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.
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 59 unmedicated participants with MDD in a current depressive episode and 32 healthy volunteers (HVs). Binding potential (BPP) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [11C]DASB tract, MDD showed significantly lower BPP compared with HVs (p=0.02). The BPP diagnosis difference varied by tract location at a trend-level (p=0.08), with MDD binding deficit strongest most proximal to brainstem raphe nuclei. NRU 5-HT Atlas ROIs showed trend-level lower BPPin MDD relative to HVs (p=0.06) and BPP diagnosis difference that varied by region (p=0.001). BPP was lower in MDD in 4/10 regions (p-values<0.05). Neither [11C]DASB tract or NRU 5-HT Atlas BPP correlated with depression severity, suicidal ideation or suicide attempt history. 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.
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