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

Sunnybrook Health Sciences Centre

Status and phase: Terminated; Phase 2

Conditions: Bipolar Disorder

Treatments: Drug: Midazolam; Drug: Nitrous Oxide

Study type: Interventional

Funder types: Other

Identifiers

NCT02351869

435-2013

Details and patient eligibility

About

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.

Enrollment: 25 patients

Sex: All

Ages: 20 to 60 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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25 participants in 2 patient groups, including a placebo group

Nitrous oxide

Active Comparator group

Description:

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.

Treatment:

Drug: Nitrous Oxide

Midazolam

Placebo Comparator group

Description:

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).

Treatment:

Drug: Midazolam