Eight-week antidepressant treatment reduces functional connectivity in first-episode drug-naïve patients with major depressive disorder

Abstract

Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big-data study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first-episode drug-naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty-one first-episode drug-naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting-state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big-data finding, we also conducted a cross-sectional comparison of resting-state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network-Based Statistic analyses and large-scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network-Based Statistic analyses nor large-scale network analyses detected significant functional connectivity differences between treatment-naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD.

Keywords: antidepressants; brain network; functional connectivity; major depressive disorder; resting-state fMRI.

FIGURE 1

Eight‐week antidepressant treatment decreases edge‐based FC in MDD patients (n = 40). The brain maps show the affected edges (lines) and their connecting nodes (spheres) from several perspectives. The size of a node indicates how many affected edges are connected to this sphere. Bigger nodes have more affected edges than smaller ones. The color of a node indicates which network it belongs to. The color of edges (blue) indicates that the FC is decreased in MDD patients after treatment. A, anterior; DAN, dorsal attention network; DMN, default mode network; FC, functional connectivity; FPN, frontoparietal network; L, left; P, posterior; R, right; SCN, subcortical network; SMN, somatosensory network; VAN, ventral attention network; VN, visual network

FIGURE 2

Antidepressant effect and group difference in edge‐based FC. Heatmaps show the number of significant edges for each pair of networks for each of the three contrasts: (a) 8‐week versus baseline of treatment in MDD (n = 40); (b) MDD at baseline versus HCs (n = 40 vs. n = 85); (c) MDD after treatment versus HCs (n = 40 vs. n = 85). HCs, healthy controls; MDD, patients with major depressive disorder. For network abbreviation, please refer to the legend of Figure 1

FIGURE 3

Eight‐week antidepressant treatment decreases large‐scale network FC in MDD patients (n = 40). (a) The upper‐left heatmap shows the T values of paired‐sample T tests on FC for each pair of networks between 8‐week treatment and baseline. For T value color bar, blue indicates FC decrease while red indicates FC increase after treatment. The schematic diagram on the upper‐right panel shows the network connections with significant FC decrease for the seven networks after treatment. The bottom heatmaps show the mean FC for each pair of networks in MDD patients (b) at baseline and (c) after treatment. The color bar indicates FC value. FC, functional connectivity; MDD, patients with major depressive disorder. For network abbreviations, please refer to the legend of Figure 1. *FDR‐corrected p < .05 (two‐tailed)

FIGURE 4

Indifference of large‐scale network FC between MDD patients and healthy controls. The heatmaps show T values of two‐sample T tests on FC (a) between MDD at baseline with HCs (n = 40 vs. n = 85), and (b) between MDD after treatment with HCs (n = 40 vs. n = 85), for all pairs of networks. For the T value color bar, blue indicates FC decrease while red indicates FC increase in MDD as compared to HCs. HCs, healthy controls; MDD, patients with major depressive disorder. For network abbreviations, please refer to the legend of Figure 1