Preoperative Ketamine and Perioperative Depression

Preoperative Ketamine as a Strategy to Decrease Perioperative Depression During the Perioperative Period: a Randomized Active Controlled Pilot Study

Depressive symptoms, in patients with a life history of major depressive disorder (MDD), are very common in the general population, and are especially so in elderly adults undergoing surgery.Symptoms of depression at the time of surgery is associated with risk for postoperative complications.Attenuating depressive symptoms in patients undergoing surgery is thus a plausible but not adequately tested strategy for improving patient postoperative outcomes. Conventional treatment of depression takes weeks and, therefore, is not always a realistic option, particularly when surgery is urgent. Importantly, there are currently no guidelines for diagnosing and managing MDD in surgical patients. Given its association with complications including perioperative cognitive disorders such as delirium, and over longer periods of time with dementing disorders, the feasibility and efficacy of quick-acting treatments for depressive symptoms in surgical patients are direly needed. This need is particularly acute given the rising number of elderly patients undergoing surgery who are prone to depression and surgical complications.

Aim 1: To assess the feasibility of enrolling patients in a clinical trial where a sub-anesthetic dose of ketamine (0.5 mg/kg over 40 min) or midazolam (0.045 mg/kg) is given 1 to 3 days before surgery in the preoperative clinic as a strategy to improve depressive symptoms during the perioperative period.

Aim 2: To obtain estimates of the variability in improvements of depressive symptoms (increase from baseline in MADRS score ≥ 2)1 day after surgery for patients given a sub-anesthetic dose of ketamine (0.5 mg/kg over 40 min) 1 to 3 days before surgery compared with midazolam 0.045 mg/kg.

Aim 3: To assess for the safety and tolerability of administration of a sub-anesthetic dose of ketamine (0.5 mg/kg over 40 min) given 1 to 3 days before surgery in the preoperative clinic (as an outpatient) by assessment of dysphoric symptoms or other complications including the need for hospitalization.

Hypothesis:

Aim 1: Hypothesis: Patients with preoperative depressive symptoms can be identified before surgery and successfully enrolled in a clinical trial comparing a sub-anesthetic dose of ketamine versus midazolam for improving perioperative depressive symptoms.

Aim 2: Hypothesis: Compared with midazolam, a sub-anesthetic dose of ketamine given preoperatively leads to an improvement in MADRS score ≥ 2 on day 1 after surgery.

Aim 3: Hypothesis: Compared with midazolam, a sub-anesthetic dose of ketamine is not associated with dysphoria or other complications.

Study Overview

• Status: Withdrawn
• Conditions: Depressive Disorder
• Intervention / Treatment: Drug: Ketamine Group; Drug: Midazolam injection

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Paul Fitzgerald, RN, BSN, MS; Phone Number: 312-695-1064; Email: p-fitzgerald2@northwestern.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Contact: Paul Fitzgerald, RR, BSN, MS; Phone Number: 312-695-1064; Email: p-fitzgerald2@northwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients age ≥ 65 years
• Planned lumbar surgery for degenerative disc disease or spinal stenosis involving 2 or more levels
• A life history of MDD (DSM-5 criteria) and a MADRS score ≥20
• Mini-Mental State Examination (MMSE) score ≥ 15
• MMSE is between15-26
• Ability to understand English.

Exclusion Criteria:

• MMSE < 15
• History of psychosis
• Poorly controlled hypertension
• Pre-existing aneurysmal vascular disorders
• Cocaine or other illicit drug use.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ketamine Group; Ketamine 0.5 mg/kg over 40 min via intravenous catheter.	Drug: Ketamine Group; Ketamine intravenous administration 0.5 mg/kg over 40 minutes.; Other Names: Ketamine
ACTIVE_COMPARATOR: MIdazolam Group; Midazolam 0.045 mg/kg administered via intravenous catheter.	Drug: Midazolam injection; Midazolam intravenous administration 0.045 mg/kg IV over 40 minutes.; Other Names: Midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in depressive symptoms in the perioperative period.	Ketamine administration changes depressive symptoms perioperatively. Measured using Depression will be measured with the Montgomery-Asberg Depression Scale (MADRS) scale. Scale ranges from 0 no depresson- 60 severe depression.	3 Days before surgery to 30 days after the surgical procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in depressive symptoms 1 day after surgery	Change in depressive symptoms using MADRS questionnaire measured with the Montgomery-Asberg Depression Scale scale. Scale ranges from 0 no depresson- 60 severe depression.	24 hours after surgical procedure
Safety analsysis of administration of a sub-anesthetic dose of ketamine: CADSS	To assess for the safety of administration of a sub-anesthetic dose of ketamine (0.5 mg/kg over 40 min) given 1 to 3 days before surgery in the preoperative clinic (as an outpatient) by assessment of dysphoric symptoms or other complications including the need for hospitalization. The Clinician-Administered Dissociative States Scale CADSS is a 27 question survey ,19 which are completed by the subject on a scale of 0 -4 likert scale for a possible score 0- good 76 poor and 9 questions completed by the assessor (scored yes or no).	65 minutes after study drug has been infused.

Collaborators and Investigators

• Sponsor: Northwestern University

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2022
• Primary Completion (ACTUAL): February 2, 2023
• Study Completion (ACTUAL): February 2, 2023

Study Registration Dates

• First Submitted: January 3, 2020
• First Submitted That Met QC Criteria: January 6, 2020
• First Posted (ACTUAL): January 7, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: STU00211219

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No