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

Mol Psychiatry. 2022 Aug;27(8):3417-3424. doi: 10.1038/s41380-022-01578-8. Epub 2022 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Bayes Theorem
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Depressive Disorder, Major* / drug therapy
  • Humans
  • Positron-Emission Tomography
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins* / metabolism

Substances

  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Antidepressive Agents