Clinical trial NCT02351869: Nitrous Oxide as a Putative Novel Dual-Mechanism Treatment for Bipolar Disorder
Official title: Nitrous Oxide as a Putative Novel Dual-Mechanism Treatment for Bipolar Disorder
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Bipolar Disorder
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
First posted: 2015-01-30
Enrollment: 25
Sex: ALL
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in Montgomery-Asberg Depression Scale (MADRS) score
timeFrame: 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:
measure: Young Mania Rating Scale (YMRS)
timeFrame: 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
measure: Blood Pressure
timeFrame: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
measure: Weight
timeFrame: Assessed an average of 3 days after baseline
measure: Beck Depression Inventory (BDI-II)
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: Heart Rate
timeFrame: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day
measure: Brief Psychiatric Rating Scale
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: The Clinician Administered Dissociative States Scale (CADSS)
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: General Information Sheet (Demographics)
timeFrame: Collected at baseline
measure: Hamilton Anxiety Rating Scale (HAM-A)
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: Hamilton Depression Rating Scale (HDRS)
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: Patient Rated Inventory of Side Effects
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: CANTAB Medication Listing
timeFrame: Assessed an average of 3 days after baseline
measure: Structured Clinical Interview for DSM Disorders
timeFrame: Assessed at baseline
measure: Visual Analogue Scale
timeFrame: Assessed on the drug administration day and followed for 7 days post-drug administration
measure: Height
timeFrame: Assessed an average of 3 days after baseline
measure: Endothelial Function assessed via RH-PAT using the EndoPAT.
timeFrame: Assessed an average of 3 days after baseline and lasts approximately 30 minutes
measure: Frontal Perfusion assessed using an MRI scan
timeFrame: Assessed approximately 5 days after baseline and post-drug administration
measure: Biomarkers (B12 and nitric oxide (NO))
timeFrame: Assessed an average of 3 days after baseline
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Benjamin I Goldstein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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. 2023 May;25(3):221-232. doi: 10.1111/bdi.13288. Epub 2023 Jan 5.