Background: Major depressive disorder (MDD) is heterogeneous in clinical presentation and treatment response. The COORDINATE-MDD consortium identified two magnetic resonance imaging (MRI)-derived neuroanatomical profiles: dimension 1 (D1), with relatively preserved gray and white matter, and dimension 2 (D2), showing widespread reductions aligned with immunometabolic profile. Profiles were associated with distinct responses to selective serotonin reuptake inhibitor (SSRI) antidepressant and placebo (PLA). In this study, we examined electrophysiological correlates of the neuroanatomical profiles and their relationship to treatment outcome.
Methods: Baseline resting-state, eyes-closed electroencephalography (EEG) was acquired from 237 medication-free participants with MDD who were in a current depressive episode (155 women; mean age [SD] = 37.47 [13.36] years) from CAN-BIND (Canadian Biomarker Integration Network in Depression) (SSRI) and EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) (SSRI or PLA). EEG features included spectral power, frontal alpha asymmetry (FAA), multiscale sample entropy, and intersite phase clustering. Effects of profile (D1 and D2) and clinical outcome (responder, nonresponder; defined as ≥50% symptom improvement) were examined with age, sex, and site as covariates.
Results: No significant electrophysiological differences were observed after covariate adjustment. However, among participants who subsequently responded to treatment, D1 showed greater baseline alpha power in frontal and central regions and lower relative delta posteriorly compared with D2. In PLA-treated responders, D2 showed spectral slowing, elevated low-frequency power, reduced gamma, and coarse-scale entropy compared with D1. Baseline FAA was lower in responders than nonresponders, independent of the neuroanatomical profile.
Conclusions: EEG differences between MRI-defined neuroanatomical profiles emerged in relation to clinical outcome. D1 was associated with electrophysiological patterns consistent with flexible, globally regulated cortical dynamics in SSRI responders, whereas D2 showed a distinct pattern in PLA responders, indicating partially separable neural mechanisms underlying pharmacological and PLA treatment effects.
Keywords: Antidepressant treatment response; Electrophysiological predictors; Major depressive disorder; Multimodal neuroimaging; Neuroanatomical dimensions; Resting-state EEG.
Depression is a common condition, but people differ in their symptoms, underlying biology, and response to treatment. This makes it difficult to predict which treatments will be most effective for each individual. Previous research from the COORDINATE-MDD consortium identified two brain-based groups of individuals with depression using MRI scans. One group showed relatively preserved brain structure and better response to antidepressant medication, whereas the other showed more widespread structural changes and similar improvement with medication or placebo, suggesting different underlying mechanisms. In this study, we examined whether these groups also differ in brain activity measured using electroencephalography before treatment. No clear differences were seen across all participants. However, among those who later improved, distinct patterns emerged: one group showed more organized and adaptable brain activity patterns and greater response to medication, whereas the other showed slower activity and reduced complexity linked to placebo response. These findings suggest that different biological mechanisms underlie treatment response, supporting more personalized approaches to care.
© 2026 The Authors.