Postoperative Depression
Conditions
Brief summary
This protocol describes a feasibility trial that will evaluate the feasibility of conducting a full-scale phase 3 trial testing the hypothesis that a postoperative sustained, low-dose ketamine infusion can prevent postoperative depressive symptoms when administered to a targeted population of neurosurgical patients with a history of depression.
Detailed description
This protocol describes a feasibility trial that will evaluate the feasibility of conducting a full-scale phase 3 trial. Both the feasibility trial and the full-scale trial will follow a randomized, placebo-controlled, double-blinded, parallel design. The trial will follow a superiority design. This trial will take place at a single site (Washington University in St. Louis School of Medicine/Barnes-Jewish Hospital). Following extubation, patients will be randomized to the intervention (ketamine group) or to control (control group). Patients in the ketamine group will receive a bolus of ketamine 0.5 mg/kg intravenously over 10 minutes, followed by an infusion at 0.3 mg/kg/h for an additional 2 hours 50 minutes. Patients in the control group will receive an equal volume of normal saline. Patients, research staff performing assessments, and research staff performing data analysis will be blinded to treatment allocation.
Interventions
DRUGKetamine
NMDA antagonist
DRUGNormal saline
IV fluid acting as a placebo
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able to provide written, informed consent 2. Aged 18 or older 3. Scheduled for non-ambulatory surgery scheduled to last at least 2 hours at Barnes-Jewish Hospital 4. Past medical history of depression, defined as one or more of the following criteria 1. Previous diagnosis by a psychiatrist or primary care physician in an outpatient or inpatient setting, by patient report or chart documentation 2. Prescription of an oral antidepressant by a psychiatrist or primary care physician for a mood disorder
Exclusion criteria
1. Bipolar depression 2. Concurrent use of a medication contraindicated with ketamine 3. Emergent surgery 4. Known or suspected elevation in intracranial pressure 5. Current subarachnoid hemorrhage 6. Carotid endarterectomy or arteriovenous malformation repair 7. Allergy to ketamine 8. Any condition in which a significant elevation of blood pressure would constitute a serious hazard (e.g., aortic dissection, pheochromocytoma) 9. Known history of dementia 10. Pregnancy or lactation 11. Inability to converse in English 12. Concurrent enrollment in another interventional trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fraction of Approached Patients Who Enroll and Are Randomized | 3 days after surgery | The numerator will include all patients who are randomized to receive either ketamine or placebo. The denominator will include all patients who are approached by the research team to evaluated eligibility and offer consent. |
| Fraction of Randomized Patients Who Complete the Study Infusion | 3 days after surgery | The numerator will include all participants who received the entire study medication infusion as planned. The denominator will include all participants who are randomized to receive either ketamine or the placebo. |
| Fraction of Randomized Patients With Depression Rating Scale Scores at All Specified Time Points | 14 days after the intervention | Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The numerator will include all patients with MADRS scores documented at all 6 time points. The denominator will include all participants who are randomized to receive either ketamine or the placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depressive Symptoms on Day 4 | 4 days after the intervention | Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The distribution of MADRS scores in the population will be assessed for normality using visual analysis of histograms and using the Kolmogorov-Smirnoff test. If the MADRS scores are normally distributed, then the mean scores in the two groups on post-infusion day 4 will be compared using linear regression, adjusting for preoperative score. If the MADRS scores are not normally distributed, then the median delta scores in the two groups will be compared using median regression, adjusting for preoperative score. Participants with missing MADRS scores at either time point (preoperative baseline or post-infusion day 4) will be excluded. |
| Delta Sleep Ratio on Night 1 Following Study Medication | 2 days after intervention | Electroencephalograms (EEG) will be captured during sleep using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. Sleep stages (e.g., non-rapid eye movement \[NREM\], rapid eye movement, wakefulness) will be detected using the Dreem headband's built-in automated sleep scoring algorithm. During each time epoch, slow wave activity will be defined as the EEG power in the range 1-4 Hz. The delta sleep ratio (DSR) will be defined as the ratio of slow wave activity during the first NREM epoch to slow wave activity during the second NREM epoch. Because it is a ratio, the DSR is a dimensionless number. In normal sleep, slow wave activity is greatest at the beginning of the night and decreases throughout the night. Therefore, higher DSR values reflect a more normal sleep architecture. |
| Delta Sleep Ratio on Night 1 Following Study Medication - Stratified by Sex | 2 days after intervention | NIH-required analysis. Electroencephalograms (EEG) will be captured during sleep using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. Sleep stages (e.g., non-rapid eye movement \[NREM\], rapid eye movement, wakefulness) will be detected using the Dreem headband's built-in automated sleep scoring algorithm. During each time epoch, slow wave activity will be defined as the EEG power in the range 1-4 Hz. The delta sleep ratio (DSR) will be defined as the ratio of slow wave activity during the first NREM epoch to slow wave activity during the second NREM epoch. Because it is a ratio, the DSR is a dimensionless number. In normal sleep, slow wave activity is greatest at the beginning of the night and decreases throughout the night. Therefore, higher DSR values reflect a more normal sleep architecture. |
| Delta Sleep Ratio on Night 1 Following Study Medication - Stratified by Race | 2 days after intervention | NIH-required analysis. Electroencephalograms (EEG) will be captured during sleep using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. Sleep stages (e.g., non-rapid eye movement \[NREM\], rapid eye movement, wakefulness) will be detected using the Dreem headband's built-in automated sleep scoring algorithm. During each time epoch, slow wave activity will be defined as the EEG power in the range 1-4 Hz. The delta sleep ratio (DSR) will be defined as the ratio of slow wave activity during the first NREM epoch to slow wave activity during the second NREM epoch. Because it is a ratio, the DSR is a dimensionless number. In normal sleep, slow wave activity is greatest at the beginning of the night and decreases throughout the night. Therefore, higher DSR values reflect a more normal sleep architecture. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Arm Following surgery and extubation, patients will receive ketamine 0.5 mg/kg over 10 minutes followed by an infusion of 0.3 mg/kg/h for 2 hours 50 minutes.
Ketamine: NMDA antagonist | 16 |
| Control Arm Following surgery and extubation, patients will receive normal saline at an equal rate to that used in the ketamine arm.
Normal saline: IV fluid acting as a placebo | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | Control Arm | Total | Ketamine Arm |
|---|---|---|---|
| Age, Continuous | 48.5 years | 47.9 years | 47.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 32 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Preoperative Depressive Symptoms - Montgomery-Asberg Depression Rating Scale 0-6 (No symptoms) | 5 Participants | 8 Participants | 3 Participants |
| Preoperative Depressive Symptoms - Montgomery-Asberg Depression Rating Scale 20-34 (Moderate symptoms) | 5 Participants | 11 Participants | 6 Participants |
| Preoperative Depressive Symptoms - Montgomery-Asberg Depression Rating Scale 35-60 (Severe symptoms) | 1 Participants | 2 Participants | 1 Participants |
| Preoperative Depressive Symptoms - Montgomery-Asberg Depression Rating Scale 7-19 (Mild symptoms) | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 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 | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Female | 15 Participants | 26 Participants | 11 Participants |
| Sex: Female, Male Male | 1 Participants | 6 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 1 / 16 |
| other Total, other adverse events | 0 / 16 | 3 / 16 |
| serious Total, serious adverse events | 2 / 16 | 5 / 16 |
Outcome results
Primary
Fraction of Approached Patients Who Enroll and Are Randomized
The numerator will include all patients who are randomized to receive either ketamine or placebo. The denominator will include all patients who are approached by the research team to evaluated eligibility and offer consent.
Time frame: 3 days after surgery
Population: The analysis population for this outcome includes all patients who were approached by the research team, including those who decided not to participate in the trial and those who were excluded from the trial prior to randomization. Because these patients were never randomized, it is not possible to report results for this outcome separately for the Ketamine Arm and the Control Arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protocol Version 1 | Fraction of Approached Patients Who Enroll and Are Randomized | 1 Participants |
| Protocol Version 2 | Fraction of Approached Patients Who Enroll and Are Randomized | 31 Participants |
Primary
Fraction of Randomized Patients Who Complete the Study Infusion
The numerator will include all participants who received the entire study medication infusion as planned. The denominator will include all participants who are randomized to receive either ketamine or the placebo.
Time frame: 3 days after surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protocol Version 1 | Fraction of Randomized Patients Who Complete the Study Infusion | 15 Participants |
| Protocol Version 2 | Fraction of Randomized Patients Who Complete the Study Infusion | 15 Participants |
Primary
Fraction of Randomized Patients With Depression Rating Scale Scores at All Specified Time Points
Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The numerator will include all patients with MADRS scores documented at all 6 time points. The denominator will include all participants who are randomized to receive either ketamine or the placebo.
Time frame: 14 days after the intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protocol Version 1 | Fraction of Randomized Patients With Depression Rating Scale Scores at All Specified Time Points | 13 Participants |
| Protocol Version 2 | Fraction of Randomized Patients With Depression Rating Scale Scores at All Specified Time Points | 6 Participants |
Secondary
Delta Sleep Ratio on Night 1 Following Study Medication
Electroencephalograms (EEG) will be captured during sleep using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. Sleep stages (e.g., non-rapid eye movement \[NREM\], rapid eye movement, wakefulness) will be detected using the Dreem headband's built-in automated sleep scoring algorithm. During each time epoch, slow wave activity will be defined as the EEG power in the range 1-4 Hz. The delta sleep ratio (DSR) will be defined as the ratio of slow wave activity during the first NREM epoch to slow wave activity during the second NREM epoch. Because it is a ratio, the DSR is a dimensionless number. In normal sleep, slow wave activity is greatest at the beginning of the night and decreases throughout the night. Therefore, higher DSR values reflect a more normal sleep architecture.
Time frame: 2 days after intervention
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Protocol Version 1 | Delta Sleep Ratio on Night 1 Following Study Medication | 3.01 ratio (dimensionless number) |
| Protocol Version 2 | Delta Sleep Ratio on Night 1 Following Study Medication | 0.96 ratio (dimensionless number) |
Secondary
Depressive Symptoms on Day 4
Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The distribution of MADRS scores in the population will be assessed for normality using visual analysis of histograms and using the Kolmogorov-Smirnoff test. If the MADRS scores are normally distributed, then the mean scores in the two groups on post-infusion day 4 will be compared using linear regression, adjusting for preoperative score. If the MADRS scores are not normally distributed, then the median delta scores in the two groups will be compared using median regression, adjusting for preoperative score. Participants with missing MADRS scores at either time point (preoperative baseline or post-infusion day 4) will be excluded.
Time frame: 4 days after the intervention
Population: Excludes participants with missing MADRS scores either at baseline or on post-infusion day 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Protocol Version 1 | Depressive Symptoms on Day 4 | 4 score on a scale |
| Protocol Version 2 | Depressive Symptoms on Day 4 | 6 score on a scale |