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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04173962

Enrollment

Registered

2019-11-22

Start date

2019-08-08

Completion date

2021-03-18

Last updated

2022-05-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers

Keywords

Ketamine, Resilience, Stress, Healthy Volunteers

Brief summary

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.

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.

Interventions

DRUGKetamine

administered 1 week prior to a laboratory-induced stress

DRUGMidazolam

administered 1 week prior to a laboratory-induced stress

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Midazolam has similar acute anesthetic effects compared to ketamine. This makes midazolam an appropriate substance to gauge whether ketamine can affect stress response thereby acting as an active control.

Intervention model description

Participants are assigned to one of two groups in parallel during the duration of the study: the ketamine arm or the midazolam arm.

Eligibility

Sex/Gender

ALL

Age

18 Years to 45 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in The Profile of Mood States - Bipolar Version (POMS - Bi) Composed-Anxious Subscale	baseline and 1 week after infusion	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.

Secondary

Measure	Time frame	Description
Change in Systolic Blood Pressure	baseline and 1 week after infusion	Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit
Change in Diastolic Blood Pressure	baseline and 1 week after infusion	Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit
Change in Heart Rate	baseline and 1 week after infusion	Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit
Change in Salivary Cortisol	baseline and 1 week after infusion	Change from pre- to post-TSST in salivary cortisol level. Salivary cortisol level to assess effect on the hypothalamic-pituitary-adrenal axis (HPA axis).
Change in Positive and Negative Affect Scale (PANAS)	baseline and 1 week after infusion	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.
Change in Visual Analog Scale: Stressed (VAS-Stressed)	baseline and 1 week after infusion	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.
Change in Beck Anxiety Inventory (BAI)	baseline and 1 week after infusion	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.
Change in Salivary Alpha-amylase Level	baseline and 1 week after infusion	Change from pre- to post-TSST in Salivary alpha-amylase level to assess effect on the adrenaline-noradrenaline axis (ANS axis).

Countries

United States

Participant flow

Recruitment details

Study conducted between August 2019 and March 2021 at the Icahn School of Medicine at Mount Sinai Depression and Anxiety Center for Discovery and Treatment.

Participants by arm

Arm	Count
Ketamine Group One 0.5mg/kg intravenous dose of ketamine Ketamine: administered 1 week prior to a laboratory-induced stress	12
Midazolam Group One 0.045mg/kg intravenous dose of midazolam Midazolam: administered 1 week prior to a laboratory-induced stress	12
Total	24

Baseline characteristics

Characteristic	Midazolam Group	Total	Ketamine Group
Age, Continuous	28.2 years STANDARD_DEVIATION 7.9	28.3 years STANDARD_DEVIATION 7.6	28.4 years STANDARD_DEVIATION 7.7
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	5 Participants	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants	19 Participants	9 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	4 Participants	2 Participants
Race (NIH/OMB) Black or African American	3 Participants	5 Participants	2 Participants
Race (NIH/OMB) More than one race	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) White	5 Participants	12 Participants	7 Participants
Sex: Female, Male Female	9 Participants	13 Participants	4 Participants
Sex: Female, Male Male	3 Participants	11 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 12
other Total, other adverse events	5 / 12	0 / 12
serious Total, serious adverse events	0 / 12	0 / 12

Outcome results

Primary

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.