Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant
Conditions
Keywords
Depression, treatment-resistant
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.
Interventions
DRUGNitrous 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.
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.
DRUGPlacebo Gas
Placebo gas given at 50% nitrogen \[inert\]/50% oxygen.
Sponsors
Brain & Behavior Research Foundation
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Each participant receives the 3 inhalation types in randomized, one hour sessions separated by at least 4 weeks
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Participants 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.
1. 25% nitrous oxide, 25% nitrogen, 25% oxygen
2. 50% nitrous oxide, 50% oxygen
3. Placebo gas: 50% nitrogen(inert), 50% oxygen | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 25% Nitrous Oxide | Withdrawal by Subject | 4 |
| 50% Nitrous Oxide | Withdrawal by Subject | 1 |
| Placebo Gas | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 44 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 | 0 / 23 |
| other Total, other adverse events | 5 / 22 | 8 / 20 | 14 / 23 |
| serious Total, serious adverse events | 0 / 22 | 0 / 20 | 0 / 23 |
Outcome results
Primary
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.
Time frame: 2 and 24 hours after inhalation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 25% Nitrous Oxide | Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items | 2 Hours | -3.0 score on a scale | Standard Deviation 3.9 |
| 25% Nitrous Oxide | Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items | 24 Hours | -4.0 score on a scale | Standard Deviation 6.6 |
| 50% Nitrous Oxide | Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items | 2 Hours | -3.8 score on a scale | Standard Deviation 4.3 |
| 50% Nitrous Oxide | Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items | 24 Hours | -5.5 score on a scale | Standard Deviation 5.8 |
| Placebo Gas | Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items | 2 Hours | -3.9 score on a scale | Standard Deviation 4.3 |
| Placebo Gas | Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items | 24 Hours | -6.0 score on a scale | Standard Deviation 6.4 |
Comparison: HAMD-21 at 2 Hours, placebo vs 25% nitrous oxidep-value: 0.55t-test, 2 sided
Comparison: Change in HAMD-21, 25% nitrous oxide vs placebo at 24 hoursp-value: 0.47t-test, 2 sided
Comparison: HAMD-21 at 2 Hours, placebo vs 50% nitrous oxidep-value: 0.49t-test, 2 sided
Comparison: Change in HAMD-21 at 24 hours, placebo vs 50% nitrous oxidep-value: 0.34t-test, 2 sided
Comparison: Change in HAMD-21 at 2 hours, 25% nitrous oxide vs 50% nitrous oxidep-value: 0.94t-test, 2 sided
Comparison: Change in HAMD-21 at 24 hours, 25% nitrous oxide vs 50% nitrous oxidep-value: 0.8t-test, 2 sided