Bipolar DisorderPhase 2NCT02351869
Nitrous Oxide as a Putative Novel Dual-Mechanism Treatment for Bipolar Disorder
A Phase 2 study testing Nitrous Oxide and Midazolam in people with Bipolar Disorder, run by Sunnybrook Health Sciences Centre at 1 site in Canada.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 20 to 60 years
- Conditions the study is for
- Bipolar Disorder
- What is being tested?
- Nitrous Oxide and Midazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 1 siteCanada
- Study dates
- Aug 2015to 7 Jun 2020
- 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 20 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
- Conditions
- Bipolar Disorder
- Being tested
- Nitrous Oxide, Midazolam
- Medical subject headings
- Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitrous OxideDrug
MidazolamDrug
| Study group | Role | What they receive |
|---|---|---|
| Nitrous oxide | Active comparator | 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. Receives: Drug: Nitrous Oxide |
| Midazolam | Placebo comparator | 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). Receives: Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (18)
Young Mania Rating Scale (YMRS)
Measures symptom severity
Measured: 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: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
Weight
Measured: Assessed an average of 3 days after baseline
Beck Depression Inventory (BDI-II)
Self-report measure of mood severity
Measured: Assessed on the drug administration day and followed for 7 days post-drug administration
Heart Rate
Measured: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
Brief Psychiatric Rating Scale
Measured: Assessed on the drug administration day and followed for 7 days post-drug administration
The Clinician Administered Dissociative States Scale (CADSS)
Measured: Assessed on the drug administration day and followed for 7 days post-drug administration
General Information Sheet (Demographics)
Demographics
Measured: Collected at baseline
Hamilton Anxiety Rating Scale (HAM-A)
Interview measure used to assess anxiety severity
Measured: 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
Measured: 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
Measured: 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
Measured: Assessed an average of 3 days after baseline
Structured Clinical Interview for DSM Disorders
Interview measure used to assess DSM disorders
Measured: Assessed at baseline
Visual Analogue Scale
Measured: Assessed on the drug administration day and followed for 7 days post-drug administration
Height
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Assessed an average of 3 days after baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2015 (estimated)
- Study startAug 2015
- Primary completion1 Feb 2020
- Study completion7 Jun 2020
Why it stopped: This study was terminated due to COVID-19 pandemic-related halting of recruitment in the context of an upcoming replacement of the study MRI scanner.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by Sunnybrook Health Sciences CentreThe 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
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sunnybrook Health Sciences Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Benjamin Goldstein, Sunnybrook Health Sciences Centre
- Investigators
- Benjamin I Goldstein, MD, Principal investigator, Sunnybrook Health Sciences Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02351869
- Sponsor's protocol ID
- 435-2013
- Status last verified
- Apr 2023
- First submitted
- 2 Dec 2014
- Last updated
- 6 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 32637725Kim 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. 2023 May;25(3):221-232. doi: 10.1111/bdi.13288. Epub 2023 Jan 5.
PubMed 36579458
Study at a glance
From the registry record, last updated by the sponsor on 6 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nitrous Oxide as a Putative Novel Dual-Mechanism Treatment for Bipolar Disorder
- ClinicalTrials.gov ID
- NCT02351869
- Acronym / sponsor ID
- 435-2013
- Conditions
- Bipolar Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: This study was terminated due to COVID-19 pandemic-related halting of recruitment in the context of an upcoming replacement of the study MRI scanner.
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Sunnybrook Health Sciences CentreUniversity, hospital or other
- Study start
- Aug 2015
- Primary completion
- 1 Feb 2020 (actual)
- Study completion
- 7 Jun 2020 (actual)
- First posted
- 30 Jan 2015 (estimated)
- 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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitrous oxide | Active comparator | Drug: Nitrous OxideN2O-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. |
| Midazolam | Placebo comparator | Drug: MidazolamInhaled 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). |
Who may qualify
- Ages
- 20 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- 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).
Key exclusion criteria (1 listed)
- 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.
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 | Drug | Nitrous oxide |
| Midazolam | Drug | Midazolam |
Primary outcome
Change in Montgomery-Asberg Depression Scale (MADRS) score
Time frame: 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
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.
18 secondary outcomes
Young Mania Rating Scale (YMRS)
Time frame: 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
Time frame: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
Weight
Time frame: Assessed an average of 3 days after baseline
Beck Depression Inventory (BDI-II)
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
Heart Rate
Time frame: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
Brief Psychiatric Rating Scale
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
The Clinician Administered Dissociative States Scale (CADSS)
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
General Information Sheet (Demographics)
Time frame: Collected at baseline
Hamilton Anxiety Rating Scale (HAM-A)
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
Hamilton Depression Rating Scale (HDRS)
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
Patient Rated Inventory of Side Effects
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
CANTAB Medication Listing
Time frame: Assessed an average of 3 days after baseline
Structured Clinical Interview for DSM Disorders
Time frame: Assessed at baseline
Visual Analogue Scale
Time frame: Assessed on the drug administration day and followed for 7 days post-drug administration
Height
Time frame: Assessed an average of 3 days after baseline
Endothelial Function assessed via RH-PAT using the EndoPAT.
Time frame: Assessed an average of 3 days after baseline and lasts approximately 30 minutes
Frontal Perfusion assessed using an MRI scan
Time frame: Assessed approximately 5 days after baseline and post-drug administration
Biomarkers (B12 and nitric oxide (NO))
Time frame: Assessed an average of 3 days after baseline
Results and safety
The study was stopped early (reason given: This study was terminated due to COVID-19 pandemic-related halting of recruitment in the context of an upcoming replacement of the study MRI scanner.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Apr 2023.
- Results publication: PubMed 32637725Dimick 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.
- Results publication: PubMed 36579458Kim 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. 2023 May;25(3):221-232. doi: 10.1111/bdi.13288. Epub 2023 Jan 5.
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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.
Benjamin I Goldstein, MD principal investigator
Sunnybrook Health Sciences Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitrous Oxide and Midazolam in people with Bipolar Disorder, run by Sunnybrook Health Sciences Centre at 1 site in Canada.
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 1 inclusion and 1 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: stopped early, as of the sponsor's last update on 6 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. 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 stopped early (reason given: This study was terminated due to COVID-19 pandemic-related halting of recruitment in the context of an upcoming replacement of the study MRI scanner.). Results are not available in the source record.
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 Montgomery-Asberg Depression Scale (MADRS) score (time frame: 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). 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 NCT02351869, which also lists 2 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 6 Apr 2023.