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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).

• Atlanta, Georgia, United States