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

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 (η 2 = 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 η 2 = 0.21; right thalamus η 2 = 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.

Keywords: functional connectome; graph theory; persistent depressive disorder; placebo; serotonin noradrenaline reuptake inhibitor antidepressant.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Graphical Abstract

Figure 1

Longitudinal data analyses to assess changes in global network properties of 65 patients. (A) Sigma showing significant alteration in treatment-by-time interaction (F = 4.49, P = 0.038); (B) comparison of the sigma between follow-up and baseline in the antidepressant group (P = 0.09); (C) comparison of the sigma between follow-up and baseline in the placebo group (P = 0.22); (D) Comparison of the Gamma in treatment-by-time interaction (F = 3.83, P = 0.057); (E) comparison of the gamma between follow-up and baseline in the antidepressant group (P = 0.09); (F) comparison of the gamma between follow-up and baseline in the placebo group (P = 0.34). (G) Gamma showing significant alteration in treatment-by-time interaction (F = 4.16, P = 0.044); (H) comparison of the gamma between follow-up and baseline in the antidepressant group (P = 0.15); (I) comparison of the gamma between follow-up and baseline in the placebo group (P = 0.14). Symbol ‘*’ represents P < 0.05. a2, follow-up of the antidepressant group; a1, baseline of the antidepressant group; b2, follow-up of the placebo group; b1, baseline of the placebo group.

Figure 2

Longitudinal data analyses to assess changes in regional network properties of 65 patients. (A) The nodal clustering coefficient increment of the left thalamus is positively correlated with the HAMD decrements (P = 0.011, r = −0.315); (B) clustering coefficient of the left thalamus showing significant alteration in treatment-by-time interaction (F = 17, P < 0.001, P-corrected = 0.0144); (C) comparison of clustering coefficient of the left thalamus between follow-up and baseline in the antidepressant group (P < 0.001); (D) comparison of clustering coefficient of the left thalamus between follow-up and baseline in the placebo group (P = 0.11); (E) The nodal clustering coefficient increment of the right thalamus is positively correlated with the HAMD decrements (P = 0.001, r = −0.403); (F) clustering coefficient of the right thalamus showing significant alteration in treatment-by-time interaction (F = 18.8, P < 0.001, P-corrected = 0.0141); (G) comparison of clustering coefficient of the right thalamus between follow-up and baseline in the antidepressant group (P < 0.001); (H) comparison of clustering coefficient of the right thalamus between follow-up and baseline in the placebo group (P = 0.12); Symbol ‘*’ represents P < 0.05. a2, follow-up of the antidepressant group; a1, baseline of the antidepressant group; b2, follow-up of the placebo group; b1, baseline of the placebo group; NCC, nodal clustering coefficient; HAMD, 24-item Hamilton Depression Rating Scale.

Figure 3

Longitudinal mediation analyses on 65 patients. (A)The mediation effect of the change of right thalamus nodal clustering coefficient significantly mediated the association between treatment (SNRI antidepressant/placebo) and depressive symptom response. Path C (t = 3.68, P < 0.001) represents the variance in treatment associated with depressive symptom response, and Path C’ (t = 2.314, P = 0.024) represents the association between treatment and depressive symptom response after taking into account the change of right thalamus nodal clustering coefficient as a mediator. Path AB (β = −0.249, CI [−4.007 −0.207]) is the mediation effect and is significant at P < 0.05 based on confidence intervals from bias-corrected bootstrapping of 5000 samples; (B)The mediation effect of the HAMD improvement significantly mediated the association between treatment (SNRI antidepressant/placebo) and change of right thalamus nodal clustering coefficient. Path C (t = 4.369, P < 0.001) represents the variance in treatment associated with the change of right thalamus nodal clustering coefficient, and Path C’ (t = 3.204, P = 0.002) represents the association between treatment and the change of right thalamus nodal clustering coefficient after taking into account the HAMD improvement as a mediator. Path AB is [β = 0.203, CI (0.0243 0.444)] the mediation effect and is significant at P < .05 based on confidence intervals from bias-corrected bootstrapping of 5000 samples. SNRI, serotonin noradrenaline reuptake inhibitors; CI, confidence interval.