**Brief Summary**

Depressive symptoms are frequent among patients admitted to the intensive care unit (ICU) and may be associated with worse clinical outcomes, reduced participation in care, lower treatment adherence, and increased mortality. Conventional antidepressants, including selective serotonin reuptake inhibitors (SSRIs), have limited utility in this setting because of their delayed onset of action, incomplete efficacy, and potential drug interactions in medically complex patients.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a rapid-acting antidepressant when administered at subanesthetic doses. Preliminary evidence suggests that intravenous ketamine may improve mood-related symptoms within a short time frame and may have an acceptable safety profile in selected critically ill patients.

The KID-ICU trial (Ketamine In Depression - Intensive Care Unit) is a Phase II randomized, double-blind, placebo-controlled multicenter trial designed to evaluate the efficacy and safety of subanesthetic intravenous ketamine infusions for moderate-to-severe depressive symptoms in adult ICU patients. Eligible participants are adults who have been admitted to the ICU for 6 or more days and have moderate-to-severe depressive symptoms, defined as 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 day, administered over 40 to 60 minutes on 2 consecutive days, or placebo with normal saline in an identical presentation. The primary efficacy outcome is the change in PHQ-9 score from baseline to Day 30 after the last infusion. Safety outcomes include prespecified hemodynamic, neuropsychiatric, and treatment-discontinuation events during and after infusion. Secondary outcomes include anxiety and depression symptoms assessed with the Hospital Anxiety and Depression Scale (HADS), clinical severity and improvement assessed with Clinical Global Impression scales, intensive care unit and hospital length of stay, and mortality.

A total of 50 participants will be enrolled across intensive care unit sites at Hospital Italiano de Buenos Aires. Psychiatric and clinical follow-up will be provided to all participants regardless of treatment assignment.

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.

The research pharmacy prepares and dispenses identical-appearing bags for both ketamine and normal saline. Ketamine is diluted so that both preparations are visually indistinguishable. The clinical team administering the infusion and assessing outcomes is fully blinded. Emergency unblinding is available to the treating physician in case of a life-threatening adverse event via a sealed envelope system.