Subanesthetic Ketamine Infusions for Depressive Symptoms in Intensive Care Unit Patients
This Phase II randomised, double-blind, placebo-controlled multicentre trial (n=50) will evaluate subanesthetic intravenous ketamine for depressive symptoms in adult intensive care unit patients. Adults aged 18 to 99 years who have been in the ICU for at least 6 days and have moderate-to-severe depressive symptoms (PHQ-9 score of 10 or greater) will be assigned to ketamine or placebo, with the main aim of assessing change in depressive symptoms and safety. Participants will receive either ketamine 0.5 mg/kg, up to 60 mg per infusion, infused intravenously over 40 to 60 minutes once daily for 2 consecutive days, or matching 0.9% sodium chloride placebo given on the same schedule. The trial uses 1:1 allocation, parallel groups, and quadruple masking, with study drug prepared in identical infusion bags. Outcomes include PHQ-9 change from baseline to Day 30 after the last infusion, safety events during and after infusion, and follow-up assessments at Days 1, 7, 14, and 30 post-last infusion; secondary measures include HADS, Clinical Global Impression scales, intensive care unit and hospital length of stay, and mortality.
Detailed Description
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.
Study Arms & Interventions
Ketamine
experimentalParticipants receive intravenous subanesthetic ketamine at 0.5 mg/kg (maximum 60 mg/day regardless of body weight), administered over 40-60 minutes, once daily for 2 consecutive days. The drug is prepared by the research pharmacy in bags visually identical to placebo. Administration via peripheral or central venous access with continuous hemodynamic monitoring.
Interventions
- Ketamine0.5 - 60 mg/kgvia IV• once daily for 2 consecutive days• 2 doses total
Placebo
inactiveParticipants receive intravenous normal saline (0.9% NaCl) prepared by the research pharmacy in bags visually identical to the ketamine preparation (same volume, color, and infusion duration of 40-60 minutes), once daily for 2 consecutive days. Identical hemodynamic monitoring and psychiatric assessment schedule as the experimental arm.
Interventions
- Placebovia IV• once daily for 2 consecutive days• 2 doses total
Unmatched intervention treated as placebo placeholder: Normal Saline (0.9% NaCl)
Participants
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.
Study Details
- StatusRecruiting
- PhasePhase II
- Typeinterventional
- DesignRandomizedquadruple Blind
- Target Enrollment50 participants
- TimelineStart: 2026-05-14End: 2027-10-01
- Compounds
- Topic