A Double-Blinded, Randomized, Placebo-Controlled Sub-Dissociative Dose Ketamine Pilot Study in the Treatment of Acute Depression and Suicidality in a Military Emergency Department Setting

This placebo-controlled proof-of-concept study (n=10, 7 placebo) administered sub-dissociative doses of ketamine to military personnel experiencing depression and suicidal ideation (SI), and found that the ketamine infusion resulted in significant short-term improvement in two out of the three patients who received the drug.

Abstract

“Background: Rates of completed suicide in the military have increased. Options are limited for acute relief of depression and suicidal ideation. Traditional treatments’ effects take weeks to months. A novel, rapid, therapeutic target has emerged with the N-methyl-D-aspartate antagonist ketamine. Previous studies suggest that a single dose of intravenous (IV) ketamine rapidly alleviates depression and suicidality.

Methods: In this proof of concept study, an active duty convenience sample population presenting to the emergency department (ED) meeting criteria for inpatient psychiatric admission as a result of depression and suicidal thinking were randomized to receive either a subdissociative dose (0.2 mg/kg) of IV ketamine or equivalent volume of normal saline (placebo). Subjects were evaluated for symptoms throughout a 4-hour ED course, at hospital discharge, and 2 weeks postdischarge.

Results: Methodological problems limited analyzable data to 10 subjects. Two of three who received ketamine experienced dramatic decreases in suicidality and hopelessness within 40 minutes. No such improvements were seen in any of seven controls over the 4-hour observation in the ED. At discharge from the hospital, there was no clinically significant difference. No subjects described adverse symptoms.

Conclusion: Despite methodology difficulties noted in this pilot study, there was statistical improvement in intervention group versus controls.”

Authors: John Burger, Marc Capobianco, Robert Lovern, Ben Boche, Elliot Ross, Michael A. Darracq & Robert McLay

Summary

INTRODUCTION

Service members with suicidal thinking are caught in a difficult position, as treatment typically takes weeks to months to be effective. Psychiatric hospitalization may create long-term problems by separating the individual from his or her support network, instigating stigma, and creating administrative military obstacles to returning to duty.

For over 50 years, monamines have been the focus of depression treatment. A new target has emerged with modulators of the glutamatergic system.

Ketamine has been administered for a variety of indications, and its clinical effects are often dose dependent. At lower dosages, ketamine demonstrates potent and rapidly acting antidepressant properties.

Ketamine has not become widespread as an antidepressant, because of the potential side effects of dissociative symptoms, euphoria, confusion, hallucinations, sedation, nausea, cardiovascular side effects of hypertension and tachycardia, and respiratory suppression, and the potential for addiction with chronic use.

In the emergency setting, short-term treatment of depression with ketamine might be useful to alleviate suffering and allow patients to survive long enough for slower-acting treatments of depression to become effective.

Previous studies suggest that ketamine might be an optimal therapy for the acute reversal of depression and suicidality in the emergency department setting.

The current study sought to demonstrate the potential benefits of ketamine administration to individuals presenting with suicidal thinking in a military setting. However, because of problems with administrative record-keeping, the study was ended prematurely.

Overview

All procedures were approved by the local institutional review board and the Food and Drug Administration, and participants were consented by psychiatry and ED physicians.

Participants

Participants were recruited from the Naval Medical Center, San Diego, ED between February 2012 and March 2013, and gave written, informed consent before receiving ketamine.

Assessment

Participants were assessed before and after drug administration, and were monitored clinically in the ED for 4 hours. They were then transferred to the psychiatric ward, and assessed again 2 weeks later. The BSS is a 21-item self-report instrument for detecting and measuring the current intensity of the patients’ specific attitudes, behaviors, and plans to commit suicide. The BHS is a 20-item scale for measuring negative attitudes about the future.

Study Drug Administration

Participants were randomized to receive either ketamine or placebo in the ED. Ketamine was administered over 2 minutes and regular clinical monitoring occurred during the following 240-minute stay.

Early Termination of the Trial and Data Exclusion

The trial was initially supposed to have 20 active and 20 control participants, but 8 subjects were given the wrong drug or dose. The study was suspended, and the data from these 8 subjects was excluded from future analysis.

RESULTS

On the BSS, there was a significant linear effect of time, but not group, and a significant linear time – group interaction. On the BHS, there was a significant time – group interaction.

DISCUSSION

This study was terminated early because of difficulties in record-keeping. A funded centralized research nurse will administer study drug and track outcomes.

Although this was a failed trial, the data analysis for the remaining subjects still suggests the potential of ketamine as a novel, acute intervention for service members with safety concerns from depression. Ketamine may be used in emergency settings to prevent the need for hospitalization and/or medical evacuation. It appears to be an effective means of acutely improving suicidal ideation and depression in the active duty military population. Although ketamine itself is not an ideal treatment option given its abuse potential, research is already underway looking into other NMDA receptor antagonists that may prove to be more effective than ketamine.