Ketamine in the Treatment of Suicidal Depression

• ClinicalTrials.gov Identifier: NCT01700829
• Recruitment Status: Completed
• First Posted: October 4, 2012
• Results First Posted: March 11, 2020
• Last Update Posted: March 11, 2020
• Sponsor: New York State Psychiatric Institute
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Michael Grunebaum, MD, New York State Psychiatric Institute

Tracking Information

• First Submitted Date: October 2, 2012
• First Posted Date: October 4, 2012
• Results First Submitted Date: March 12, 2019
• Results First Posted Date: March 11, 2020
• Last Update Posted Date: March 11, 2020
• Study Start Date: June 2012
• Actual Primary Completion Date: January 12, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 10, 2020)

Change in Scale for Suicidal Ideation [ Time Frame: 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.

Original Primary Outcome Measures (submitted: October 2, 2012)

Reduction of suicidal ideation [ Time Frame: At 24 hours post-Infusion ]

Reduction of 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.

Current Secondary Outcome Measures (submitted: March 10, 2020)

• Saliva Cortisol Awakening Response (CAR). [ Time Frame: 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 [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: October 2, 2012)

• Effects on saliva stress hormone (cortisol) [ Time Frame: 24 hours post-infusion ]
  Effects on levels of the stress hormone cortisol in saliva from before to 24 hours after the infusion.
• Neuropsychological effects [ Time Frame: 24 hours post-infusion ]
  Effects of the infusion on neuropsychological variables including decision-making and memory.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketamine in the Treatment of Suicidal Depression
• Official Title: Ketamine vs. Midazolam: Testing Rapid Relief of Suicide Risk in Depression

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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Major Depressive Disorder
• Suicidal Ideation

Intervention

• Drug: Ketamine
  Single dose of 0.5 mg/kg of ketamine given intravenously (in the vein) over 40 minutes
  Other Names:

  • Ketalar
  • Ketamine Hydrochloride Injection
• Drug: Midazolam
  Single dose of 0.02 mg/kg of Midazolam given intravenously (in the vein) over 40 minutes
  Other Name: Midazolam Injection

Study Arms

• Active Comparator: Midazolam
  0.02 mg/kg, I.V. (in the vein)
  Intervention: Drug: Midazolam
• Active Comparator: Ketamine
  0.5 mg/kg, I.V. (in the vein)
  Intervention: Drug: Ketamine

• Publications *: Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, Marver JE, Burke AK, Milak MS, Sublette ME, Oquendo MA, Mann JJ. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. 2018 Apr 1;175(4):327-335. doi: 10.1176/appi.ajp.2017.17060647. Epub 2017 Dec 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 10, 2020): 82
• Original Estimated Enrollment (submitted: October 2, 2012): 70
• Actual Study Completion Date: July 31, 2017
• Actual Primary Completion Date: January 12, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01700829
• Other Study ID Numbers: #6598; R01MH096784 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Michael Grunebaum, MD, New York State Psychiatric Institute
• Study Sponsor: New York State Psychiatric Institute
• Collaborators: National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Michael F. Grunebaum, M.D.; Columbia University/New York State Psychiatric Institute

• PRS Account: New York State Psychiatric Institute
• Verification Date: March 2020