Treatment Resistant Depressive Disorder
Conditions
Keywords
ketamine, depression, treatment resistant, treatment resistant depression, late life depression, depression in the elderly, geriatric depression
Brief summary
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.
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.
Interventions
DRUGKetamine
randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
DRUGMidazolam
single 40 min infusion of MID 0.03mg/Kg
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
We use a Bayesian, adaptive, randomized design initially allocating subjects to 2 arms in a 1:3 ratio: ARM 1: MID 0.03 mg/kg (active placebo); ARM 2: four conditions KET 0.1 mg/kg, KET 0.25 mg/kg, KET 0.5 mg/kg or MID 0.03 mg/kg. After 1:1:1:1 allocation of the first 20 subjects to ARM 2, Bayesian adaptive randomization may stop for superiority, change randomization ratios and/or prune arms for futility based on the probability of a day 7 treatment response. ARM 1 remains open for allocation to ensure a placebo group sufficiently large for comparison with best dose KET. For analyses, MID of ARM 1 and ARM 2 will be combined so that there are 4 conditions (or arms) for final statistical analyses. We expected to enroll a maximum 72 patients.
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinician-Administered Dissociative States Scale (CADSS) | 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. |
| Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | 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. |
| Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | Baseline to 30 minutes after start of infusion | Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion |
| Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | Baseline to 30 minutes after start of infusion | Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine 0.10 mg/kg randomly assigned to a single 40 min infusion of KET 0.1 mg/kg | 4 |
| Ketamine 0.25 mg/kg randomly assigned to a single 40 min infusion of KET 0.25 mg/kg | 5 |
| Ketamine 0.50 mg/kg randomly assigned to a single 40 min infusion of KET 0.50 mg/kg | 11 |
| Midazolam 0.03 mg/kg randomly assigned to a single 40 min infusion of MID 0.03 mg/kg | 13 |
| Total | 33 |
Baseline characteristics
| Characteristic | Ketamine 0.10 mg/kg | Ketamine 0.25 mg/kg | Ketamine 0.50 mg/kg | Midazolam 0.03 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 66.75 Years STANDARD_DEVIATION 5.54 | 61.8 Years STANDARD_DEVIATION 6.06 | 60.91 Years STANDARD_DEVIATION 4.97 | 62.15 Years STANDARD_DEVIATION 5.54 | 62.24 Years STANDARD_DEVIATION 5.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 11 Participants | 12 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 4 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 7 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 8 Participants | 9 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 11 / 11 | 13 / 13 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 | 0 / 11 | 1 / 13 |
Outcome results
Primary
Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores
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.
Time frame: Day 7 post-infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine 0.10 mg/kg | Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores | 0 Participants |
| Ketamine 0.25 mg/kg | Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores | 2 Participants |
| Ketamine 0.50 mg/kg | Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores | 8 Participants |
| Midazolam 0.03 mg/kg | Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores | 6 Participants |
Secondary
Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS
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.
Time frame: 28 days post-infusion follow-up
Population: Day 7 responders were followed until day 28 post-infusion or until relapse
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine 0.10 mg/kg | Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS | 0 Participants |
| Ketamine 0.25 mg/kg | Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS | 1 Participants |
| Ketamine 0.50 mg/kg | Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS | 7 Participants |
| Midazolam 0.03 mg/kg | Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS | 4 Participants |
Other Pre-specified
Change in Clinician-Administered Dissociative States Scale (CADSS)
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.
Time frame: Baseline to 40 minutes after start of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine 0.10 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | Pre-infusion baseline | 1.41 Score on CADSS scale | Standard Deviation 0.71 |
| Ketamine 0.10 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | End of infusion at 40 minutes | 4.79 Score on CADSS scale | Standard Deviation 2.39 |
| Ketamine 0.25 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | End of infusion at 40 minutes | 14.98 Score on CADSS scale | Standard Deviation 6.7 |
| Ketamine 0.25 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | Pre-infusion baseline | 0 Score on CADSS scale | Standard Deviation 0 |
| Ketamine 0.50 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | Pre-infusion baseline | 0.09 Score on CADSS scale | Standard Deviation 0.3 |
| Ketamine 0.50 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | End of infusion at 40 minutes | 21.36 Score on CADSS scale | Standard Deviation 20.53 |
| Midazolam 0.03 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | Pre-infusion baseline | 0.23 Score on CADSS scale | Standard Deviation 0.6 |
| Midazolam 0.03 mg/kg | Change in Clinician-Administered Dissociative States Scale (CADSS) | End of infusion at 40 minutes | 4.38 Score on CADSS scale | Standard Deviation 6.73 |
Other Pre-specified
Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg)
Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
Time frame: Baseline to 30 minutes after start of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine 0.10 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 80.5 mm Hg | Standard Deviation 7.05 |
| Ketamine 0.10 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 91.25 mm Hg | Standard Deviation 14.24 |
| Ketamine 0.25 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 74.6 mm Hg | Standard Deviation 13.37 |
| Ketamine 0.25 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 82.6 mm Hg | Standard Deviation 18.53 |
| Ketamine 0.50 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 95.45 mm Hg | Standard Deviation 16.01 |
| Ketamine 0.50 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 82.64 mm Hg | Standard Deviation 4.72 |
| Midazolam 0.03 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 72.23 mm Hg | Standard Deviation 9.36 |
| Midazolam 0.03 mg/kg | Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 73.54 mm Hg | Standard Deviation 12.29 |
Other Pre-specified
Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared)
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.
Time frame: Baseline to 30 minutes after start of infusion
Population: Missing data due to poor data quality for KET 0.1 (n=1), KET 0.5 (n=3) or MID (n=3)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine 0.10 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | Pre-infusion baseline | 0.0019 uV^2 | Standard Deviation 0.0004 |
| Ketamine 0.10 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | 30 minutes after start of infusion | 0.0035 uV^2 | Standard Deviation 0.0012 |
| Ketamine 0.25 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | 30 minutes after start of infusion | 0.0057 uV^2 | Standard Deviation 0.0044 |
| Ketamine 0.25 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | Pre-infusion baseline | 0.055 uV^2 | Standard Deviation 0.003 |
| Ketamine 0.50 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | Pre-infusion baseline | 0.0042 uV^2 | Standard Deviation 0.0026 |
| Ketamine 0.50 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | 30 minutes after start of infusion | 0.0098 uV^2 | Standard Deviation 0.0067 |
| Midazolam 0.03 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | Pre-infusion baseline | 0.0061 uV^2 | Standard Deviation 0.0078 |
| Midazolam 0.03 mg/kg | Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) | 30 minutes after start of infusion | 0.004 uV^2 | Standard Deviation 0.0027 |
Other Pre-specified
Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg)
Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
Time frame: Baseline to 30 minutes after start of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine 0.10 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 154.25 mm Hg | Standard Deviation 5.91 |
| Ketamine 0.10 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 152.75 mm Hg | Standard Deviation 12.97 |
| Ketamine 0.25 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 148.2 mm Hg | Standard Deviation 18.07 |
| Ketamine 0.25 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 142.2 mm Hg | Standard Deviation 15.97 |
| Ketamine 0.50 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 132.91 mm Hg | Standard Deviation 10.56 |
| Ketamine 0.50 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 160.36 mm Hg | Standard Deviation 25.94 |
| Midazolam 0.03 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | Pre-infusion baseline | 125.54 mm Hg | Standard Deviation 213.01 |
| Midazolam 0.03 mg/kg | Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) | 30 minutes after start of infusion | 116.62 mm Hg | Standard Deviation 15.56 |