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. [(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.