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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05357040




Registration number
NCT05357040
Ethics application status
Date submitted
9/11/2021
Date registered
2/05/2022
Date last updated
8/05/2024

Titles & IDs
Public title
Antidepressant Effects of Nitrous Oxide
Scientific title
Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
Secondary ID [1] 0 0
IRB18-1856
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 0 0
Treatment Resistant Depression 0 0
Condition category
Condition code
Mental Health 0 0 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Nitrous oxide gas for inhalation
Treatment: Drugs - Placebo

Active comparator: Treatment; Nitrous Oxide 50% or 25%, group - Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.

Placebo comparator: Control; Oxygen-air mixture, group - Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.


Treatment: Drugs: Nitrous oxide gas for inhalation
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.

Treatment: Drugs: Placebo
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in HDRS-21 score
Timepoint [1] 0 0
Over 4-weeks from baseline
Secondary outcome [1] 0 0
Treatment response
Timepoint [1] 0 0
At 24-hours (following treatment-1)
Secondary outcome [2] 0 0
Changes in 'Profile of Mood States' scores
Timepoint [2] 0 0
Up to 1-week (following treatment-1)
Secondary outcome [3] 0 0
Sustainability of treatment response
Timepoint [3] 0 0
Over 7-weeks (length of study participation).
Secondary outcome [4] 0 0
Treatment dose response comparison
Timepoint [4] 0 0
Over 7-weeks (length of study participation)
Secondary outcome [5] 0 0
Treatment cycle compliance
Timepoint [5] 0 0
Over 4-weeks (weekly treatment sessions)
Secondary outcome [6] 0 0
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
Timepoint [6] 0 0
Over 7-weeks (length of study participation) from Baseline
Secondary outcome [7] 0 0
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
Timepoint [7] 0 0
Over 7-weeks (length of study participation) from Baseline
Secondary outcome [8] 0 0
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
Timepoint [8] 0 0
Over 7-weeks (length of study participation) from Baseline
Secondary outcome [9] 0 0
Suicidal ideation tracking
Timepoint [9] 0 0
Over 7-weeks (length of study participation) from Baseline
Secondary outcome [10] 0 0
Visual Analog Scale (VAS)
Timepoint [10] 0 0
At Baseline (Prior to treatment-1)
Secondary outcome [11] 0 0
Treatment remission
Timepoint [11] 0 0
At 24-hours (following treatment-1)

Eligibility
Key inclusion criteria
1. Adult (=18 years, both sexes)
2. 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
2. Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
3. Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
4. Active or recent (<12 months) substance use disorder; excluding nicotine
5. Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
6. Ongoing treatment with ECT
7. Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
8. Pregnancy or breastfeeding
9. 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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/06/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/08/2025
Actual
Sample size
Target
172
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
The Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Illinois

Funding & Sponsors
Primary sponsor type
Other
Name
University of Chicago
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
The Alfred
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/study/NCT05357040
Trial related presentations / publications
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Conway 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.
McIntyre 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.
Schlaepfer 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.
Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:10-7.
Kim 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.
Lener 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.
Palucha-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.
Gerhard 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.
Autry 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.
McCloud 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.
Katalinic 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.
Hu 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.
Iadarola 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. Erratum In: Ther Adv Chronic Dis. 2016 May;7(3):184. doi: 10.1177/2040622316650349.
Kavalali 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.
Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014 Apr;4(2):75-99. doi: 10.1177/2045125313507739.
Lenze EJ, Farber NB, Kharasch E, Schweiger J, Yingling M, Olney J, Newcomer JW. Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J Biol Psychiatry. 2016 Apr;17(3):230-8. doi: 10.3109/15622975.2016.1142607. Epub 2016 Feb 26.
Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology (Berl). 2006 Nov;188(4):408-24. doi: 10.1007/s00213-006-0572-3. Epub 2006 Sep 28.
Morgan CJ, Curran HV; Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 2012 Jan;107(1):27-38. doi: 10.1111/j.1360-0443.2011.03576.x. Epub 2011 Jul 22.
Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008 Oct;109(4):707-22. doi: 10.1097/ALN.0b013e3181870a17.
Nagele P, Metz LB, Crowder CM. Nitrous oxide (N(2)O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8791-6. doi: 10.1073/pnas.0402825101. Epub 2004 May 24.
Zorumski CF, Nagele P, Mennerick S, Conway CR. Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy. Front Psychiatry. 2015 Dec 9;6:172. doi: 10.3389/fpsyt.2015.00172. eCollection 2015.
Certosimo F, Walton M, Hartzell D, Farris J. Clinical evaluation of the efficacy of three nitrous oxide scavenging units during dental treatment. Gen Dent. 2002 Sep-Oct;50(5):430-5.
Myles PS, Leslie K, Chan MT, Forbes A, Peyton PJ, Paech MJ, Beattie WS, Sessler DI, Devereaux PJ, Silbert B, Schricker T, Wallace S; ANZCA Trials Group for the ENIGMA-II investigators. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet. 2014 Oct 18;384(9952):1446-54. doi: 10.1016/S0140-6736(14)60893-X.
Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E; ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology. 2007 Aug;107(2):221-31. doi: 10.1097/01.anes.0000270723.30772.da.
Nagele P, Brown F, Francis A, Scott MG, Gage BF, Miller JP; VINO Study Team. Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial. Anesthesiology. 2013 Jul;119(1):19-28. doi: 10.1097/ALN.0b013e31829761e3.
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Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, Janski A, Panagopoulos VN, Cristancho P, Miller JP, Zorumski CF, Conway CR. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biol Psychiatry. 2015 Jul 1;78(1):10-18. doi: 10.1016/j.biopsych.2014.11.016. Epub 2014 Dec 9.
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Public notes

Contacts
Principal investigator
Name 0 0
Peter Nagele, MD, MSc
Address 0 0
University of Chicago, Department of Anesthesia and Critical Care
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Frank Brown Jr
Address 0 0
Country 0 0
Phone 0 0
773-834-5778
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05357040