Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies (NARSAD)

• ClinicalTrials.gov Identifier: NCT03283670
• Recruitment Status: Completed
• First Posted: September 14, 2017
• Results First Posted: April 4, 2022
• Last Update Posted: April 4, 2022
• Sponsor: Washington University School of Medicine
• Collaborator: Brain & Behavior Research Foundation
• Information provided by (Responsible Party): Ben Palanca, Washington University School of Medicine

Tracking Information

• First Submitted Date: November 9, 2016
• First Posted Date: September 14, 2017
• Results First Submitted Date: February 9, 2021
• Results First Posted Date: April 4, 2022
• Last Update Posted Date: April 4, 2022
• Actual Study Start Date: November 22, 2016
• Actual Primary Completion Date: February 18, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 28, 2022)

Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items [ Time Frame: 2 and 24 hours after inhalation ]

Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items. The HAMD-21 is designed to rate the severity of depression in patients. Although it contains 21 areas, calculate the patient's score as the total score on the first 17 answers. Scale: 0=absent, 4=worst level possible) the scores on the individual items are summed. Changes will be based on measurements obtained at baseline, approximately 2 hours after inhalation, and approximately 24 hours after inhalation. Changes are based on subtracti on of baseline score.

Original Primary Outcome Measures (submitted: September 13, 2017)

Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items [ Time Frame: 2 and 24 hours after inhalation ]

Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies
• Official Title: Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies
• Brief Summary: The purpose of the study aims to determine whether different concentrations of nitrous oxide (N2O) have different antidepressant effects for adults with treatment-resistant major depression.

Detailed Description

Most clinical major depression responds to standard treatments (medication and psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond to these treatments and are referred to as treatment-resistant major depression (TRMD). New treatments for TRMD are needed, and one promising line of research are drugs known as N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, our group demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD.

All patients will receive 3 randomized, one hour nitrous oxide inhalations to placebo (0% N2O), low dose (25% N2O), and high dose (50% N2O). Inhalation sessions will be at least 4 weeks apart. Mood will be assessed at baseline, 2 and 24 hours, and 1, 2, and 4 weeks post-inhalation for each dose.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Each participant receives the 3 inhalation types in randomized, one hour sessions separated by at least 4 weeks

Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment

Condition

• Depressive Disorder, Major
• Depressive Disorder, Treatment-Resistant

Intervention

• Drug: Nitrous Oxide 25%
  Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at a concentration of 25% nitrous oxide/50% oxygen/25% nitrogen.
  Other Name: One hour inhalation of 25% nitrous oxide
• Drug: Nitrous Oxide 50%
  Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at a concentration of 50% nitrous oxide/50% oxygen.
  Other Name: One hour inhalation of 50% nitrous oxide
• Drug: Placebo Gas
  Placebo gas given at 50% nitrogen [inert]/50% oxygen.
  Other Name: One hour inhalation of placebo gas

Study Arms

• Experimental: 1. 25% nitrous oxide, 25% nitrogen, 25% oxygen
  Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.
  Intervention: Drug: Nitrous Oxide 25%
• Experimental: 2. 50% nitrous oxide, 50% oxygen
  Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.
  Intervention: Drug: Nitrous Oxide 50%
• Placebo Comparator: 3. Placebo gas: 50% nitrogen(inert), 50% oxygen
  Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.
  Intervention: Drug: Placebo Gas

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 28, 2022): 24
• Original Estimated Enrollment (submitted: September 13, 2017): 30
• Actual Study Completion Date: February 18, 2020
• Actual Primary Completion Date: February 18, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Adults 18-75 years of age;
2. Current diagnosis of unipolar major depressive disorder (MDD) without psychosis as confirmed by structured clinical interview for DSM-IV disorders;
3. A score of >= 9 on the Montgomery-Åsberg Depression Rating Scale (MADRS);
4. Documented (i.e., chart review) lifetime failure to respond to >=3 adequate dose/duration antidepressant treatment trials, ≥1 medication failure in the current depressive episode;
5. Good command of the English language.

Exclusion Criteria

1. Meets criteria for any DSM-IV diagnosis for schizophrenia, bipolar, schizoaffective, obsessive-compulsive, personality, or panic disorders;
2. Any recent (within past 12 months) history of substance dependence or abuse (except tobacco), determined by reported history or urine drug screen;
3. Ability to become pregnant and not using effective contraception;

4. Contraindication against the use of nitrous oxide:

   1. Pneumothorax
   2. Bowel obstruction
   3. Middle ear occlusion
   4. Elevated intracranial pressure
   5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
   6. Pregnant patients
   7. Breastfeeding women
5. Inability to provide informed consent;
6. Any other factor that in the investigators' judgment may affect patient safety or compliance

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03283670
• Other Study ID Numbers: 201608024
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: There is no plan to share IPD.

• Current Responsible Party: Ben Palanca, Washington University School of Medicine
• Original Responsible Party: Peter Nagele, Washington University School of Medicine, Associate Professor of Anesthesiology
• Current Study Sponsor: Washington University School of Medicine
• Original Study Sponsor: Same as current
• Collaborators: Brain & Behavior Research Foundation

Investigators

• Principal Investigator: Ben Palanca, MD; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: March 2022