Major Depressive DisorderPhase 2NCT05357040
Antidepressant Effects of Nitrous Oxide
A Phase 2 study testing Nitrous oxide gas for inhalation in people with Major Depressive Disorder and Treatment Resistant Depression, run by University of Chicago at 2 sites in 2 countries.
Trial summary
To evaluate the acute and sustained antidepressant effects of nitrous oxide in people with major depressive disorder; and further evaluate these effects by identifying the optimal dose and regimen to guide current practice, and to plan a future large pragmatic trial. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Major Depressive Disorder, Treatment Resistant Depression
- What is being tested?
- Nitrous oxide gas for inhalation
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 30 Jun 2021to 27 Feb 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Adult (≥18 years, both sexes)
- DSM-5 criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview], MDD, defined by a pre-treatment score >16 on the HDRS-21 scale and meeting DSM-5 for MDD
Who cannot join
- A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
- Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
- Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
- Active or recent (<12 months) substance use disorder; excluding nicotine
- Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
- Ongoing treatment with ECT
Show all 9Show fewer
- Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
- Pregnancy or breastfeeding
- Any contraindications to the use of nitrous oxide (e.g., pneumothorax, middle ear occlusion, elevated intracranial pressure, chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United States1 site
University of Chicago Medicine
Chicago, Illinois, 60637
About this study
Official title: Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
To evaluate the acute and sustained antidepressant effects of nitrous oxide in people with major depressive disorder; and further evaluate these effects by identifying the optimal dose and regimen to guide current practice, and to plan a future large pragmatic trial.
Read the detailed description
The investigators are conducting a randomized controlled trial to evaluate the antidepressant effects of nitrous oxide in people with Major Depressive Disorder (MDD). MDD is a global medical condition that causes significant health and economic burden. Recent studies have shown that a single dose of ketamine, an NMDA-antagonist, has fast and long lasting anti-depressant effect. Nitrous oxide, another NMDA-antagonist, is widely used for anesthesia and analgesia, safer to administer and has fewer side effects than ketamine.
A randomized controlled crossover feasibility study showed significant reduction in depressive symptoms at 2 and 24 hours after a single 1-hour treatment session of inhaled nitrous oxide compared with placebo. Nitrous oxide is inexpensive and can be safely administered by any trained clinician. If found to be efficacious, it could be used to provide rapid anti-depressant effect whilst the benefit of traditional anti-depressants has its delayed effect. Another potential application could be in acutely suicidal patients.
This trial will enable confirmation and extension of the findings from the feasibility study, and identify the optimal dose and regimen in a broader population of those with MDD. Participants will be randomized to receive a weekly 1-hour inhalational session of either nitrous oxide or placebo (oxygen-air mixture) for 4 weeks, and the nitrous group will be further randomly assigned to a dose of 50% or 25% nitrous oxide. Depression severity and outcomes related to treatment responses will be continuously assessed by a 'blinded-to-randomization' psychiatry (MD) rater at weekly intervals during study patient participation, using validated psychiatric diagnostics (Hamilton Depression Rating Scale-21 [HDRS-21 or HAM-D]; Profile of Mood States [POMS]; Computerized Adaptive Test-Mental Health [CAT-MH]; Sheehan-STS [S-STS]; Visual Analog Scale [VAS]).
- Being tested
- Nitrous oxide gas for inhalation, Placebo
- Keywords
- Depression, Antidepressant, Nitrous Oxide
- Medical subject headings
- Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitrous oxide gas for inhalationDrug
Also called N2O, Laughing gas, Nitrous Oxide, Nitrous
60-minute sessions of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75), administered weekly for 4-weeks.
Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.
PlaceboDrug
60-minute sessions of inhaled oxygen-air mixture (FiO2 ≈0.3) to be administered weekly for 4-weeks.
Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.
| Study group | Role | What they receive |
|---|---|---|
| Treatment; Nitrous Oxide 50% or 25%, group | Active comparator | Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned. Receives: Drug: Nitrous oxide gas for inhalation |
| Control; Oxygen-air mixture, group | Placebo comparator | Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in HDRS-21 score
Monitor changes in Hamilton Depression Rating Scale-21 (HDRS-21) scores to determine whether a series of four, 60-minute sessions of inhaled nitrous oxide vs placebo (once-per-week) has significant antidepressant activity.
The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.
Higher scores are associated with more severe depression:
0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52
Measured: Over 4-weeks from baseline
Secondary outcomes (11)
Treatment response
Treatment response (≥50% reduction on HDRS-21) to nitrous oxide vs placebo will be measured.
Measured: At 24-hours (following treatment-1)
Changes in 'Profile of Mood States' scores
Monitoring daily mood changes using the Profile of Mood States (POMS) a validated 'self-report' psychological diagnostic containing 65 emotions or 'mood states' to determine the pattern of treatment response
Patients rank their current mood states using a scale of 'not-at-all', 'a-little', 'moderately', 'quite-a-lot', 'extremely'. Responses are scored to calculated the Total Mood Disturbance (TMD):
TMD = (tension + depression + anger + fatigue + confusion) - Vigor
Measured: Up to 1-week (following treatment-1)
Sustainability of treatment response
Determine sustained response and remission following study treatments (nitrous vs placebo) using Hamilton Depression Rating Scale-21 (HDRS-21) score.
The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.
Higher scores are associated with more severe depression:
0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52
Measured: Over 7-weeks (length of study participation).
Treatment dose response comparison
Compare dose response of 25% vs 50% nitrous oxide to establish whether the concentration is related to outcome.
Determined with treatment-by-dose (group) interaction term in a logistic regression model to assess for statistical significance.
Measured: Over 7-weeks (length of study participation)
Treatment cycle compliance
Evaluate compliance to complete 4-cycle inhalation treatments of nitrous oxide vs placebo.
Determined by ability, inability, or refusal to receive all 4-treatments of randomized inhalation sessions (nitrous oxide vs placebo).
Measured: Over 4-weeks (weekly treatment sessions)
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'depression'.
Generated scores include severity and liklihood percentile:
- depression = (%) normal, mild, moderate, severe
Measured: Over 7-weeks (length of study participation) from Baseline
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'anxiety'.
Generated scores include severity and liklihood percentile:
- anxiety = (%) normal, mild, moderate, severe
Measured: Over 7-weeks (length of study participation) from Baseline
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide'.
Generated scores include severity and liklihood percentile:
- suicide = (%) low, intermediate, high
Measured: Over 7-weeks (length of study participation) from Baseline
Suicidal ideation tracking
Suicidal ideation will be be tracked using the Sheehan Suicidality Tracking Scale (S-STS), a validated self-report diagnostic tool designed to assess and monitor suicidality.
The standard S-STS consists of 14 core questions related to suicidality phenomena and is designed for use in clinical research studies and in clinical settings.
Scores are summed based on individual responses 'not-at-all = 0', 'a little = 1', 'moderately = 2', 'very = 3', 'extremely = 4', to generate a summated score (total score), individual factor scores for suicidal ideation, suicidal intent, suicidal planning, suicidal behavior, and non-suicidal self-injury.
All results are monitored in real time by a trained psychiatry (MD) rater.
Measured: Over 7-weeks (length of study participation) from Baseline
Visual Analog Scale (VAS)
The VAS is a unidimensional measure of pain intensity and use in the field of psychology to measure 'well-being'.
Patients mark on a line the point that they feel represents their perception of their current state, with the score determined by measuring in millimetres from the left hand end of the line to the point that the patient marks.
The range of score from 0-100 mm and represent: no pain (0-4 mm), mild pain(5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm).
Measured: At Baseline (Prior to treatment-1)
Treatment remission
Treatment remission (HDRS-21 ≤7 points) to nitrous oxide vs. placebo will be measured.
Measured: At 24-hours (following treatment-1)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2022
- Study start30 Jun 2021
- Primary completion27 Feb 2026
- Study completion27 Feb 2026
Why it stopped: PI has left the university
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (36)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Parallel-group, controlled trial; randomized participants (1:1) to nitrous oxide (Nitrous group) or oxygen-air mixture (FiO2 ≈0.3, Control group). The Nitrous group will be further randomly assigned to either 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75).
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Collaborators
- The Alfred
- Responsible party
- Sponsor
- Investigators
- Peter Nagele, MD, MSc, Principal investigator, University of Chicago, Department of Anesthesia and Critical CarePaul Myles, MD, Principal investigator, The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05357040
- Sponsor's protocol ID
- IRB18-1856
- Status last verified
- May 2026
- First submitted
- 9 Nov 2021
- Last updated
- 14 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442. doi: 10.1371/journal.pmed.0030442.
PubMed 17132052Conway CR, George MS, Sackeim HA. Toward an Evidence-Based, Operational Definition of Treatment-Resistant Depression: When Enough Is Enough. JAMA Psychiatry. 2017 Jan 1;74(1):9-10. doi: 10.1001/jamapsychiatry.2016.2586. No abstract available.
PubMed 27784055McIntyre RS, Filteau MJ, Martin L, Patry S, Carvalho A, Cha DS, Barakat M, Miguelez M. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014 Mar;156:1-7. doi: 10.1016/j.jad.2013.10.043. Epub 2013 Nov 15.
PubMed 24314926Schlaepfer TE, Agren H, Monteleone P, Gasto C, Pitchot W, Rouillon F, Nutt DJ, Kasper S. The hidden third: improving outcome in treatment-resistant depression. J Psychopharmacol. 2012 May;26(5):587-602. doi: 10.1177/0269881111431748. Epub 2012 Jan 11.
PubMed 22236505Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:10-7.
PubMed 11480879Kim YK, Na KS. Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Oct 3;70:117-26. doi: 10.1016/j.pnpbp.2016.03.009. Epub 2016 Apr 1.
PubMed 27046518Lener MS, Niciu MJ, Ballard ED, Park M, Park LT, Nugent AC, Zarate CA Jr. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biol Psychiatry. 2017 May 15;81(10):886-897. doi: 10.1016/j.biopsych.2016.05.005. Epub 2016 May 12.
PubMed 27449797Palucha-Poniewiera A, Pilc A. Glutamate-Based Drug Discovery for Novel Antidepressants. Expert Opin Drug Discov. 2016 Sep;11(9):873-83. doi: 10.1080/17460441.2016.1213234. Epub 2016 Aug 2.
PubMed 27409299Gerhard DM, Wohleb ES, Duman RS. Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discov Today. 2016 Mar;21(3):454-64. doi: 10.1016/j.drudis.2016.01.016. Epub 2016 Feb 6.
PubMed 26854424Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011 Jun 15;475(7354):91-5. doi: 10.1038/nature10130.
PubMed 21677641McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD011611. doi: 10.1002/14651858.CD011611.pub2.
PubMed 26415966Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Aust N Z J Psychiatry. 2013 Aug;47(8):710-27. doi: 10.1177/0004867413486842. Epub 2013 May 9.
PubMed 23661785Hu YD, Xiang YT, Fang JX, Zu S, Sha S, Shi H, Ungvari GS, Correll CU, Chiu HF, Xue Y, Tian TF, Wu AS, Ma X, Wang G. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med. 2016 Feb;46(3):623-35. doi: 10.1017/S0033291715002159. Epub 2015 Oct 19.
PubMed 26478208Iadarola ND, Niciu MJ, Richards EM, Vande Voort JL, Ballard ED, Lundin NB, Nugent AC, Machado-Vieira R, Zarate CA Jr. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis. 2015 May;6(3):97-114. doi: 10.1177/2040622315579059.
PubMed 25954495Kavalali ET, Monteggia LM. How does ketamine elicit a rapid antidepressant response? Curr Opin Pharmacol. 2015 Feb;20:35-9. doi: 10.1016/j.coph.2014.11.005. Epub 2014 Nov 25.
PubMed 25462290
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
- ClinicalTrials.gov ID
- NCT05357040
- Acronym / sponsor ID
- IRB18-1856
- Keywords
- Depression, Antidepressant, Nitrous Oxide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: PI has left the university
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Collaborators
- The Alfred
- Study start
- 30 Jun 2021 (actual)
- Primary completion
- 27 Feb 2026 (actual)
- Study completion
- 27 Feb 2026 (actual)
- First posted
- 2 May 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To evaluate the acute and sustained antidepressant effects of nitrous oxide in people with major depressive disorder; and further evaluate these effects by identifying the optimal dose and regimen to guide current practice, and to plan a future large pragmatic trial.
Detailed description
The investigators are conducting a randomized controlled trial to evaluate the antidepressant effects of nitrous oxide in people with Major Depressive Disorder (MDD). MDD is a global medical condition that causes significant health and economic burden. Recent studies have shown that a single dose of ketamine, an NMDA-antagonist, has fast and long lasting anti-depressant effect. Nitrous oxide, another NMDA-antagonist, is widely used for anesthesia and analgesia, safer to administer and has fewer side effects than ketamine.
A randomized controlled crossover feasibility study showed significant reduction in depressive symptoms at 2 and 24 hours after a single 1-hour treatment session of inhaled nitrous oxide compared with placebo. Nitrous oxide is inexpensive and can be safely administered by any trained clinician. If found to be efficacious, it could be used to provide rapid anti-depressant effect whilst the benefit of traditional anti-depressants has its delayed effect. Another potential application could be in acutely suicidal patients.
This trial will enable confirmation and extension of the findings from the feasibility study, and identify the optimal dose and regimen in a broader population of those with MDD. Participants will be randomized to receive a weekly 1-hour inhalational session of either nitrous oxide or placebo (oxygen-air mixture) for 4 weeks, and the nitrous group will be further randomly assigned to a dose of 50% or 25% nitrous oxide. Depression severity and outcomes related to treatment responses will be continuously assessed by a 'blinded-to-randomization' psychiatry (MD) rater at weekly intervals during study patient participation, using validated psychiatric diagnostics (Hamilton Depression Rating Scale-21 [HDRS-21 or HAM-D]; Profile of Mood States [POMS]; Computerized Adaptive Test-Mental Health [CAT-MH]; Sheehan-STS [S-STS]; Visual Analog Scale [VAS]).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- Parallel-group, controlled trial; randomized participants (1:1) to nitrous oxide (Nitrous group) or oxygen-air mixture (FiO2 ≈0.3, Control group). The Nitrous group will be further randomly assigned to either 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75).
| Arm | Type | Receives |
|---|---|---|
| Treatment; Nitrous Oxide 50% or 25%, group | Active comparator | Drug: Nitrous oxide gas for inhalationFour-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned. |
| Control; Oxygen-air mixture, group | Placebo comparator | Drug: PlaceboFour-weekly, 60-minute inhalation sessions of an oxygen and air mixture. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Adult (≥18 years, both sexes)
- DSM-5 criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview], MDD, defined by a pre-treatment score >16 on the HDRS-21 scale and meeting DSM-5 for MDD
Key exclusion criteria (9 listed)
- A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
- Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
- Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
- Active or recent (<12 months) substance use disorder; excluding nicotine
- Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitrous oxide gas for inhalationAlso: N2O, Laughing gas, Nitrous Oxide, Nitrous60-minute sessions of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75), administered weekly for 4-weeks. Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide. | Drug | Treatment; Nitrous Oxide 50% or 25%, group |
| Placebo60-minute sessions of inhaled oxygen-air mixture (FiO2 ≈0.3) to be administered weekly for 4-weeks. Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide. | Drug | Control; Oxygen-air mixture, group |
Primary outcome
Change in HDRS-21 score
Time frame: Over 4-weeks from baseline
Monitor changes in Hamilton Depression Rating Scale-21 (HDRS-21) scores to determine whether a series of four, 60-minute sessions of inhaled nitrous oxide vs placebo (once-per-week) has significant antidepressant activity. The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire. Higher scores are associated with more severe depression: 0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52
11 secondary outcomes
Treatment response
Time frame: At 24-hours (following treatment-1)
Changes in 'Profile of Mood States' scores
Time frame: Up to 1-week (following treatment-1)
Sustainability of treatment response
Time frame: Over 7-weeks (length of study participation).
Treatment dose response comparison
Time frame: Over 7-weeks (length of study participation)
Treatment cycle compliance
Time frame: Over 4-weeks (weekly treatment sessions)
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
Time frame: Over 7-weeks (length of study participation) from Baseline
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
Time frame: Over 7-weeks (length of study participation) from Baseline
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
Time frame: Over 7-weeks (length of study participation) from Baseline
Suicidal ideation tracking
Time frame: Over 7-weeks (length of study participation) from Baseline
Visual Analog Scale (VAS)
Time frame: At Baseline (Prior to treatment-1)
Treatment remission
Time frame: At 24-hours (following treatment-1)
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2026.
- Background: PubMed 17132052Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442. doi: 10.1371/journal.pmed.0030442.
- Background: PubMed 27784055Conway CR, George MS, Sackeim HA. Toward an Evidence-Based, Operational Definition of Treatment-Resistant Depression: When Enough Is Enough. JAMA Psychiatry. 2017 Jan 1;74(1):9-10. doi: 10.1001/jamapsychiatry.2016.2586. No abstract available.
- Background: PubMed 24314926McIntyre RS, Filteau MJ, Martin L, Patry S, Carvalho A, Cha DS, Barakat M, Miguelez M. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014 Mar;156:1-7. doi: 10.1016/j.jad.2013.10.043. Epub 2013 Nov 15.
- Background: PubMed 22236505Schlaepfer TE, Agren H, Monteleone P, Gasto C, Pitchot W, Rouillon F, Nutt DJ, Kasper S. The hidden third: improving outcome in treatment-resistant depression. J Psychopharmacol. 2012 May;26(5):587-602. doi: 10.1177/0269881111431748. Epub 2012 Jan 11.
- Background: PubMed 11480879Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:10-7.
- Background: PubMed 27046518Kim YK, Na KS. Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Oct 3;70:117-26. doi: 10.1016/j.pnpbp.2016.03.009. Epub 2016 Apr 1.
- Background: PubMed 27449797Lener MS, Niciu MJ, Ballard ED, Park M, Park LT, Nugent AC, Zarate CA Jr. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biol Psychiatry. 2017 May 15;81(10):886-897. doi: 10.1016/j.biopsych.2016.05.005. Epub 2016 May 12.
- Background: PubMed 27409299Palucha-Poniewiera A, Pilc A. Glutamate-Based Drug Discovery for Novel Antidepressants. Expert Opin Drug Discov. 2016 Sep;11(9):873-83. doi: 10.1080/17460441.2016.1213234. Epub 2016 Aug 2.
- Background: PubMed 26854424Gerhard DM, Wohleb ES, Duman RS. Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discov Today. 2016 Mar;21(3):454-64. doi: 10.1016/j.drudis.2016.01.016. Epub 2016 Feb 6.
- Background: PubMed 21677641Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011 Jun 15;475(7354):91-5. doi: 10.1038/nature10130.
- Background: PubMed 26415966McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD011611. doi: 10.1002/14651858.CD011611.pub2.
- Background: PubMed 23661785Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Aust N Z J Psychiatry. 2013 Aug;47(8):710-27. doi: 10.1177/0004867413486842. Epub 2013 May 9.
- Individual participant dataSharing planned: No
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Assessing of Behavioral Risk and Response to Electromagnetic and Psychedelic Therapies
PTSD, PTSD - Post Traumatic Stress Disorder
RecruitingPhase 2
A Study to Evaluate TNX-102 SL Monotherapy Versus Placebo in Participants With Major Depressive Disorder (MDD)
Major Depressive Episode (MDE), Major Depressive Disorder (MDD)
RecruitingPhase 1
Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
Depression, Major Depressive Disorder
Not yet recruiting
Acceptance and Committment Therapy Combined With Ketamine in Difficult-to-Treat Depression.
Major Depressive Disorder (MDD)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Nagele, MD, MSc principal investigator
University of Chicago, Department of Anesthesia and Critical Care
Paul Myles, MD principal investigator
The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitrous oxide gas for inhalation in people with Major Depressive Disorder and Treatment Resistant Depression, run by University of Chicago at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 14 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in HDRS-21 score (time frame: Over 4-weeks from baseline). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05357040, which also lists 36 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2026.