Electrophysiologic Mechanisms of Ketamine Antidepressant Response

Depressive symptoms are common among individuals with epilepsy and are associated with reduced quality of life and poorer clinical outcomes. Although neuromodulation therapies have shown promise for treatment-resistant depression, the development of objective biomarkers to guide treatment remains a major challenge. Patients undergoing clinically indicated stereo-electroencephalography (sEEG) monitoring for epilepsy provide a unique opportunity to study human brain circuits with high spatial and temporal resolution.

This prospective, single-site, open-label, within-subject mechanistic clinical trial will enroll adults with epilepsy undergoing inpatient sEEG monitoring who have at least mild depressive symptoms at baseline. Participants will receive a single intravenous ketamine infusion (0.5 mg/kg over 40 minutes) while hospitalized in the Epilepsy Monitoring Unit. Research assessments will be completed before infusion and approximately 24 hours afterward.

The study examines candidate intracranial electrophysiologic measures of prefrontal-posterior midline connectivity and local cortical excitability, drawn from regions implicated in mood-relevant circuits. Behavioral and symptom measures include a task-based measure of thought content and a validated self-report measure of hedonic capacity. Investigators will test whether ketamine-induced neural changes correspond to changes in these behavioral and symptom measures. Additional exploratory analyses will examine whether acute effects during infusion predict delayed responses observed 24 hours later.

All research procedures occur during routine clinical epilepsy monitoring, and no research-driven intracranial stimulation, surgery, imaging, or biospecimen collection is performed.

Inclusion criteria

• Admitted to the Emory EMU for clinically indicated sEEG monitoring for epilepsy.
• At least mild depressive symptoms at baseline, defined as MADRS ≥7 or BDI-II ≥14.
• Electrode coverage that includes midline regions sufficient for enrollment and analyses.
• Ability to provide informed consent and to complete bedside tasks/questionnaires in English.
• Expected to remain under inpatient monitoring through the planned ~24-hour post-infusion follow-up unless clinical needs dictate otherwise.

Exclusion criteria

• Documented IQ <70, intellectual disability, severe cognitive impairment, delirium, severe aphasia, or other condition that prevents valid consent or task participation.
• Current or past schizophrenia-spectrum disorder or other psychotic disorder.
• Current manic/hypomanic episode or bipolar-spectrum illness judged by study psychiatrist/investigator to increase risk or confound interpretation.
• Active alcohol or substance abuse/dependence within the past 3 months.
• Imminent suicide risk or active suicidal intent requiring urgent intervention as determined by clinical assessment. Passive ideation without imminent intent may be considered on a case-by-case basis with psychiatric approval and enhanced monitoring.
• Contraindication to subanesthetic ketamine, including uncontrolled hypertension, unstable cardiovascular disease, aneurysm/vascular malformation or similar condition conferring unacceptable risk, pregnancy, breastfeeding, or other clinically significant medical instability.
• Clinical team determination that ketamine administration or study timing would interfere with epilepsy care or perioperative management.
• Sedative or other medication exposure at a level that, in the judgment of the clinical team, precludes safe ketamine administration or reliable behavioral assessment (participant may be deferred rather than permanently excluded if the issue resolves).