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Background:  Individuals with major depressive disorder (MDD) vary in their response to antidepressants. However, identifying objective biomarkers, prior to or early in the course of treatment that can predict antidepressant efficacy, remains a challenge.   Methods:  Individuals with MDD participated in a 12-week antidepressant pharmacotherapy trial. Electroencephalographic (EEG) data was collected before and 1 week post-treatment initiation in 51 patients. Response status at week 12 was established with the Montgomery-Asberg Depression Scale (MADRS), with a ≥50% decrease characterizing responders ( N  = 27/24 responders/non-responders). We used a machine learning (ML)-approach for predicting response status. We focused on Random Forests, though other ML methods were compared. First, we used a tree-based estimator to select a relatively small number of significant features from: (a) demographic/clinical data (age, sex, individual item/total MADRS scores at baseline, week 1, change scores); (b) scalp-level EEG power; (c) source-localized current density (via exact low-resolution electromagnetic tomography [eLORETA] software). Second, we applied kernel principal component analysis to reduce and map important features. Third, a set of ML models were constructed to classify response outcome based on mapped features. For each dataset, predictive features were extracted, followed by a model of all predictive features, and finally by a model of the  most  predictive features.   Results:  Fifty eLORETA features were predictive of response (across bands, both time-points); alpha 1 /theta eLORETA features showed the highest predictive value. Eighty-eight scalp EEG features were predictive of response (across bands, both time-points), with theta/alpha 2  being most predictive. Clinical/demographic data consisted of 31 features, with the most important being week 1 “concentration difficulty” scores. When all features were included into one model, its predictive utility was high (88% accuracy). When the  most  important features were extracted in the final model, 12 predictive features emerged (78% accuracy), including baseline scalp-EEG frontopolar theta, parietal alpha 2  and frontopolar alpha 1 .   Conclusions:  These findings suggest that ML models of pre- and early treatment-emergent EEG profiles and clinical features can serve as tools for predicting antidepressant response. While this must be replicated using large independent samples, it lays the groundwork for research on personalized, “biomarker”-based treatment approaches.

Leveraging Machine Learning Approaches for Predicting Antidepressant Treatment Response Using Electroencephalography (EEG) and Clinical Data