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

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 (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.

Figure 1:

Average volume of distribution (V_T) across all participants (top), 3D rendering of the serotonin axonal tract in MNI space as a standard ROI (middle; blue), and the parcellated tract for analyses with the pattern of binding along the tract (bottom; multi-colored). All are shown sagitally (left) and rotated (right) to show the tract depth.

Figure 2:

Mean [¹¹C]DASB binding potential BP_P (y-axis) in each of the 56 parcels within the serotonin axon tract plotted as a function of distance from the origin of the tract in centimeters. Diagnostic group averages plotted in thick, bold lines with HV = healthy volunteer in pink and MDD = major depressive disorder in blue. Additionally, spaghetti plots of each participant are plotted with thin lines according to their group designation. Below plot is a depiction of the x-axis regions according to their location on the tract.

Figure 3:

Diagnostic group difference test: The estimated difference in 5-HTT BP_P between MDD = major depressive disorder and HV = healthy volunteer groups is shown plotted against the distance along the tract. The group difference in the original dataset is plotted with a thick, solid red line. Permutation testing, examining the area under the curve for the main effect of diagnostic group yielded a p-value of 0.02. Black lines show the 95% confidence intervals obtained via bootstrapping. Locations along the tract with both confidence intervals above or below 0 indicate locations of significant group differences.

Figure 4:

Displaying the estimated lower 5-HTT binding potential in MDD relative to the HV group found within the NRU 5-HT Atlas, where 5-HTT binding potential (BP_p) is plotted for all regions in the NRU 5-HT Atlas, broken down by diagnosis (HV=healthy volunteer with circles, MDD = major depressive disorder with triangles) (top). Regions with p<0.05 in post hoc analysis denoted with * and p-value is shown. The color-coding for each region in the top graph matches the corresponding region in the NRU 5-HT Atlas shown at bottom with labeling for region number.