BACKGROUND: A reliable physiological biomarker for major depressive disorder is essential for developing and optimizing neuromodulatory treatment paradigms. In this study, we investigated a passive electrophysiologic biomarker that tracks changes in depressive symptom severity on the order of minutes to hours. METHODS: We analyzed brief recordings from intracranial electrodes implanted deep in the brain during a clinical trial of deep brain stimulation for treatment-resistant depression in 5 human participants (n RESULTS: Our findings demonstrated that shifts in aperiodic slope correlated with depression severity, with flatter (less negative) slopes indicating reduced depression severity. This significant correlation was observed in all 5 participants, particularly in the ventromedial prefrontal cortex. CONCLUSIONS: This biomarker offers a new way to track patient responses to major depressive disorder treatment, thus paving the way for individualized therapies in both intracranial and noninvasive monitoring contexts.