Effect of Ketamine on Laboratory-induced Stress in Healthy Subjects

Effect of Ketamine on Laboratory-induced Stress in Healthy Subjects: A Proof-of-Concept Translational Study

The objective of this study is to examine the effect of a single IV dose of ketamine (0.5 mg/kg) on laboratory-induced stress in healthy participants.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Ketamine; Drug: Midazolam

Detailed Description

Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Stress resilience is the ability to experience stress without developing psychopathology. Enhancing stress resilience in at-risk populations could potentially protect against the development of stress-induced psychiatric disorders. Despite this, no resilience-enhancing pharmaceuticals have been identified yet. Pre-clinical studies showed that the administration of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine one week before an acute stress prevents the developing of depressive-like behavior in animals. In this project the study team proposes a pilot study to test if this stress prophylactic effect of ketamine applies also to humans. Ketamine will be compared to an active placebo control condition, the anesthetic midazolam, in a sample of healthy volunteers. The specific aims of this project are to test the effect of ketamine administered 1-week prior a laboratory-induced stress (1) on the positive and negative affect as measured with the Profile of Mood States (POMS) - Bipolar and (2) on the hypothalamic-pituitary-adrenal axis (HPA axis), adrenaline-noradrenaline axis (ANS axis), and self-reports of anxiety. The study team expects that subjects treated with ketamine, compared to midazolam, will experience reduced symptoms of negative affect and anxiety and a blunted hormonal response to an acute stress.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females aged 18-45 years;
• Does not meet for any current or past psychiatric diagnoses as defined by DSM-V criteria;
• Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process.

Exclusion Criteria:

• Any current or lifetime psychiatric disorder as determined by the Structured Clinical Interview for DSM-V Axis Disorders (SCID-5);
• Concomitant use of any medication with central nervous system activity, including treatment with antidepressants (classified as SSRIs, SNRIs, Atypical Antidepressants, TCAs);
• Any unstable medical illnesses including hepatic, renal impairment, gastroenterologic (including gastro-esophageal reflux disease), respiratory (including obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics), cardiovascular (including ischemic heart disease and uncontrolled hypertension), endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
• Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg) at screening or immediately prior to treatment with ketamine/midazolam;
• Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG; clinically significant is defined by an abnormality that suggests a disease and/or organ toxicity that is new or has worsened from screening, or if the abnormality is of a degree that requires additional active management (e.g., further diagnostic investigation).
• Patients who have a positive urine toxicology test for illicit substances at screening and on the treatment day.
• Previous recreational use of PCP or ketamine.
• Subjects who have received ketamine in the past.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ketamine group; One 0.5mg/kg intravenous dose of ketamine	Drug: Ketamine; administered 1 week prior to a laboratory-induced stress
ACTIVE_COMPARATOR: Midazolam group; One 0.045mg/kg intravenous dose of midazolam	Drug: Midazolam; administered 1 week prior to a laboratory-induced stress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in The Profile of Mood States - Bipolar Version (POMS - Bi) Composed-Anxious Subscale	Change from pre- to post-TSST in The Profile of Mood States - Bipolar Version (POMS - Bi) scale measures moods and feelings primarily in clinical rather than nonclinical settings. The POMS-Bi consists of 72 adjectives that form six bipolar sub-scale scores (Composed - Anxious, Clear - Confused, Confident - Unsure, Agreeable - Hostile, Energetic - Tired, Elated - Depressed). Each of the 12 adjectives within each subscale is rated on a 4-point Likert scale with anchors of 0 = "much unlike this," 1 = "slightly unlike this," 2 = "slightly like this," and 3 = "much like this." The Composed-Anxious Subscale score is the sum of positive minus the sum of negative responses plus a constant of 18. The subscale score range is from 0 to 36. Higher score indicates higher functioning. Each subscale is separate and there is no overall score.	baseline and 1 week after infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Salivary Cortisol	Change from pre- to post-TSST in salivary cortisol level. Salivary cortisol level to assess effect on the hypothalamic-pituitary-adrenal axis (HPA axis).	baseline and 1 week after infusion
Change in Systolic Blood Pressure	Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit	baseline and 1 week after infusion
Change in Diastolic Blood Pressure	Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit	baseline and 1 week after infusion
Change in Heart Rate	Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit	baseline and 1 week after infusion
Change in Salivary Alpha-amylase Level	Change from pre- to post-TSST in Salivary alpha-amylase level to assess effect on the adrenaline-noradrenaline axis (ANS axis).	baseline and 1 week after infusion
Change in Positive and Negative Affect Scale (PANAS)	Change from pre- to post-TSST in The Positive and Negative Affect Scale (PANAS) measures both positive and negative affect and is utilized within clinical and non-clinical populations. The PANAS is a 20-item instrument, each item is scored on a 5-likert scale from 1 (very slightly or not at all) to 5 (extremely). Positive Affect Score - total score from 10-50, with higher score indicating higher levels of positive affect. Negative Affect Score - total score from 10-50, with lower scores representing lower levels of negative affect.	baseline and 1 week after infusion
Change in Visual Analog Scale: Stressed (VAS-Stressed)	Change from pre- to post-TSST in The Visual Analog Scales are scored in millimeters from the left-hand side of a 100-mm line to a perpendicular mark made by the patient at a point corresponding to the apparent magnitude of the feeling state. Full range: 0 ("not at all") to 100 ("most ever"), with higher score indicating poorer health status. The VAS-Stressed prompts participants to rate their level of stress in that exact moment on the visual analog scale.	baseline and 1 week after infusion
Change in Beck Anxiety Inventory (BAI)	Change from pre- to post-TSST in Beck Anxiety Inventory (BAI). This is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety in adults. The questions used in this measure ask about common symptoms of anxiety (such as numbness and tingling, sweating not due to heat, and fear of the worst happening). It is designed for individuals who are of 17 years of age or older and takes 5 to 10 minutes to complete. Total score range of 0-63, with higher score indicating more severe anxiety symptoms.	baseline and 1 week after infusion

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988 Dec;56(6):893-7. doi: 10.1037//0022-006x.56.6.893. No abstract available.
• O'Halloran PD, Murphy GC, Webster KE. Reliability of the bipolar form of the profile of mood states using an alternative test protocol. Psychol Rep. 2004 Oct;95(2):459-63. doi: 10.2466/pr0.95.2.459-463.
• Crawford JR, Henry JD. The positive and negative affect schedule (PANAS): construct validity, measurement properties and normative data in a large non-clinical sample. Br J Clin Psychol. 2004 Sep;43(Pt 3):245-65. doi: 10.1348/0144665031752934.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 8, 2019
• Primary Completion (ACTUAL): March 18, 2021
• Study Completion (ACTUAL): March 18, 2021

Study Registration Dates

• First Submitted: November 21, 2019
• First Submitted That Met QC Criteria: November 21, 2019
• First Posted (ACTUAL): November 22, 2019

Study Record Updates

• Last Update Posted (ACTUAL): May 10, 2022
• Last Update Submitted That Met QC Criteria: April 18, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Stress; Ketamine; Healthy Volunteers; Resilience
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: GCO 17-2440

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No