Subanesthetic Ketamine Improves Depressive Symptoms in Critically Ill Adults

Managing Depressive Symptoms in the High-Acuity Setting

Depressive symptoms in the intensive care unit often complicate the clinical course of critically ill patients, yet traditional antidepressants typically require weeks to achieve therapeutic efficacy [1]. While subanesthetic doses of ketamine, an N-methyl-D-aspartate receptor antagonist (a drug that blocks a specific glutamate receptor involved in neural signaling), have demonstrated rapid antidepressant effects in outpatient psychiatric populations, its utility in the acute critical care setting remains less defined [2, 3]. Meta-analytic data from 20 randomized controlled trials indicate that ketamine achieves its maximal effect at 24 hours (standardized mean difference -0.89; 95% confidence interval -1.24 to -0.53; p < 0.00001), with clinical benefits persisting for up to seven days [4]. Clinicians face significant challenges in managing psychological distress in the intensive care unit, where hemodynamic stability is paramount and the risk of delirium or adverse drug interactions is high [5]. Current guidelines for the intensive care unit emphasize multimodal strategies for pain and agitation, but specific interventions for acute depressive symptoms are often limited to supportive care [6, 5]. A new retrospective analysis now examines the clinical impact of intravenous ketamine on mood and hemodynamic parameters within this vulnerable patient population.

Retrospective Analysis of ICU Ketamine Use

The researchers conducted a retrospective analysis of 34 adults admitted to the intensive care unit who received intravenous ketamine specifically for the management of depressive symptoms. This study cohort was characterized by a median age of 59 years, and 61.8% of the participants were male. A notable subset of this population included 18 solid organ transplant recipients, representing a complex clinical group often managed in high-acuity settings where traditional psychiatric interventions may be limited by physiological instability or potential drug interactions. The inclusion of transplant recipients is particularly relevant for the practicing intensivist, as these patients often require delicate immunosuppressive regimens and are at high risk for neuropsychiatric complications following major surgery.

Dosing Protocol and Symptom Assessment

The therapeutic intervention followed a standardized subanesthetic protocol designed to minimize psychotropic side effects while maximizing antidepressant activity. Patients received intravenous ketamine at a dosage of 0.3 to 0.75 mg/kg, which was administered over a 40 minute infusion period on three consecutive days. This multi day approach allowed for the observation of cumulative symptomatic changes in a population where rapid stabilization is often a clinical priority. To ensure patient safety during the administration of a known sympathomimetic agent (a substance that mimics the effects of the sympathetic nervous system, potentially increasing heart rate and blood pressure), the researchers implemented a rigorous monitoring schedule for hemodynamic parameters. These measurements, which included blood pressure and heart rate, were recorded immediately before the infusion and at regular intervals up to 120 minutes post infusion. Because the intensive care unit environment often precludes the use of lengthy, standardized psychiatric rating scales, the researchers utilized a multidisciplinary assessment strategy to track clinical progress. Changes in depressive symptoms were assessed using routine clinical documentation generated by the entire care team, including physicians, nurses, and occupational and physical therapists. This method of data collection captures a broad spectrum of patient behavior and functional status, reflecting the real world observations of clinicians who interact with the patient throughout the day. By integrating notes from multiple specialties, the study aimed to provide a comprehensive view of the patient's affective state, focusing on observable indicators of mood and engagement that are critical for recovery in a high acuity setting.

Reductions in Apparent and Reported Sadness

The researchers observed substantial improvements in the primary indicators of mood following the three day ketamine protocol, noting changes in both objective and subjective measures of distress. Specifically, ketamine was associated with a significant improvement in apparent sadness, which refers to the objective observation of a patient's melancholy or flat affect by clinical staff. This metric improved from a baseline of 52.2% to 90.0% (P < .05). Similarly, the study found that ketamine was associated with a significant improvement in reported sadness, representing the patient's own subjective description of their emotional state during clinical interviews. This subjective measure increased from 59.1% at baseline to 95.0% following the intervention (P < .05). These findings suggest that subanesthetic infusions may address both the external manifestations and the internal experience of depression in the intensive care unit. The clinical impact of the treatment was also evident within the high risk subgroup of solid organ transplant recipients, who often face unique psychological stressors and complex pharmacological profiles. Among these 18 transplant recipients, the improvement in apparent sadness remained significant, rising from 41.7% at baseline to 80.0% post intervention (P < .05). For the practicing intensivist, these data points are particularly relevant as they indicate that the antidepressant effects of low dose ketamine are robust even in patients with significant surgical and medical comorbidities. The ability to achieve such high rates of symptomatic improvement within a 72 hour window provides a potential strategy for managing acute depressive episodes that might otherwise hinder a patient's participation in physical therapy or weaning from mechanical ventilation.

Hemodynamic Stability and Neuropsychiatric Tolerability

Safety concerns regarding the sympathomimetic effects of ketamine, such as hypertension and tachycardia, often serve as a barrier to its use in the intensive care unit. However, the researchers found that hemodynamic parameters remained stable throughout the study period for the 34 patients involved. While the medication did influence cardiac rhythm, the effect was short-lived; heart rate increased transiently at 15 to 30 minutes post-infusion before stabilizing. These elevations were not sustained, as the heart rate returned to baseline by 60 to 90 minutes post-infusion. This suggests that the subanesthetic dose of 0.3 to 0.75 mg/kg administered over 40 minutes does not induce prolonged cardiovascular stress in critically ill adults, including those who have undergone solid organ transplantation. The neuropsychiatric tolerability of the three day infusion protocol was also monitored, as ketamine is known for its potential to induce emergence delirium or dissociative states. In this cohort, anxiety was observed as an adverse effect in 12.5% of patients, while restlessness and/or agitation occurred in 10.4% of patients. Furthermore, dissociation (a feeling of detachment from one's body or surroundings) was observed in 8.16% of patients. These percentages indicate that while side effects do occur, they affect a relatively small portion of the intensive care population receiving subanesthetic doses. For clinicians, these data provide a framework for risk-benefit discussions, suggesting that the rapid improvement in depressive symptoms may be achieved with a manageable side effect profile in the high-acuity setting.

References

1. Peiris TE, Pokhrel A, Paudel Y. Ketamine for unipolar depression: A systematic review of efficacy and safety.. Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists. 2025. doi:10.1177/10398562251328805

2. Zarate CA, Singh J, Carlson PJ, et al. A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Archives of General Psychiatry. 2006. doi:10.1001/archpsyc.63.8.856

3. Lang UE, Borgwardt S. Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies. Cellular Physiology and Biochemistry. 2013. doi:10.1159/000350094

4. Kryst J, Kawalec P, Mitoraj AM, Pilc A, Lasoń W, Brzostek T. Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials.. Pharmacological reports : PR. 2020. doi:10.1007/s43440-020-00097-z

5. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical Care Medicine. 2018. doi:10.1097/ccm.0000000000003299

6. Zaman H, Khan M, Khan MA, Hassan M. A SYSTEMATIC REVIEW ON THE EFFECTIVENESS OF OPIOID-SPARING STRATEGIES IN ICU PATIENTS. 2025. doi:10.62019/p3n7c964