Subanesthetic Ketamine Infusions for Depressive Symptoms in Intensive Care Unit Patients

Major depressive disorder and depressive symptoms are clinically relevant mental health conditions in critically ill patients. In the intensive care unit (ICU), depressive symptoms may be exacerbated by acute illness, pain, delirium, immobility, sleep disruption, loss of autonomy, and prolonged hospitalization. These symptoms may negatively affect recovery, participation in care, treatment adherence, quality of life, and survival after critical illness.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects when administered at subanesthetic doses. In non-ICU populations, intravenous ketamine has been associated with early improvement in depressive symptoms after infusion. However, evidence regarding its efficacy and safety for depressive symptoms in critically ill patients remains limited. The KID-ICU trial (Ketamine In Depression - Intensive Care Unit) is designed to evaluate whether subanesthetic intravenous ketamine can safely reduce depressive symptoms in adult ICU patients.

This is a Phase II randomized, double-blind, placebo-controlled multicenter clinical trial with two parallel groups and 1:1 allocation. Eligible participants will be adult ICU patients with moderate-to-severe depressive symptoms, defined as a Patient Health Questionnaire-9 (PHQ-9) score of 10 or greater after 6 or more days of ICU admission. Participants will be randomized to receive either intravenous ketamine or placebo.

Participants assigned to the ketamine group will receive intravenous ketamine at 0.5 mg/kg, with a maximum dose of 60 mg per day, administered over 40 to 60 minutes once daily for 2 consecutive days. Participants assigned to the placebo group will receive intravenous normal saline in an identical volume, appearance, and infusion duration. Study medication will be prepared by the research pharmacy in indistinguishable infusion bags. Patients, care providers, investigators, and outcome assessors will remain blinded to treatment assignment. Emergency unblinding will be available if required for participant safety.

Participants will undergo continuous clinical monitoring during and after each infusion. Monitoring will include heart rate, electrocardiogram, blood pressure, and peripheral oxygen saturation. Mental status and adverse events will be assessed before infusion and at prespecified time points after infusion using the Ketamine Side Effect Tool (KSET). Infusion may be suspended in the presence of clinically significant hypertension, tachycardia, arrhythmia, deterioration in consciousness, severe agitation, psychotic symptoms, or any serious adverse event according to investigator judgment. Emergency psychiatric consultation will be available throughout hospitalization.

Randomization will be stratified by participating ICU site and performed using the Research Electronic Data Capture (REDCap) randomization module. Only the research pharmacist and the trial statistician will have access to the allocation list. Clinical teams administering the intervention and investigators assessing outcomes will remain blinded.

Study visits will include baseline assessment before the first infusion, Infusion Day 1, Infusion Day 2, 24 hours after the last infusion, Day 7, Day 14, and Day 30 after the last infusion. Telephone follow-up will be permitted for participants discharged before completion of follow-up. Depressive symptoms will be assessed using the Patient Health Questionnaire-9 (PHQ-9). Anxiety and depression symptoms will be assessed using the Hospital Anxiety and Depression Scale (HADS). Global clinical severity and improvement will be assessed using the Clinical Global Impression - Severity (CGI-S) and Clinical Global Impression - Improvement (CGI-I) scales. Ketamine-related adverse effects will be assessed using the Ketamine Side Effect Tool (KSET).

The primary efficacy outcome is the change in PHQ-9 score from baseline to Day 30 after the last infusion. Safety outcomes include the incidence of prespecified hemodynamic events, acute neuropsychiatric events, and treatment discontinuation due to adverse events. Secondary outcomes include change in HADS score, HADS response rate, CGI-S score, CGI-I score, ICU length of stay, hospital length of stay, in-hospital mortality, and 30-day mortality.

All data will be collected prospectively using the Research Electronic Data Capture (REDCap) platform. Bedside assessments may initially be recorded on paper source documents and subsequently transcribed into REDCap. The PHQ-9 will be used as a symptom severity measurement tool and not as a standalone diagnostic instrument. Psychiatric consultation will be requested for participants with elevated depressive symptom scores according to the study protocol.

The primary efficacy analysis will compare the change in PHQ-9 score from baseline to Day 30 between treatment groups. Longitudinal changes in depressive symptom scores will be evaluated using repeated-measures models. Safety outcomes and categorical secondary outcomes will be compared between groups using appropriate statistical tests. Time-to-event outcomes, including ICU discharge and hospital discharge, will account for death as a competing event when applicable. The planned sample size is 50 participants, with 25 participants per group.

**Inclusion Criteria:**

• Age 18 to 99 years.
• Male or female.
• Admission to an intensive care unit for 6 or more days at the time of screening.
• Moderate to severe depressive symptoms, defined as a Patient Health Questionnaire-9 score of 10 or greater at screening.
• Ability to provide informed consent.

**Exclusion Criteria:**

• History of psychosis or hallucinations, as assessed by review of the electronic medical record and patient interview during screening.
• History of prolonged QT interval.
• History of dementia.
• History of major depressive disorder before the current intensive care unit admission.
• History of psychiatric diagnosis, including dissociative disorder, primary psychotic disorder, mania with psychosis, pervasive developmental disorder, cognitive disorder, or anorexia nervosa.
• Known allergy to ketamine or diphenhydramine.
• History of increased intracranial pressure, hypertensive hydrocephalus, or increased intraocular pressure.
• Hemodynamic instability at the time of screening, defined as peripheral oxygen saturation <95%, systolic blood pressure <90 mmHg or >180 mmHg, heart rate <50 or >120 beats/min, or respiratory rate <10 or >30 breaths/min.
• Patient refusal to participate or to provide informed consent.
• Pregnancy, postpartum period within 2 months, or breastfeeding.
• Presence of intracranial mass or vascular lesion.
• Altered mental status precluding informed consent.
• Body weight >115 kg or <45 kg.
• Active psychosis.
• Current treatment with medications that may interfere with the N-methyl-D-aspartate receptor system, including lamotrigine, acamprosate, memantine, riluzole, or lithium.
• Current treatment with aminophylline or theophylline.
• Active substance withdrawal or use of hallucinogens, including cannabis, in the past month, as determined by clinical interview and urine drug screening.