Major Depressive Disorder, Suicidal Ideation
Conditions
Keywords
Ketamine, Midazolam, Major Depressive Disorder, Suicidal ideation, Suicide, Depression, Treatment, Ketamine Treatment
Brief summary
This study is designed to compare the effectiveness of two medications, Ketamine and Midazolam, for rapidly relieving suicidal thoughts in people suffering from depression. The first drug, Ketamine, is an experimental antidepressant that early studies have shown may quickly reduce suicidal thoughts, but we are not sure how well it may work. Midazolam, the comparison drug, is not thought to reduce depression or suicidal thoughts.
Detailed description
Patients currently taking psychiatric medications may continue them during the study. However, if a patient is taking a benzodiazepine (such as Ativan, Klonopin, or Xanax), they will be able to take up to 2mg per day of Lorazepam during the week before the infusion, but none will be permitted in the 24 hours pre-infusion. Also, Zolpidem (Ambien) will not be permitted in the 24 hours pre-infusion. If a person chooses to participate, their dose of benzodiazepine may need to be reduced so that they can do without it during the 24 hours pre-infusion. Depressed participants are randomly assigned to receive a single dose of Ketamine(0.5 mg/kg) or Midazolam (0.02 mg/kg), which is given slowly, in a vein, over about 40 minutes. The study is double-blind, meaning patients and study staff will not know which medication is in the infusion. If a patient does not respond to the first infusion, and s/he received Midazolam, then s/he will be offered the option of a second infusion, this time with Ketamine (0.5 mg/kg). S/he will then start treatment with a standard antidepressant, unless s/he is not already taking one. After the infusion(s), participants will have weekly research interviews for 6 weeks to monitor response. If a patient does have a sufficient infusion response, and s/he is not already taking an antidepressant, then s/he will receive 6-weeks antidepressant research treatment with Sertraline, Fluoxetine, Paroxetine, or Escitalopram, followed by open clinical treatment. However, if s/he is already taking an antidepressant, then s/he will receive open treatment. If s/he does not have a sufficient infusion response, then s/he will receive open treatment. Participation in this study requires a brief inpatient stay, at no cost, at the New York State Psychiatric Institute (NYSPI). Eligible participants enrolled in this study will be offered medication management visits at no cost for a total of up to 6 months from the date of enrollment combining inpatient and outpatient treatment. Study medications (Sertraline, Fluoxetine, Paroxetine, Escitalopram, Lorazepam, Zolpidem) will be at no cost during the 6 months. The study will not provide other medications at no cost.
Interventions
DRUGKetamine
Single dose of 0.5 mg/kg of ketamine given intravenously (in the vein) over 40 minutes
DRUGMidazolam
Single dose of 0.02 mg/kg of Midazolam given intravenously (in the vein) over 40 minutes
Sponsors
National Institute of Mental Health (NIMH)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Unipolar depression with current major depressive episode (MDE). Participants may be psychiatric medication-free, or if on psychiatric medication, not responding adequately given current MDE with suicidal ideation (See 2). * Moderate to severe suicidal ideation * 18-65 years old * Participants must agree to a voluntary admission to an inpatient research unit at the New York State Psychiatric Institute (NYSPI)for the infusion(s), for a brief stay, or longer if clinically necessary. * Pre-menopausal female participants of child-bearing potential must be willing to use an acceptable form of birth control during study participation such as condoms, diaphragm, or oral contraceptive pills. * Able to provide informed consent * Participants 61-65 years old must score a 25 or higher on the Mini-Mental State Examination (MMSE) at screening.
Exclusion criteria
* Unstable medical condition or neurological illness, including baseline hypertension (BP\>140/90) or significant history of cardiovascular illness. * Significant ECG abnormality * Pregnant or lactating * Diagnosis of bipolar disorder or psychotic disorder * Contraindication to any study treatment. * Inadequate understanding of English. * Prior ineffective trial of or adverse reaction to Ketamine or Midazolam. * Opiate use greater than total daily dose of 20mg Oxycodone or equivalent during the 3 days pre-infusion. * A diagnosis of sleep apnea.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Scale for Suicidal Ideation | Day 1 (24 hours) post-treatment | Change in suicidal ideation in depressed patients with moderate to severe suicidal thoughts from the pre-infusion baseline to 24 hours after the infusion with ketamine or midazolam, a sedative not known to reduce suicidal ideation, measured with Beck Scale for Suicidal Ideation - clinician rated version. This scale has 19 items scaled 0 (least severe) to 2 (most severe) and a potential score ranging from 0 to 38, with higher score indicating greater severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Saliva Cortisol Awakening Response (CAR). | Cort2 - Cort1 = (Day 1 30-mins post-awakening cortisol) - (Day 1 awakening cortisol) | On the mornings of an infusion day and on post-treatment day1, participants used salivettes (Sarstedt AG & Co.) to provide saliva samples upon awakening (Cort1) and 30 minutes later (Cort2) to measure cortisol awakening response (CAR) = (Cort2 - Cort1). Differences between the midazolam and ketamine groups were tested using an analysis of covariance (ANCOVA) model of the change in CAR from baseline to day1, with treatment group and baseline measurement of the outcome variable as predictors. Range from 0.1 to 12.5 ng/ml and lower means less stress response, higher means greater stress response. |
| Neuropsychological Effects | Baseline and Day 1 | The average Z-scores reported below are the average of the Z-scores for all tests administered. The Z-scores for each test were based on published normative data and normative data available in our laboratory. The population mean for a Z-score is zero, with a SD of 1, thus scores below zero would indicate performance below the population norm; a score close to zero indicates performance close to the population norm (or a normalizing of performance). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Midazolam 0.02 mg/kg, I.V. (in the vein)
Midazolam: Single dose of 0.02 mg/kg of Midazolam given intravenously (in the vein) over 40 minutes | 40 |
| Ketamine 0.5 mg/kg, I.V. (in the vein)
Ketamine: Single dose of 0.5 mg/kg of ketamine given intravenously (in the vein) over 40 minutes | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Midazolam | Total | Ketamine |
|---|---|---|---|
| Age, Continuous | 40.7 years STANDARD_DEVIATION 13.1 | 39.5 years STANDARD_DEVIATION 13.1 | 38.4 years STANDARD_DEVIATION 13.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 79 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 74 Participants | 35 Participants |
| Region of Enrollment United States | 40 participants | 80 participants | 40 participants |
| Scale for Suicidal Ideation | 15.7 units on a scale STANDARD_DEVIATION 6.9 | 14.98 units on a scale STANDARD_DEVIATION 6.6 | 14.3 units on a scale STANDARD_DEVIATION 6.3 |
| Sex: Female, Male Female | 26 Participants | 48 Participants | 22 Participants |
| Sex: Female, Male Male | 14 Participants | 32 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 40 |
| other Total, other adverse events | 12 / 40 | 10 / 40 |
| serious Total, serious adverse events | 4 / 40 | 5 / 40 |
Outcome results
Primary
Change in Scale for Suicidal Ideation
Change in suicidal ideation in depressed patients with moderate to severe suicidal thoughts from the pre-infusion baseline to 24 hours after the infusion with ketamine or midazolam, a sedative not known to reduce suicidal ideation, measured with Beck Scale for Suicidal Ideation - clinician rated version. This scale has 19 items scaled 0 (least severe) to 2 (most severe) and a potential score ranging from 0 to 38, with higher score indicating greater severity.
Time frame: Day 1 (24 hours) post-treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Change in Scale for Suicidal Ideation | -3.66 units on a scale | Standard Error 0.93 |
| Ketamine | Change in Scale for Suicidal Ideation | -8.62 units on a scale | Standard Error 0.93 |
Secondary
Neuropsychological Effects
The average Z-scores reported below are the average of the Z-scores for all tests administered. The Z-scores for each test were based on published normative data and normative data available in our laboratory. The population mean for a Z-score is zero, with a SD of 1, thus scores below zero would indicate performance below the population norm; a score close to zero indicates performance close to the population norm (or a normalizing of performance).
Time frame: Baseline and Day 1
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Neuropsychological Effects | Pre-infusion overall neuropsych performance | -0.252 score on a scale | Standard Error 0.096 |
| Midazolam | Neuropsychological Effects | Day1 post-infusion overall neuropsych performance | -0.146 score on a scale | Standard Error 0.106 |
| Ketamine | Neuropsychological Effects | Pre-infusion overall neuropsych performance | -0.306 score on a scale | Standard Error 0.096 |
| Ketamine | Neuropsychological Effects | Day1 post-infusion overall neuropsych performance | -0.01 score on a scale | Standard Error 0.106 |
Secondary
Saliva Cortisol Awakening Response (CAR).
On the mornings of an infusion day and on post-treatment day1, participants used salivettes (Sarstedt AG & Co.) to provide saliva samples upon awakening (Cort1) and 30 minutes later (Cort2) to measure cortisol awakening response (CAR) = (Cort2 - Cort1). Differences between the midazolam and ketamine groups were tested using an analysis of covariance (ANCOVA) model of the change in CAR from baseline to day1, with treatment group and baseline measurement of the outcome variable as predictors. Range from 0.1 to 12.5 ng/ml and lower means less stress response, higher means greater stress response.
Time frame: Cort2 - Cort1 = (Day 1 30-mins post-awakening cortisol) - (Day 1 awakening cortisol)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Saliva Cortisol Awakening Response (CAR). | Baseline awakening | 0.94 log(ng/mL) | Standard Deviation 0.61 |
| Midazolam | Saliva Cortisol Awakening Response (CAR). | Baseline 30 mins post-awakening | 1.29 log(ng/mL) | Standard Deviation 0.53 |
| Midazolam | Saliva Cortisol Awakening Response (CAR). | Day1 awakening | 0.77 log(ng/mL) | Standard Deviation 0.76 |
| Midazolam | Saliva Cortisol Awakening Response (CAR). | Day1 30 minutes post-awakening | 1.19 log(ng/mL) | Standard Deviation 0.74 |
| Ketamine | Saliva Cortisol Awakening Response (CAR). | Day1 30 minutes post-awakening | 1.06 log(ng/mL) | Standard Deviation 0.84 |
| Ketamine | Saliva Cortisol Awakening Response (CAR). | Baseline awakening | 0.47 log(ng/mL) | Standard Deviation 1.16 |
| Ketamine | Saliva Cortisol Awakening Response (CAR). | Day1 awakening | 0.74 log(ng/mL) | Standard Deviation 0.88 |
| Ketamine | Saliva Cortisol Awakening Response (CAR). | Baseline 30 mins post-awakening | 0.88 log(ng/mL) | Standard Deviation 1.17 |