Antidepressants are widely prescribed, but their efficacy relative to placebo is modest, in part because the clinical diagnosis of major depression encompasses biologically heterogeneous conditions. Here, we sought to identify a neurobiological signature of response to antidepressant treatment as compared to placebo. We designed a latent-space machine learning algorithm tailored for resting-state electroencephalography (rsEEG) and applied it to data from the largest imaging-coupled, placebo-controlled antidepressant study (n=309). Symptom improvement was robustly predicted in a manner both specific for the antidepressant sertraline (versus placebo) and generalizable across different study sites and EEG equipment. This sertraline-predictive EEG signature generalized to two depression samples, wherein it reflected general antidepressant medication responsivity, and related differentially to repetitive transcranial magnetic stimulation (rTMS) treatment outcome. Furthermore, we found that the sertraline rsEEG signature indexed prefrontal neural responsivity, as measured by concurrent TMS/EEG. Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression.

Highlights QEEG-informed neurofeedback resulted in remission rates of 55%. In the total sample, non-remitters had higher hyperactivity scores at baseline. In women, non-remitters had longer P300 latencies. In boys, a low individual alpha peak frequency (iAPF) was associated with remission.

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