Subanesthetic Ketamine Infusions for Depressive Symptoms in Intensive Care Unit Patients

Depressive symptoms are common among patients admitted to the intensive care unit (ICU) and may adversely affect recovery, participation in care, treatment adherence, quality of life, and outcomes after critical illness. Conventional antidepressants have limited utility for rapidly treating depressive symptoms during an ICU admission because of their delayed onset of action and potential drug interactions in medically complex patients. Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects when administered intravenously at subanesthetic doses. However, evidence regarding its efficacy and safety for depressive symptoms developing during critical illness remains limited. The KID-ICU trial is a Phase II randomized, double-blind, placebo-controlled, multicenter trial evaluating subanesthetic intravenous ketamine for moderate-to-severe depressive symptoms in adult ICU patients. Eligible participants are adults who have been admitted to an ICU for 6 or more days and have a Patient Health Questionnaire-9 (PHQ-9) score of 10 or greater. Participants will be randomized in a 1:1 ratio to receive either intravenous ketamine at 0.5 mg/kg, with a maximum dose of 60 mg per infusion, administered over 60 minutes once daily for 2 consecutive days, or normal saline placebo with an identical volume, appearance, and infusion duration. The primary efficacy outcome is the change in PHQ-9 total score from baseline to Day 14 after the second scheduled infusion. Secondary outcomes include the longitudinal trajectory of PHQ-9 scores through Day 30, clinically meaningful PHQ-9 response at Day 14, anxiety and depressive symptoms assessed with the Hospital Anxiety and Depression Scale, Clinical Global Impression scores, prespecified safety events, time to ICU and hospital discharge alive, and 30-day all-cause mortality. A total of 50 participants will be enrolled across participating ICUs in Argentina. Psychiatric and clinical follow-up will be provided to all participants regardless of treatment assignment.