Background Major depressive disorder (MDD) is heterogeneous in clinical presentation and treatment response. COORDINATE-MDD consortium identified two MRI-derived neuroanatomical profiles: Dimension 1 (D1), with relatively preserved grey and white matter, and Dimension 2 (D2), showing widespread reductions aligned with immuno-metabolic profile. Profiles were associated with distinct responses to SSRI antidepressant and placebo. This study examined electrophysiological correlates and relationship to treatment outcome. Methods Baseline resting-state, eyes-closed EEG was acquired from 237 medication-free MDD participants in current depressive episode (155 women; mean age 37.47 ± 13.36 years) from CAN-BIND (SSRI) and EMBARC (SSRI or placebo). EEG features included spectral power, frontal alpha asymmetry (FAA), multiscale sample entropy and inter-site phase clustering. Effects of profile (D1, D2) and clinical outcome (responder, non-responder; 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 placebo-treated responders, D2 showed spectral slowing, elevated low-frequency power, reduced gamma and coarse-scale entropy relative to D1. Baseline FAA was lower in responders than non-responders, independent of neuroanatomical profile. Conclusions EEG differences between MRI-defined neuroanatomical profiles emerge in relation to clinical outcome. D1 is associated with electrophysiological patterns consistent with flexible, globally regulated cortical dynamics in SSRI responders, whereas D2 shows distinct pattern in placebo responders, indicating partially separable neural mechanisms underlying pharmacological and placebo treatment effects. Plain Language Summary : 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 depression using MRI scans. One group showed relatively preserved brain structure and better response to antidepressant medication, while the other showed more widespread 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 EEG before treatment. No clear differences were seen across all participants. However, among those who later improved, distinct patterns emerged: one group showed activity consistent with more flexible and coordinated brain function and greater response to medication, while the other showed slower activity and reduced complexity linked to placebo response.These findings suggest that different biological mechanisms underlie treatment response, supporting more personalised approaches to care.
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