Ketamine for Treatment Resistant Late-Life Depression

December 15, 2021 updated by: VA Office of Research and Development
The purpose of this study is to examine the effectiveness of a single infusion of ketamine (KET), to determine which dose is optimal 7 days after infusion using Bayesian Adaptive Randomization, and to learn about how ketamine works in the body and brain in persons with late-life treatment resistant depression.

Study Overview

Detailed Description

Primary Aim: To identify the best performing condition across a single intravenous infusion of ketamine (KET) 0.1 mg/kg, KET 0.25 mg/kg, KET 0.50 mg/kg) and midazolam (MID) 0.03 mg/kg on Montgomery-Asberg Depression Rating Scale (MADRS) treatment response (at least a 50% improvement in depression from baseline) 7 days after the infusion in up to 72 Veterans with Late-Life Treatment Resistant Depression (LL-TRD) , using a triple blind (patient, rater, anesthesiologist) Bayesian adaptive randomization design.

Hypothesis 1: Single KET 0.5 mg/kg infusion is superior to KET 0.1 mg/kg, KET 0.25 mg/kg, and MID 0.03 mg/kg measured by the proportion of participants demonstrating > 50% reduction on MADRS scores 7 days post-treatment.

Secondary Aim: To evaluate the durability of day 7 treatment response across 3 sub-anesthetic doses of a single KET (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and MID (0.03 mg/kg) infusion in veterans with LL-TRD during a 4 week follow-up.

Hypothesis 2: a single KET 0.5 mg/kg infusion will be superior to a single infusion of KET 0.1 mg/kg, KET 0.25 mg/kg, and MID 0.03 mg/kg as measured by the proportion of participants demonstrating > 50% reduction on MADRS scores at 28 days post-infusion.

Tertiary Aim: To evaluate the immediate and longer-term safety and tolerability of the most effective KET infusion relative to MID in vets with LL-TRD.

Hypothesis 3: KET infusion at the most effective dose will be safe and well tolerated compared to MID, as assessed by psychoactive and general side effect rating scales during and up to 4 weeks post study infusion.

Exploratory Aims:

  1. To measure the effects of the most effective dose of KET relative to MID on neurocognitive performance.
  2. To measure the effects the most effective dose of KET relative to MID on peripheral biomarkers of cellular plasticity and inflammation.
  3. To measure the effects the most effective dose of KET relative to MID on resting-state quantitative electroencephalography.

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Texas
      • Houston, Texas, United States, 77030
        • Michael E. DeBakey VA Medical Center, Houston, TX

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

55 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male or female patients, 55 years of age,
  • Participants must fulfill DSM 5 criteria for a Major Depressive Episode (Unipolar), based on a structured diagnostic interview, the DSM 5 M.I.N.I. 7.0
  • Participants must have a history of at least one previous episode of depression prior to the current episode (recurrent MDD) or have chronic MDD (of at least two years' duration),
  • Participants have not responded to two or more adequate trials of FDA-approved antidepressants, determined by Antidepressant Treatment Response Questionnaire (ATRQ) criteria.
  • Participants must score 14 or greater on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), and score 27 on the Montgomery Asberg Depression Rating Scale (MADRS),
  • Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document.

Exclusion Criteria:

  • Patients currently on fluoxetine,
  • History of schizophrenia, schizoaffective disorder or any psychotic disorder, or bipolar disorder,
  • Documented history of a psychotic disorder in a first-degree relative,
  • Current diagnosis of obsessive-compulsive disorder (OCD) or eating disorder [bulimia nervosa or anorexia nervosa],
  • Alcohol or substance use [except nicotine] within the preceding 6 months,
  • Patients with any clinically significant personality disorder that would, in the investigator's judgment, preclude safe study participation,
  • Patients judged to be at serious and imminent suicidal or homicidal risk,
  • Serious, unstable medical illnesses including respiratory [obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics], cardiovascular [including ischemic heart disease and uncontrolled hypertension], and neurologic [including history of severe head injury],
  • For study entry, patients must be reasonable medical candidates for ketamine or midazolam infusion, as determined by a board-certified physician co-investigator during study Screening,
  • Clinically significant abnormal findings of laboratory parameters [including urine toxicology screen for drugs of abuse], physical examination, or ECG,
  • Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg),
  • Patients with one or more 11 seizures without a clear and resolved etiology,
  • Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening,
  • Past intolerance or hypersensitivity to ketamine, or history of recreational use of phencyclidine (PCP) or ketamine,
  • Past intolerance or hypersensitivity to midazolam,
  • Age-related cognitive decline or mild dementia suggested by a score of < 25 on the Mini-Mental State Examination (MMSE) at Screening,
  • Patients taking medications with known activity at the N-methyl-D-aspartate receptor (NMDA) or AMPA glutamate receptor [e.g., riluzole, amantadine, lamotrigine, memantine, topiramate, dextromethorphan, D-cycloserine], or the muopioid receptor,
  • Patients taking any of the following medications: St John's Wort, theophylline, tramadol, metrizamide,
  • Patients who demonstrate > 25% decrease in depressive symptoms as reflected by the QIDS-SR score from Screening to Randomization,
  • Patients who have received electroconvulsive therapy (ECT) in the past 6 months prior to Screening,
  • Patients currently receiving treatment with vagus nerve stimulation (VNS) or repetitive transcranial stimulation (rTMS).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ketamine 0.10 mg/kg
randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg
Experimental: Ketamine 0.25 mg/kg
randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg
Experimental: Ketamine 0.50 mg/kg
randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg
randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg
Active Comparator: Midazolam 0.03 mg/kg
randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg
single 40 min infusion of MID 0.03mg/Kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores
Time Frame: Day 7 post-infusion
To determine the best performing intervention among three sub-anesthetic doses of a single ketamine (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and midazolam (0.03 mg/kg) in Veterans with LL-TRD as measured by the percentage of participants demonstrating at least a 50% reduction from pre-treatment baseline on Montgomery-Asberg Depression Rating Scale (MADRS; score range 0 - 60, higher scores meaning more severe depression) scores at 7 days post-infusion.
Day 7 post-infusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS
Time Frame: 28 days post-infusion follow-up
Patients with a day 7 treatment response (at least a 50% improvement from baseline in Montgomery-Asberg Depression Rating Scale [MADRS]) are followed until day 28 post-infusion; day 7 non-responders are not followed. Outcome measure is the percentage of patients who continue to be responder at day 28, and is interpreted as a measure of durability of efficacy.
28 days post-infusion follow-up

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Clinician-Administered Dissociative States Scale (CADSS)
Time Frame: Baseline to 40 minutes after start of infusion
Change from pre-infusion baseline to end of infusion at 40 minutes after start of infusion on the Clinician-Administered Dissociative States Scale (CADSS; scale form 0 [no psychosis-like symptoms] to 90 [severe psychosis-like symptoms]) to assess psychosis-like side effect on day of infusion.
Baseline to 40 minutes after start of infusion
Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared)
Time Frame: Baseline to 30 minutes after start of infusion
Change in EEG frontal gamma power from pre-infusion baseline to 30 minutes after start of infusion to assess engagement of the study drug with the N-methyl-D-aspartate receptor.
Baseline to 30 minutes after start of infusion
Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg)
Time Frame: Baseline to 30 minutes after start of infusion
Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
Baseline to 30 minutes after start of infusion
Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg)
Time Frame: Baseline to 30 minutes after start of infusion
Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
Baseline to 30 minutes after start of infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Sanjay Mathew, MD, Michael E. DeBakey VA Medical Center, Houston, TX

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2015

Primary Completion (Actual)

March 31, 2020

Study Completion (Actual)

March 31, 2020

Study Registration Dates

First Submitted

June 25, 2015

First Submitted That Met QC Criteria

September 18, 2015

First Posted (Estimate)

September 22, 2015

Study Record Updates

Last Update Posted (Actual)

January 11, 2022

Last Update Submitted That Met QC Criteria

December 15, 2021

Last Verified

December 1, 2021

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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