Effect of Intrinsic Patterns of Functional Brain Connectivity in Moderating Antidepressant Treatment Response in Major Depression

Abstract

Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo.Methods: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest-based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms.Results: Prediction of response to sertraline involved several within-and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity.Conclusions: This study identified specific functional network-based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder.

Neuroimaging as a Tool for Individualized Treatment Choice in Depression: the Past, the Present and the Future

“…Intriguingly, some brain patterns seemed to favour placebo over sertraline. Lower connectivity of the hippocampus with the limbic and sensorimotor networks predicted better response to placebo, while higher connectivity had good response to sertraline [34]. In line with findings suggesting pgACC as a general predictor of response, stronger baseline connectivity between pgACC and rostral anterior insula, a hub in the salience network, predicted good response to both sertraline and placebo [23,37].…”

“…Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC), another large multisite trial [33], provided interesting observations on sertraline and placebo response over 8 weeks of treatment, with about 300 neuroimaging datasets available for analysis. Responders to sertraline, as compared to placebo, were characterized by higher baseline connectivity within the default mode network (DMN), greater betweennetwork connectivity of the DMN and executive control networks [34], an abnormal pattern of baseline pretreatment ventro-striatal response to reward expectancy and prediction error [35], and abnormal perfusion across a number of structures [36]. Intriguingly, some brain patterns seemed to favour placebo over sertraline.…”

Individual-Specific Areal-Level Parcellations Improve Functional Connectivity Prediction of Behavior

“…Therefore, various groups (including ours) have most frequently utilized the 400-region Schaefer group-level parcellation (Varikuti et al, 2018; Franzmeier et al, 2019; Kebets et al, 2019; Murphy et al, 2020; Orban et al, 2020). Other studies have opted to utilize different resolutions of the Schaefer group-level parcellation, e.g., 100 regions (Chin Fatt et al, 2019), 200 regions (Anderson et al, 2020; Faskowitz et al, 2020) and 800 regions (Valk et al, 2020). Despite our focus on the 400-region areal-level parcellations in the current study, we do not believe that there is an optimal number of cortical parcels because of the multi-resolution organization of the cerebral cortex (Churchland and Sejnowski, 1988; van den Heuvel and Yeo, 2017).…”

Research Review: Brain network connectivity and the heterogeneity of depression in adolescence – a precision mental health perspective

“…Similarly, lower RN connectivity and stronger anhedonic symptoms have been shown to predict less responsiveness to TMS placed at the dorsomedial PFC, suggesting that patients with greater RN dysfunction require either TMS that is targeted to different locations or other forms of therapy altogether (Downar et al, 2014). In addition, higher connectivity within the DMN and between the DMN and CCN has been shown to predict response to sertraline, an antidepressant (Chin Fatt et al, 2019). Taken together, these findings with depressed adults suggest that heterogeneous symptom profiles are associated with variations in RSFC and that specific neural markers may forecast treatment effectiveness.…”