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This study evaluates whether ketamine, given as part of an anesthetic, improves depression symptoms in depressed patients undergoing non-cardiac surgery. Half of participants will receive a ketamine infusion during surgery, while the other half will receive a placebo (normal saline) during surgery.
Major Depressive Disorder (MDD) is widely prevalent among patients preparing to have surgery, and is a known risk factor for complications after surgery, including wound infection, myocardial infarction and opioid use disorder. Ketamine has emerged as an effective, rapid-acting antidepressant therapy for patients with MDD, and may be a useful tool to prevent MDD-related morbidity in the perioperative period. Ketamine has been well studied for MDD in outpatient clinics where it is given as an infusion (0.5 mg/kg over 40 minutes) in awake patients. Ketamine is often used as part of an anesthetic cocktail in sedated or anesthetized patients, but it is unknown whether ketamine has an antidepressant effect in this context. The investigators will determine whether a ketamine infusion, compared to placebo (normal saline infusion), has an antidepressant effect when given during surgical anesthesia. If ketamine is an effective antidepressant in this population under anesthesia, its use could be incorporated into a set of interventions to minimize the perioperative complications associated with MDD.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open label ketamine | Experimental | Patients will receive an intravenous ketamine infusion during surgery. |
|
| Double blind ketamine | Experimental | Patients will receive an intravenous ketamine infusion during surgery. |
|
| Double blind placebo | Placebo Comparator | Participants will receive placebo (normal saline infusion) during surgery. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine | Drug | 0.5 mg/kg over 40 minutes, intravenous. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale (MADRS) Score | The MADRS is a 10-item scale for the evaluation of depressive symptoms (Montgomery et al 1979). Each MADRS item is rated on a 0 to 6 scale. Total score range from 0-60, where lower MADRS scores indicate lower levels of depressive symptoms. The assessment for this outcome will be taken once daily on days 1, 2 and 3 post procedure. A mixed model for repeated measures (MMRM) was used to analyze the difference in postoperative MADRS score between ketamine and placebo groups.. | Post-intervention days 1, 2 and 3 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Clinical Response | Clinical response defined as >=50% reduction in MADRS score from baseline. MADRS score range: 0 to 60, a lower score indicates lower severity of symptoms. | Post-intervention days 1, 2 and 3 |
| Number of Participants With Remission |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Boris D Heifets, MD, PhD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 444788 | Background | Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382. | |
| 38188539 | Derived | Lii TR, Smith AE, Flohr JR, Okada RL, Nyongesa CA, Cianfichi LJ, Hack LM, Schatzberg AF, Heifets BD. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat Ment Health. 2023 Nov;1(11):876-886. doi: 10.1038/s44220-023-00140-x. Epub 2023 Oct 19. |
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No current plan to share data.
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Five participants were recruited for an open label study to evaluate and optimize study procedures prior to randomizing participants enrolled in the double-blind trial ("Double blind ketamine" vs "Double blind placebo").
For the open-label arm, recruitment occurred between August 2019 and March 2020. For the double-blind arms, recruitment occurred between February 2020 and August 2022. In all arms, recruitment occurred in medical clinics and by telephone and video visits.
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| ID | Title | Description |
|---|---|---|
| FG000 | Open Label Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. |
| FG001 | Double Blind Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. |
| FG002 | Double Blind Placebo | Participants received placebo (normal saline infusion over 40 minutes) during surgery. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Open Label Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. |
| BG001 | Double Blind Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Montgomery-Asberg Depression Rating Scale (MADRS) Score | The MADRS is a 10-item scale for the evaluation of depressive symptoms (Montgomery et al 1979). Each MADRS item is rated on a 0 to 6 scale. Total score range from 0-60, where lower MADRS scores indicate lower levels of depressive symptoms. The assessment for this outcome will be taken once daily on days 1, 2 and 3 post procedure. A mixed model for repeated measures (MMRM) was used to analyze the difference in postoperative MADRS score between ketamine and placebo groups.. | Missing data occurred when the number of participants analyzed on specific days was fewer than the overall number of participants analyzed. This situation arose when some participants did not complete the instrument. | Posted | Mean | Standard Deviation | score on a scale | Post-intervention days 1, 2 and 3 |
|
Average approximately 19 days
Patients reported adverse events during follow-up assessments
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Open Label Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute pulmonary embolism | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea/vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boris Heifets, MD, PhD | Stanford University | (650) 497-8057 | bheifets@stanford.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 22, 2021 | Aug 10, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 28, 2021 | Aug 10, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| D009140 | Musculoskeletal Diseases |
| D003863 | Depression |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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Masking is for double blind phase only.
| Normal saline (placebo) | Drug | Normal saline infusion over 40 minutes, equivalent volume to ketamine infusion. |
|
Remission defined as a MADRS score of <=12 on day 14. MADRS score range: 0 to 60, a lower score indicates lower severity of symptoms. |
| Post-intervention day 14 |
| Hospital Anxiety and Depression Scale (HADS) Scale Score | This outcome measures self-reported symptoms of anxiety and depression on a scale that ranges from 0 to 42. A lower score indicates lower severity of symptoms. | Post-intervention days 1, 2, 3, 5, 7 and 14 |
| Cumulative Opioid Use | This outcome measures how many cumulative morphine-equivalents milligrams of opioid pain medication the patient has taken as an inpatient and after discharge from hospital | Post-intervention days 1, 2, 3, 5, 7 and 14 |
| Hospital Length of Stay | Number of days from admission (day of surgery) through discharge after surgery. | Average approximately 3 days post-intervention |
| Brief Pain Inventory Pain Intensity Scale Score | Average pain intensity in the past 24 hours, rated on a numerical scale from 0 to 10 (with 0 representing "No pain" and 10 representing "Pain as bad as you can imagine"). | Post-intervention days 1, 2, 3, 5, 7 and 14 |
| Brief Pain Inventory Pain Interference Scale Score | Pain interference in the past 24 hours, rated on a numerical scale from 0 to 10 (with 0 representing "Does not interfere" and 10 representing "Completely interferes"). | Post-intervention days 1, 2, 3, 5, 7 and 14 |
| 37205558 | Derived | Lii TR, Smith AE, Flohr JR, Okada RL, Nyongesa CA, Cianfichi LJ, Hack LM, Schatzberg AF, Heifets BD. Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. medRxiv [Preprint]. 2023 Jun 15:2023.04.28.23289210. doi: 10.1101/2023.04.28.23289210. |
| BG002 | Double Blind Placebo | Participants received placebo (normal saline infusion over 40 minutes) during surgery. |
| BG003 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| OG001 | Double Blind Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. |
| OG002 | Double Blind Placebo | Participants received placebo (normal saline infusion over 40 minutes) during surgery. |
|
|
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| Secondary | Number of Participants With Clinical Response | Clinical response defined as >=50% reduction in MADRS score from baseline. MADRS score range: 0 to 60, a lower score indicates lower severity of symptoms. | Includes all participants still enrolled in the trial | Posted | Count of Participants | Participants | Post-intervention days 1, 2 and 3 |
|
|
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| Secondary | Number of Participants With Remission | Remission defined as a MADRS score of <=12 on day 14. MADRS score range: 0 to 60, a lower score indicates lower severity of symptoms. | Posted | Count of Participants | Participants | Post-intervention day 14 |
|
|
|
| Secondary | Hospital Anxiety and Depression Scale (HADS) Scale Score | This outcome measures self-reported symptoms of anxiety and depression on a scale that ranges from 0 to 42. A lower score indicates lower severity of symptoms. | Missing data occurred when the number of participants analyzed on specific days was fewer than the overall number of participants analyzed. This situation arose when some participants did not complete the instrument. | Posted | Mean | Standard Deviation | score on a scale | Post-intervention days 1, 2, 3, 5, 7 and 14 |
|
|
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| Secondary | Cumulative Opioid Use | This outcome measures how many cumulative morphine-equivalents milligrams of opioid pain medication the patient has taken as an inpatient and after discharge from hospital | In the open-label group, total opioid consumption was recorded only for the first 3 postoperative days | Posted | Mean | Standard Deviation | milligram morphine equivalents | Post-intervention days 1, 2, 3, 5, 7 and 14 |
|
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| Secondary | Hospital Length of Stay | Number of days from admission (day of surgery) through discharge after surgery. | Posted | Mean | Standard Deviation | days | Average approximately 3 days post-intervention |
|
|
|
| Secondary | Brief Pain Inventory Pain Intensity Scale Score | Average pain intensity in the past 24 hours, rated on a numerical scale from 0 to 10 (with 0 representing "No pain" and 10 representing "Pain as bad as you can imagine"). | Missing data occurred when the number of participants analyzed on specific days was fewer than the overall number of participants analyzed. This situation arose when some participants did not complete the instrument. | Posted | Mean | Standard Deviation | score on a scale | Post-intervention days 1, 2, 3, 5, 7 and 14 |
|
|
|
| Secondary | Brief Pain Inventory Pain Interference Scale Score | Pain interference in the past 24 hours, rated on a numerical scale from 0 to 10 (with 0 representing "Does not interfere" and 10 representing "Completely interferes"). | Missing data occurred when the number of participants analyzed on specific days was fewer than the overall number of participants analyzed. This situation arose when some participants did not complete the instrument. | Posted | Mean | Standard Deviation | units on a scale | Post-intervention days 1, 2, 3, 5, 7 and 14 |
|
|
|
| 0 |
| 5 |
| 0 |
| 5 |
| 1 |
| 5 |
| EG001 | Double Blind Ketamine | Patients received intravenous ketamine (0.5 mg/kg over 40 minutes) infusion during surgery. | 1 | 20 | 1 | 20 | 7 | 20 |
| EG002 | Double Blind Placebo | Participants received placebo (normal saline infusion over 40 minutes) during surgery. | 0 | 20 | 2 | 20 | 6 | 20 |
| Cardiac arrest | Cardiac disorders | Systematic Assessment |
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| Postoperative wound infection | Infections and infestations | Systematic Assessment |
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| Uncontrolled muscle movement in fingers | Nervous system disorders | Systematic Assessment |
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| Dizziness | Nervous system disorders | Systematic Assessment |
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| Knee pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Hallucinations | Nervous system disorders | Systematic Assessment |
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| Hemoptysis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| IV site pain | Surgical and medical procedures | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
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| Surgical revision of implanted neurostimulator | Surgical and medical procedures | Systematic Assessment |
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| Pruritis | Immune system disorders | Systematic Assessment |
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| Postoperative delirium | Nervous system disorders | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Baker's cyst | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| D001519 |
| Behavior |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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