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

Study Overview
=================
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.

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

Conditions
-----------------
Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant

Intervention / Treatment
-----------------
* Drug: Nitrous Oxide 25%
* Drug: Nitrous Oxide 50%
* Drug: Placebo Gas


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Adults 18-75 years of age; Current diagnosis of unipolar major depressive disorder (MDD) without psychosis as confirmed by structured clinical interview for DSM-IV disorders; A score of >= 9 on the Montgomery-Åsberg Depression Rating Scale (MADRS); 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; Good command of the English language. Exclusion Criteria Meets criteria for any DSM-IV diagnosis for schizophrenia, bipolar, schizoaffective, obsessive-compulsive, personality, or panic disorders; Any recent (within past 12 months) history of substance dependence or abuse (except tobacco), determined by reported history or urine drug screen; Ability to become pregnant and not using effective contraception; Contraindication against the use of nitrous oxide: Pneumothorax Bowel obstruction Middle ear occlusion Elevated intracranial pressure Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12 Pregnant patients Breastfeeding women Inability to provide informed consent; Any other factor that in the investigators' judgment may affect patient safety or compliance

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Each participant receives the 3 inhalation types in randomized, one hour sessions separated by at least 4 weeks
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1. 25% nitrous oxide, 25% nitrogen, 25% oxygen<br>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%<br>* 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.<br>* Other names: One hour inhalation of 25% nitrous oxide;|
| Experimental: 2. 50% nitrous oxide, 50% oxygen<br>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%<br>* 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.<br>* Other names: One hour inhalation of 50% nitrous oxide;|
| Placebo Comparator: 3. Placebo gas: 50% nitrogen(inert), 50% oxygen<br>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<br>* Placebo gas given at 50% nitrogen [inert]/50% oxygen.<br>* Other names: One hour inhalation of placebo gas;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, treatment-resistant