Depression, Major Depressive Disorder
Conditions
Keywords
Treatment
Brief summary
Major depressive disorder (MDD) is a global medical problem with significant shortcomings in current therapy. Chief among these is the delay between initiation of pharmacologic therapy and clinical improvement in symptoms. Recently ketamine, an NDMA-receptor antagonist has been shown to rapidly and effectively reverse the symptoms of MDD. Nitrous oxide, another NMDA-receptor antagonist, may produce the same effect with a cleaner side-effect profile and perhaps without the need for intravenous access and anesthesia personnel. Therefore, we propose conducting a pilot randomized placebo controlled double-blind crossover study in which patients will receive up to 50% nitrous oxide in oxygen or up to 50% oxygen in air for a period of one hour in addition to standard medical therapy. Depression severity will be assessed by a blinded observer pre-treatment, 30 minutes and 2 hours post treatment using the Hamilton depression rating scale.
Detailed description
We will study 20 patients with non-treatment resistant major depression and 20 patients with treatment-resistant major depression, defined as failure of at least 2 antidepressants in the current depressive episode and 3 lifetime medication failures.
Interventions
DRUGNitrous Oxide
Patients will receive either up to 50% nitrous oxide/50% oxygen for 1 hour or placebo (50% nitrogen \[inert\]/50% oxygen) in two separate sessions. Both sessions will be 1 week apart.
DRUGPlacebo
50% nitrogen \[inert\]/50% oxygen - otherwise completely identical administration and setup
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Adults 18-65 years of age 2. Major depressive disorder without psychosis with as determined by structured interview using the Mini-International Neuropsychiatric Interview (MINI). (baseline ) 3. HDRS-21 score of \>18 4. Good command of the English language
Exclusion criteria
History of: 1. Bipolar disorder 2. Schizoprenia 3. Schizoaffective disorder 4. Obsessive-compulsive disorder, panic disorder 5. Substance abuse or dependence (except for remote substance abuse or dependence with remission at least 1 year prior to the study and except for nicotine use disorders) 6. Axis II diagnoses that may interfere with the patient's ability to improve on nitrous oxide 7. Acute medical illness that may pose subject at risk during nitrous oxide administration 8. Active suicidal intention (inability to contract for safety) 9. Active psychotic symptoms 10. Patients with significant pulmonary disease and/or requiring supplemental oxygen 11. 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 12. Previous administration of NMDA-receptor antagonists (e.g., ketamine) within the last 3 months 13. Current electro-convulsive therapy treatment 14. Any active suicidal ideation, intention, or planning (clinical assessment of suicidality will be used)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hamilton Depression Rating Scale HDRS-21 | baseline and 24 hours | (21-point Hamilton Depression Rating Scale) Scoring is based on the first 17 items on the 21 point scale. Eight items are scored on a 5-point scale, ranging form 0=not present to 4= severe. Nine are scored from 0-2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quick Inventory of Depressive Symptomatology - Self Report - QIDS -SR | baseline and 24 hours | \[Quick Inventory of Depressive Symptomatology - Self Report\] An item-by-item severity scale of 0 to 3, with possible total scores ranging from 0 to 84. The items on the scale are added together for a total score. Higher scores mean worse outcome. |
Countries
United States
Participant flow
Recruitment details
21 Participants were consented, however only 20 continued.
Participants by arm
| Arm | Count |
|---|---|
| N2O/Placebo First session: Nitrous oxide Second session: placebo
Nitrous Oxide: Patients will receive either up to 50% nitrous oxide/50% oxygen for 1 hour or placebo (50% nitrogen \[inert\]/50% oxygen) in two separate sessions. Both sessions will be 1 week apart.
Placebo: 50% nitrogen \[inert\]/50% oxygen - otherwise completely identical administration and setup | 10 |
| Placebo/N2O First session: Placebo Second session: Nitrous Oxide
Nitrous Oxide: Patients will receive either up to 50% nitrous oxide/50% oxygen for 1 hour or placebo (50% nitrogen \[inert\]/50% oxygen) in two separate sessions. Both sessions will be 1 week apart.
Placebo: 50% nitrogen \[inert\]/50% oxygen - otherwise completely identical administration and setup | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | N2O/Placebo | Placebo/N2O | Total |
|---|---|---|---|
| Age, Continuous | 48 years | 48 years | 48 years |
| Region of Enrollment United States | 11 participants | 10 participants | 21 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 14 / 20 | 5 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Hamilton Depression Rating Scale HDRS-21
(21-point Hamilton Depression Rating Scale) Scoring is based on the first 17 items on the 21 point scale. Eight items are scored on a 5-point scale, ranging form 0=not present to 4= severe. Nine are scored from 0-2.
Time frame: baseline and 24 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nitrous Oxide | Change in Hamilton Depression Rating Scale HDRS-21 | 5.5 score on a scale |
| Placebo | Change in Hamilton Depression Rating Scale HDRS-21 | 2.8 score on a scale |
Comparison: The primary outcome (HDRS-21) was analyzed with a repeated-measures mixed effects linear model using restricted maximum likelihood estimation. To adjust for the observed carryover effect, the model included a randomization group term and a three-way interaction (treatment × time × randomization group)p-value: <0.05Mixed Models Analysis
Secondary
Change in Quick Inventory of Depressive Symptomatology - Self Report - QIDS -SR
\[Quick Inventory of Depressive Symptomatology - Self Report\] An item-by-item severity scale of 0 to 3, with possible total scores ranging from 0 to 84. The items on the scale are added together for a total score. Higher scores mean worse outcome.
Time frame: baseline and 24 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nitrous Oxide | Change in Quick Inventory of Depressive Symptomatology - Self Report - QIDS -SR | 3.2 score on a scale |
| Placebo | Change in Quick Inventory of Depressive Symptomatology - Self Report - QIDS -SR | 1.0 score on a scale |
p-value: <0.05Mixed Models Analysis