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

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT03283670
• Collaborator: Brain & Behavior Research Foundation (Other)
• Enrollment: 24
• Location: 1
• Arms: 3
• Actual Duration (Months): 38.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant	Drug: Nitrous Oxide 25%; Drug: Nitrous Oxide 50%; Drug: Placebo Gas	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• 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 weeksEach 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
• Official Title: Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies
• Actual Study Start Date: Nov 22, 2016
• Actual Primary Completion Date: Feb 18, 2020
• Actual Study Completion Date: Feb 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
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.	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 Names: One hour inhalation of 25% nitrous oxide
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.	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 Names: One hour inhalation of 50% nitrous oxide
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.	Drug: Placebo Gas; Placebo gas given at 50% nitrogen [inert]/50% oxygen.; Other Names: One hour inhalation of placebo gas

Outcome Measures

Primary Outcome Measures

1. Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. Pneumothorax

6. Bowel obstruction

7. Middle ear occlusion

8. Elevated intracranial pressure

9. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12

10. Pregnant patients

11. Breastfeeding women

12. Inability to provide informed consent;

13. Any other factor that in the investigators' judgment may affect patient safety or compliance

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• Brain & Behavior Research Foundation

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 24, 2019

More Information

Publications

None provided.

• Responsible Party: Ben Palanca, Associate Professor of Anesthesiology and Psychiatry, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03283670
• Other Study ID Numbers: 201608024
• First Posted: Sep 14, 2017
• Last Update Posted: Apr 4, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Ben Palanca, Associate Professor of Anesthesiology and Psychiatry, Washington University School of Medicine: Depression; treatment-resistant
• Additional relevant MeSH terms: Disease; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major; Nitrous Oxide

Study Results

Participant Flow

Arm/Group Title	Study Participants
Arm/Group Description	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. 25% nitrous oxide, 25% nitrogen, 25% oxygen 50% nitrous oxide, 50% oxygen Placebo gas: 50% nitrogen(inert), 50% oxygen
Period Title: Placebo Gas
STARTED	24
COMPLETED	22
NOT COMPLETED	2
Period Title: Placebo Gas
STARTED	24
COMPLETED	20
NOT COMPLETED	4
Period Title: Placebo Gas
STARTED	24
COMPLETED	23
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Study Participants
Arm/Group Description	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. 25% nitrous oxide, 25% nitrogen, 25% oxygen 50% nitrous oxide, 50% oxygen Placebo gas: 50% nitrogen(inert), 50% oxygen
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 83.3%
>=65 years	4 16.7%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	44
Sex: Female, Male (Count of Participants)
Female	17 70.8%
Male	7 29.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4.2%
White	23 95.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items
Description	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.
Time Frame	2 and 24 hours after inhalation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	25% Nitrous Oxide	50% Nitrous Oxide	Placebo Gas
Arm/Group Description	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.	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.	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.
Measure Participants	20	23	22
2 Hours	-3.0 (3.9)	-3.8 (4.30)	-3.9 (4.3)
24 Hours	-4.0 (6.6)	-5.5 (5.8)	-6.0 (6.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	25% Nitrous Oxide, Placebo Gas
	Comments	HAMD-21 at 2 Hours, placebo vs 25% nitrous oxide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	25% Nitrous Oxide, Placebo Gas
	Comments	Change in HAMD-21, 25% nitrous oxide vs placebo at 24 hours
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	50% Nitrous Oxide, Placebo Gas
	Comments	HAMD-21 at 2 Hours, placebo vs 50% nitrous oxide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	50% Nitrous Oxide, Placebo Gas
	Comments	Change in HAMD-21 at 24 hours, placebo vs 50% nitrous oxide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	25% Nitrous Oxide, 50% Nitrous Oxide
	Comments	Change in HAMD-21 at 2 hours, 25% nitrous oxide vs 50% nitrous oxide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	25% Nitrous Oxide, 50% Nitrous Oxide
	Comments	Change in HAMD-21 at 24 hours, 25% nitrous oxide vs 50% nitrous oxide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.80
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	18 weeks
Arm/Group Title	Placebo		25% Nitrous Oxide		50% Nitrous Oxide
Arm/Group Description	Placebo gas: 50% nitrogen(inert), 50% oxygen		25% nitrous oxide, 25% nitrogen, 25% oxygen		50% nitrous oxide, 50% oxygen
All Cause Mortality
	Placebo		25% Nitrous Oxide		50% Nitrous Oxide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/20 (0%)		0/23 (0%)
Serious Adverse Events
	Placebo		25% Nitrous Oxide		50% Nitrous Oxide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/20 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		25% Nitrous Oxide		50% Nitrous Oxide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/22 (22.7%)		8/20 (40%)		14/23 (60.9%)
Gastrointestinal disorders
Nausea	0/22 (0%)	0	1/20 (5%)	1	5/23 (21.7%)	5
Vomiting	0/22 (0%)	0	0/20 (0%)	0	2/23 (8.7%)	2
Intestinal gas	0/22 (0%)	0	1/20 (5%)	1	0/23 (0%)	0
Stomach virus	2/22 (9.1%)	2	0/20 (0%)	0	0/23 (0%)	0
General disorders
Car crash (minor)	0/22 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1
Infections and infestations
Common cold/strep throat	0/22 (0%)	0	2/20 (10%)	2	3/23 (13%)	3
Musculoskeletal and connective tissue disorders
Cramps	0/22 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1
Nervous system disorders
Haziness	0/22 (0%)	0	1/20 (5%)	1	3/23 (13%)	3
Dizziness	0/22 (0%)	0	0/20 (0%)	0	3/23 (13%)	3
Lightheadedness	0/22 (0%)	0	1/20 (5%)	1	2/23 (8.7%)	2
Feeling high	0/22 (0%)	0	0/20 (0%)	0	3/23 (13%)	3
Headache	3/22 (13.6%)	3	2/20 (10%)	2	4/23 (17.4%)	4
Sleepiness	0/22 (0%)	0	1/20 (5%)	1	2/23 (8.7%)	2
Weakness/heave	0/22 (0%)	0	1/20 (5%)	1	2/23 (8.7%)	2
Dry Mouth	0/22 (0%)	0	0/20 (0%)	0	2/23 (8.7%)	2
Tingling	0/22 (0%)	0	1/20 (5%)	1	3/23 (13%)	3
Fainting spell	0/22 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1
Psychiatric disorders
Laughing	0/22 (0%)	0	0/20 (0%)	0	3/23 (13%)	3
Feeling disconnected	1/22 (4.5%)	1	0/20 (0%)	0	6/23 (26.1%)	6
Memory gaps	0/22 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1
Paranoia	0/22 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1
Surgical and medical procedures
Sore throat	0/22 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.