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

Study Overview
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Brief Summary
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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.

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

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Nitrous Oxide
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nitrous oxide<br>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<br> <br> |
| Placebo Comparator: Midazolam<br>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<br> <br> |

What is the study measuring?
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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 |