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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.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.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.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.

The authors evaluated improvement in irritability with antidepressant treatment and its prognostic utility in treatment-seeking adult outpatients with major depressive disorder.Mixed-model analyses were used to assess changes in irritability (as measured with the five-item irritability domain of the Concise Associated Symptom Tracking [CAST-IRR] scale) from baseline to week 4 after controlling for depression severity (as measured with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C]) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (N=664). An interactive calculator for remission (QIDS-C score ≤5) and no meaningful benefit (30% reduction in QIDS-C score from baseline) at week 8 was developed with logistic regression analyses in the CO-MED trial using participants with complete data (N=431) and independently replicated in the Suicide Assessment and Methodology Study (SAMS) (N=163).In the CO-MED trial, irritability was significantly reduced (effect size=1.06) from baseline to week 4, and this reduction remained significant after adjusting for QIDS-C change (adjusted effect size=0.36). A one-standard-deviation greater reduction in CAST-IRR score from baseline to week 4 predicted a 1.73 times higher likelihood of remission and a 0.72 times lower likelihood of no meaningful benefit at week 8, independent of baseline QIDS-C and CAST-IRR scores and reduction in QIDS-C score from baseline to week 4. The model estimates for remission (area under the curve [AUC]=0.79) and no meaningful benefit (AUC=0.76) in the CO-MED trial were used to predict remission (AUC=0.80) and no meaningful benefit (AUC=0.84) in SAMS and to develop an interactive calculator.Irritability is an important symptom domain of major depressive disorder that is not fully reflected in depressive symptom severity measures. Early reductions in irritability, when combined with changes in depressive symptom severity, provide a robust estimate of likelihood of remission or no meaningful benefit in outpatients with major depression.