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. [ 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.

Translational bioinformatics and data science for biomarker discovery in mental health: an analytical review

“…Enrichment analysis was performed on the gene network on the left side using EnrichR and was found to be involved in serotonin signaling receptor pathway and serotonin metabolism. Serotonin binding deficits have been well documented in MDD literature [ 125 ]. Enrichment analysis performed on the genes network on the right side revealed RNA editing mechanisms which have been documented in association with MDD in a publication [ 126 ].…”

White matter integrity and medication response to antidepressants in major depressive disorder: a review of the literature

“…Among neurotransmitters, serotonin is one of the most involved due to its crucial role in mood regulation ( 5 ). Indeed, decreased levels of serotonin were observed in MDD ( 6 ), maybe due to deficits in the serotonin transporter (5-HTT) within raphe nuclei, at the level of brainstem ( 7 ), or within the amygdala and midbrain ( 8 ), as well as in the hippocampus, whose neurochemical disruption has been suggested to contribute to developing depressive and anxiety behaviors ( 9 ).…”

The Cerebellum’s Role in Affective Disorders: The Onset of Its Social Dimension

“…Serotonin, discharged from the raphe nucleus (RN) [5,10], has surely the leading position in the etiopathogenesis of MDD and BD [14][15][16]. Deficits of 5-HT transporters have been registered in MDD [15,17] and it has been supposed that 5-HT is linked with the severity of the symptoms of these conditions [15]. Among all its receptors (5-HTR), only 5-HT3 receptor (5-HT3R) has captured attention because of its expression in regions linked with the reward system, cognition and depression [14].…”