Serotonin–norepinephrine reuptake inhibitor antidepressant effects on regional connectivity of the thalamus in persistent depressive disorder: evidence from two randomized, double-blind, placebo-controlled clinical trials
Authors: Yang Jie , Hellerstein David J. , Chen Ying , McGrath Patrick J. , Stewart Jonathan W. , Peterson Bradley S. , Wang Zhishun 
Published: April 2022

Abstract
Previous neuroimaging studies have shown that serotonin–norepinephrine reuptake inhibitor antidepressants alter functional activity in large expanses of brain regions. However, it is not clear how these regions are systemically organized on a connectome level with specific topological properties, which may be crucial to revealing neural mechanisms underlying serotonin–norepinephrine reuptake inhibitor treatment of persistent depressive disorder. To investigate the effect of serotonin–norepinephrine reuptake inhibitor antidepressants on brain functional connectome reconfiguration in persistent depressive disorder and whether this reconfiguration promotes the improvement of clinical symptoms, we combined resting-state functional magnetic resonance imaging (fMRI) scans acquired in two randomized, double-blind, placebo-controlled trial studies of serotonin–norepinephrine reuptake inhibitor antidepressant treatment of patients with persistent depressive disorder. One was a randomized, double-blind, placebo-controlled trial of 10-week duloxetine medication treatment, which included 17 patients in duloxetine group and 17 patients in placebo group (ClinicalTrials.gov Identifier: NCT00360724); the other one was a randomized, double-blind, placebo-controlled trial of 12-week desvenlafaxine medication treatment, which included 16 patients in desvenlafaxine group and 15 patients in placebo group (ClinicalTrials.gov Identifier: NCT01537068). The 24-item Hamilton Depression Rating Scale was used to measure clinical symptoms, and graph theory was employed to examine serotonin–norepinephrine reuptake inhibitor antidepressant treatment effects on the topological properties of whole-brain functional connectome of patients with persistent depressive disorder. We adopted a hierarchical strategy to examine the topological property changes caused by serotonin–norepinephrine reuptake inhibitor antidepressant treatment, calculated their small-worldness, global integration, local segregation and nodal clustering coefficient in turn. Linear regression analysis was used to test associations of treatment, graph properties changes and clinical symptom response. Symptom scores were more significantly reduced after antidepressant than placebo administration (η2 = 0.18). There was a treatment-by-time effect that optimized the functional connectome in a small-world manner, with increased global integration and increased nodal clustering coefficient in the bilateral thalamus (left thalamus η2 = 0.21; right thalamus η2 = 0.23). The nodal clustering coefficient increment of the right thalamus (ratio = 29.86; 95% confidence interval, −4.007 to −0.207) partially mediated the relationship between treatment and symptom improvement, and symptom improvement partially mediated (ratio = 21.21; 95% confidence interval, 0.0243–0.444) the relationship between treatment and nodal clustering coefficient increments of the right thalamus. Our study may indicate a putative mutually reinforcing association between nodal clustering coefficient increment of the right thalamus and symptom improvement from serotonin–norepinephrine reuptake inhibitor antidepressant treatments with duloxetine or desvenlafaxine.