Nitrous Oxide as a Putative Novel Dual-Mechanism Treatment for Bipolar Disorder

This study is a 7-day randomized, double-blind proof-of-concept pilot study of nitrous oxide vs. midazolam in 40 adults (20-60 years) with bipolar disorder (BD) (type I or II). Ongoing pharmacological and psychosocial treatments may continue, provided that they have not been initiated or significantly modified in the preceding 2 weeks. Participants' current treatment as prescribed by clinical psychiatrists will not be modified or interfered in this study. The study involves 3 visits. During study visit 1, participants will complete screening to ensure study eligibility. This will be done using interview measures. During study visit 2, participants will complete anthropomorphic measurements, measurement of endothelial function, screening blood work, ECGs, and an anaesthesia screener. During study visit 3, participants will receive the treatment (nitrous oxide or midazolam), complete an MRI scan, and complete interview measures and self-reports. There will be anthropomorphic measurements taken as well. The participant will be required to complete phone interviews and self-reports over the subsequent 7 days. There are 4 main predictions: 1. Nitrous oxide will significantly reduce depression symptoms vs. midazolam. 2. Nitrous oxide will significantly increase frontal cortical perfusion vs. midazolam. 3. Lower perfusion in frontal cortical regions at baseline will be associated with greater improvement in depression symptoms following nitrous oxide treatment. 4. Poorer endothelial function will be associated with greater improvement in depression symptoms following nitrous oxide treatment.

Study Overview

• Status: Terminated
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: Midazolam; Drug: Nitrous Oxide

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

English-speaking; age 20-60 years; BD-I or BD-II, current major depressive episode ≥4 weeks duration; MADRS≥22; taking ≥1 mood stabilizing medication/s (i.e. antimanic anticonvulsant, antipsychotic, and/or lithium).

Exclusion Criteria:

New medications or changes in dosing, or ECT or TMS, in the preceding 2 weeks; MADRS item 10, > 4; YMRS≥12; acute significant suicidality; psychosis; substance abuse (past 3 months); active major medical conditions (hepatic, renal, respiratory, or cardio/cerebrovascular disease; diabetes; esophageal reflux; sleep apnea); B12 deficiency/disorders; pregnant; MRI contraindications; history of adverse anaesthetic reactions; anaesthesia class >2; scuba diving in preceding week.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nitrous oxide; N2O-condition participants will inhale an initial mixture of 10% N2O in oxygen (O2) for 5 minutes, followed by 25% N2O in O2 for 20 minutes. N2O-condition participants will also receive 5ml intravenous saline concomitantly with 10% N2O, and again with 25% N2O.	Drug: Nitrous Oxide
Placebo Comparator: Midazolam; Inhaled room air plus intravenous midazolam bolus (total 2mg). Midazolam-condition participants will receive intravenous infusions of 0.5mg midazolam in 5ml saline (start of 1st inhalation epoch), followed by 1.5mg midazolam in 5ml saline (start of 2nd inhalation epoch).	Drug: Midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Montgomery-Asberg Depression Scale (MADRS) score	Measures mood symptom severity, used to select patients and assess treatment efficacy. Although other time-points will be examined, 24h was selected as the primary outcome to minimize the impact of acute sedation and psychoactive effects.	Assessed at baseline, an average of 3 days later, again at up to 5 days after baseline on the day of drug administration, and participants will be followed for 7 days after the drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Young Mania Rating Scale (YMRS)	Measures symptom severity	Assessed at baseline, an average of 3 days later, again at up to 5 days after baseline on the day of drug administration, and participants will be followed for 7 days after the drug administration
Blood Pressure		Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
Weight		Assessed an average of 3 days after baseline
Beck Depression Inventory (BDI-II)	Self-report measure of mood severity	Assessed on the drug administration day and followed for 7 days post-drug administration
Heart Rate		Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
Brief Psychiatric Rating Scale		Assessed on the drug administration day and followed for 7 days post-drug administration
The Clinician Administered Dissociative States Scale (CADSS)		Assessed on the drug administration day and followed for 7 days post-drug administration
General Information Sheet (Demographics)	Demographics	Collected at baseline
Hamilton Anxiety Rating Scale (HAM-A)	Interview measure used to assess anxiety severity	Assessed on the drug administration day and followed for 7 days post-drug administration
Hamilton Depression Rating Scale (HDRS)	Interview measure used to assess mood severity	Assessed on the drug administration day and followed for 7 days post-drug administration
Patient Rated Inventory of Side Effects	Self-report used to assess side effects	Assessed on the drug administration day and followed for 7 days post-drug administration
CANTAB Medication Listing	Used to collect medications taken the day before and on the day of blood work	Assessed an average of 3 days after baseline
Structured Clinical Interview for DSM Disorders	Interview measure used to assess DSM disorders	Assessed at baseline
Visual Analogue Scale		Assessed on the drug administration day and followed for 7 days post-drug administration
Height		Assessed an average of 3 days after baseline
Endothelial Function assessed via RH-PAT using the EndoPAT.	Will be assessed via RH-PAT using the EndoPAT.	Assessed an average of 3 days after baseline and lasts approximately 30 minutes
Frontal Perfusion assessed using an MRI scan	Will be assessed using an MRI scan.	Assessed approximately 5 days after baseline and post-drug administration
Biomarkers (B12 and nitric oxide (NO))	B12 and nitric oxide (NO) will be examined as predictors of response owing to known associations with the mechanism of action of N2O.	Assessed an average of 3 days after baseline

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre

Publications and helpful links

General Publications

• Dimick MK, Omrin D, MacIntosh BJ, Mitchell RHB, Riegert D, Levitt A, Schaffer A, Belo S, Iazzetta J, Detzler G, Choi M, Choi S, Orser BA, Goldstein BI. Nitrous oxide as a putative novel dual-mechanism treatment for bipolar depression: Proof-of-concept study design and methodology. Contemp Clin Trials Commun. 2020 Jun 23;19:100600. doi: 10.1016/j.conctc.2020.100600. eCollection 2020 Sep.
• Kim WSH, Dimick MK, Omrin D, Mitchell RHB, Riegert D, Levitt A, Schaffer A, Belo S, Iazzetta J, Detzler G, Choi M, Choi S, Herrmann N, McIntyre RS, MacIntosh BJ, Orser BA, Goldstein BI. Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement. Bipolar Disord. 2022 Dec 29. doi: 10.1111/bdi.13288. Online ahead of print.

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): February 1, 2020
• Study Completion (Actual): June 7, 2020

Study Registration Dates

• First Submitted: December 2, 2014
• First Submitted That Met QC Criteria: January 29, 2015
• First Posted (Estimate): January 30, 2015

Study Record Updates

• Last Update Posted (Actual): April 6, 2023
• Last Update Submitted That Met QC Criteria: April 4, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Bipolar and Related Disorders; Bipolar Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anesthetics, Inhalation; Midazolam; Nitrous Oxide
• Other Study ID Numbers: 435-2013