

Copyright

(Copyright © 2022, Nature Publishing Group)

DOI

10.1038/s41380-022-01578-8

PMID

35487966

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. [(11)C]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 (BP(P)) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [(11)C]DASB tract, the MDD group showed significantly lower BP(P) compared with HVs (p = 0.02). This BP(P) 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 BP(P) diagnosis difference that varied by region (p < 0.001). BP(P) was lower in MDD in 3/10 regions (p-values < 0.05). Neither [(11)C]DASB tract or NRU 5-HT Atlas BP(P) 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.

Language: en