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

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 (BP_P) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [¹¹C]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 [¹¹C]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.