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

Am J Psychiatry. 2020 Feb 1;177(2):143-154. doi: 10.1176/appi.ajp.2019.18070870. Epub 2019 Sep 20.


Objective: 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.

Trial registration: ClinicalTrials.gov NCT01407094.

Keywords: EMBARC; Functional Connectivity; Major Depressive Disorder; Moderators of Treatment Outcome.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antidepressive Agents / therapeutic use*
  • Brain / physiopathology*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology*
  • Female
  • Functional Neuroimaging
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neural Pathways / physiopathology*
  • Predictive Value of Tests*
  • Sertraline / therapeutic use*
  • Treatment Outcome
  • Young Adult


  • Antidepressive Agents
  • Sertraline

Associated data

  • ClinicalTrials.gov/NCT01407094