Antidepressant Effects of Nitrous Oxide

Major Depressive Disorder Clinical Trial

Official title:

Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05357040
• Other study ID #: IRB18-1856
• Status: Recruiting
• Phase: Phase 2
• Start date: June 30, 2021
• Est. completion date: August 1, 2025

Study information

• Verified date: May 2024
• Source: University of Chicago
• Contact: Frank Brown Jr
• Phone: 773-834-5778
• Email: fbrown[@]dacc.uchicago.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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]).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 172
• Est. completion date: August 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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).

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Depressive Disorder, Treatment-Resistant
• Major Depressive Disorder
• Treatment Resistant Depression

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
Australia	The Alfred Hospital	Melbourne	Victoria
United States	University of Chicago Medicine	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
University of Chicago	The Alfred

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (36)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Djulbegovic B, Hozo I, Ioannidis JP. Improving the drug development process: more not less randomized trials. JAMA. 2014 Jan 22-29;311(4):355-6. doi: 10.1001/jama.2013.283742. No abstract available. — View Citation

Furukawa TA, Akechi T, Azuma H, Okuyama T, Higuchi T. Evidence-based guidelines for interpretation of the Hamilton Rating Scale for Depression. J Clin Psychopharmacol. 2007 Oct;27(5):531-4. doi: 10.1097/JCP.0b013e31814f30b1. No abstract available. — View Citation

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. — View Citation

Gibbons RD, Kupfer D, Frank E, Moore T, Beiser DG, Boudreaux ED. Development of a Computerized Adaptive Test Suicide Scale-The CAT-SS. J Clin Psychiatry. 2017 Nov/Dec;78(9):1376-1382. doi: 10.4088/JCP.16m10922. — View Citation

Gibbons RD, Weiss DJ, Pilkonis PA, Frank E, Moore T, Kim JB, Kupfer DJ. Development of a computerized adaptive test for depression. Arch Gen Psychiatry. 2012 Nov;69(11):1104-12. doi: 10.1001/archgenpsychiatry.2012.14. Erratum In: Arch Gen Psychiatry. 2013 Jan;70(1):30. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Kyle PR, Lemming OM, Timmerby N, Sondergaard S, Andreasson K, Bech P. The Validity of the Different Versions of the Hamilton Depression Scale in Separating Remission Rates of Placebo and Antidepressants in Clinical Trials of Major Depression. J Clin Psychopharmacol. 2016 Oct;36(5):453-6. doi: 10.1097/JCP.0000000000000557. — View Citation

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. — View Citation

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. — View Citation

Leucht S, Fennema H, Engel R, Kaspers-Janssen M, Lepping P, Szegedi A. What does the HAMD mean? J Affect Disord. 2013 Jun;148(2-3):243-8. doi: 10.1016/j.jad.2012.12.001. Epub 2013 Jan 26. — View Citation

Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, Xia G, Tendler A, Daskalakis ZJ, Winston JL, Dannon P, Hafez HM, Reti IM, Morales OG, Schlaepfer TE, Hollander E, Berman JA, Husain MM, Sofer U, Stein A, Adler S, Deutsch L, Deutsch F, Roth Y, George MS, Zangen A. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry. 2015 Feb;14(1):64-73. doi: 10.1002/wps.20199. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:10-7. — View Citation

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. — View Citation

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. — View Citation

Snaith RP. Present use of the Hamilton Depression Rating Scale: observation on method of assessment in research of depressive disorders. Br J Psychiatry. 1996 May;168(5):594-7. doi: 10.1192/bjp.168.5.594. — View Citation

Ueno F, Nakajima S, Suzuki T, Abe T, Sato Y, Mimura M, Uchida H. Whether to increase or maintain dosage of mirtazapine in early nonimprovers with depression. J Clin Psychiatry. 2015 Apr;76(4):434-9. doi: 10.4088/JCP.14m09201. — View Citation

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. — View Citation

* Note: There are 36 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events	Psychiatric AEs, such as new suicidal ideation and psychotic symptoms; AEs such as nausea and vomiting; or any other AEs determined probably, possibly, or unrelated to the study intervention.; Study patient safety is monitored by the investigators (MD) with experience in critical care anesthesia, and psychiatry, as well as an experienced clinical research team responsible for monitoring and reporting events.	Over 7-weeks (length of study participation).
Primary	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	Over 4-weeks from baseline
Secondary	Treatment response	Treatment response (=50% reduction on HDRS-21) to nitrous oxide vs placebo will be measured.	At 24-hours (following treatment-1)
Secondary	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	Up to 1-week (following treatment-1)
Secondary	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	Over 7-weeks (length of study participation).
Secondary	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.	Over 7-weeks (length of study participation)
Secondary	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).	Over 4-weeks (weekly treatment sessions)
Secondary	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	Over 7-weeks (length of study participation) from Baseline
Secondary	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	Over 7-weeks (length of study participation) from Baseline
Secondary	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	Over 7-weeks (length of study participation) from Baseline
Secondary	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.	Over 7-weeks (length of study participation) from Baseline
Secondary	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).	At Baseline (Prior to treatment-1)
Secondary	Treatment remission	Treatment remission (HDRS-21 =7 points) to nitrous oxide vs. placebo will be measured.	At 24-hours (following treatment-1)