Cortical Connectivity Patterns May Distinguish Antidepressant vs Placebo Response in Major Depressive Disorder

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The trial enrolled patients with major depressive disorder from 4 clinical sites in the United States who were not receiving medication. Enrollees were randomly assigned to receive either sertraline hydrochloride or placebo for 8 weeks.

Connectivity patterns in parietal cortical regions may predict placebo outcomes vs antidepressant response in patients with major depressive disorder (MDD), according to data published in JAMA Psychiatry. These results also support the use of electroencephalography (EEG) network analyses for identifying potential treatment response.

Camarin E. Rolle, BS, from the department of psychiatry and behavioral sciences at Stanford University in California, and colleagues conducted a secondary analysis of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care (EMBARC) study. The EMBARC trial enrolled patients with MDD from 4 clinical sites in the United States who were not receiving medication. Enrollees were randomly assigned to receive either sertraline hydrochloride or placebo for 8 weeks.

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Patients underwent EEG at baseline, performed for 8 minutes total, alternating between 2-minute blocks of eyes-open and eyes-closed conditions. Power envelope connectivity (PEC) analyses were applied to resting-state EEG data to characterize baseline functional connectivity networks between 31 regions of interest (ROIs). The researchers applied linear mixed-effects models to identify pretreatment connectivity patterns associated with sertraline response over placebo and analyzed data on an intent-to-treat basis.

A total of 221 treatment-randomized patients with high-quality EEG data were included in analyses (mean age, 37.8±12.7 years; 67.9% women). Significant moderation effects for treatment response were observed at several ROI-to-ROI connections for both the antidepressant and placebo groups.

Greater alpha-band PEC in parietal, temporal, and visual regions, as well as reduced gamma-band PEC within the frontal, visual, somatomotor, parietal, and temporal regions, predicted better outcomes with placebo and worse outcomes with sertraline in the closed-eyes condition. For the open-eyes condition, greater alpha-band in visual and parietal regions; lower gamma-band PEC in frontal, temporal, parietal, anterior cingulate, visual, and somatosensory regions; and lower beta-PEC in frontal and parietal regions predicted similarly divergent outcomes.

Baseline anhedonia levels were negatively associated with alpha and gamma band connectivity for the closed-eyes condition, and depressive symptom severity was positively correlated with higher baseline gamma PEC in frontal, parietal, temporal, insular, and cingulate cortical regions in the closed-eyes condition. However, anhedonia and depression severity accounted for 5% to 10% of variance in connectivity.

The findings support the utility of pretreatment EEG connectivity assessment for predicting treatment response in patients with depression. However, the long-term prognostic capacity of this mechanism remains unknown, and the study was limited by small effect sizes. “From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response could provide an alternative direction toward clinical treatment of patients with depression,” investigators wrote.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Rolle CE, Fonzo GA, Wu W, et al. Cortical connectivity moderators of antidepressant vs placebo treatment response in major depressive disorder: secondary analysis of a randomized clinical trial [published online January 2, 2020]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.3867