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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketamine group | Experimental | One 0.5mg/kg intravenous dose of ketamine |
|
| Midazolam group | Active Comparator | One 0.045mg/kg intravenous dose of midazolam |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine | Drug | administered 1 week prior to a laboratory-induced stress |
| |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| James Murrough, MD, PhD | Icahn School of Medicine at Mount Sinai | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Icahn School of Medicine at Mount Sinai | New York | New York | 10029 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15587208 | Background | 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. | |
| 3204199 | Background | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Ketamine Group | One 0.5mg/kg intravenous dose of ketamine Ketamine: administered 1 week prior to a laboratory-induced stress |
| FG001 | Midazolam Group | One 0.045mg/kg intravenous dose of midazolam Midazolam: administered 1 week prior to a laboratory-induced stress |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Ketamine Group | One 0.5mg/kg intravenous dose of ketamine Ketamine: administered 1 week prior to a laboratory-induced stress |
| BG001 | Midazolam Group | One 0.045mg/kg intravenous dose of midazolam Midazolam: administered 1 week prior to a laboratory-induced stress |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 1 week after infusion |
|
1 week
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketamine Group | One 0.5mg/kg intravenous dose of ketamine Ketamine: administered 1 week prior to a laboratory-induced stress |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. James Murrough | Icahn School of Medicine at Mount Sinai | 212-585-4640 | james.murrough@mssm.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 9, 2021 | Mar 15, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 26, 2021 | Mar 15, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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Participants are assigned to one of two groups in parallel during the duration of the study: the ketamine arm or the midazolam arm.
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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.
| Midazolam |
| Drug |
administered 1 week prior to a laboratory-induced stress |
|
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 |
| 15333231 | Background | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
One 0.5mg/kg intravenous dose of ketamine Ketamine: administered 1 week prior to a laboratory-induced stress |
| OG001 | Midazolam Group | One 0.045mg/kg intravenous dose of midazolam Midazolam: administered 1 week prior to a laboratory-induced stress |
|
|
| Secondary | 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). | Posted | Mean | Standard Deviation | ug/dL | baseline and 1 week after infusion |
|
|
|
| Secondary | Change in Systolic Blood Pressure | Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit | Posted | Mean | Standard Deviation | mmHg | baseline and 1 week after infusion |
|
|
|
| Secondary | Change in Diastolic Blood Pressure | Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit | Posted | Mean | Standard Deviation | mmHg | baseline and 1 week after infusion |
|
|
|
| Secondary | Change in Heart Rate | Change from pre- to post-TSST in Cardiovascular response to stressor during assessment visit | Posted | Mean | Standard Deviation | beats per minute (bpm) | baseline and 1 week after infusion |
|
|
|
| Secondary | 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). | Posted | Mean | Standard Deviation | U/mL | baseline and 1 week after infusion |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 1 week after infusion |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 1 week after infusion |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | score on a scale | baseline and 1 week after infusion |
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| 5 |
| 12 |
| EG001 | Midazolam Group | One 0.045mg/kg intravenous dose of midazolam Midazolam: administered 1 week prior to a laboratory-induced stress | 0 | 12 | 0 | 12 | 0 | 12 |
| Headache | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Muscle Weakness | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
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| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |