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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02351869
Recruitment Status : Terminated (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.)
First Posted : January 30, 2015
Last Update Posted : June 24, 2020
Sponsor:
Information provided by (Responsible Party):
Dr. Benjamin Goldstein, Sunnybrook Health Sciences Centre

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.

Condition or disease Intervention/treatment Phase
Bipolar Disorder Drug: Nitrous Oxide Drug: Midazolam Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Nitrous Oxide as a Putative Novel Dual-Mechanism Treatment for Bipolar Disorder
Study Start Date : August 2015
Actual Primary Completion Date : February 1, 2020
Actual Study Completion Date : June 7, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bipolar Disorder

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



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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 ]
    Measures symptom severity

  2. Blood Pressure [ Time Frame: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day ]
  3. Weight [ Time Frame: Assessed an average of 3 days after baseline ]
  4. Beck Depression Inventory (BDI-II) [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
    Self-report measure of mood severity

  5. Heart Rate [ Time Frame: Measured an average of 3 days post-baseline and again approximately every hour on the drug administration day ]
  6. Brief Psychiatric Rating Scale [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
  7. The Clinician Administered Dissociative States Scale (CADSS) [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
  8. General Information Sheet (Demographics) [ Time Frame: Collected at baseline ]
    Demographics

  9. Hamilton Anxiety Rating Scale (HAM-A) [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
    Interview measure used to assess anxiety severity

  10. Hamilton Depression Rating Scale (HDRS) [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
    Interview measure used to assess mood severity

  11. Patient Rated Inventory of Side Effects [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
    Self-report used to assess side effects

  12. CANTAB Medication Listing [ Time Frame: Assessed an average of 3 days after baseline ]
    Used to collect medications taken the day before and on the day of blood work

  13. Structured Clinical Interview for DSM Disorders [ Time Frame: Assessed at baseline ]
    Interview measure used to assess DSM disorders

  14. Visual Analogue Scale [ Time Frame: Assessed on the drug administration day and followed for 7 days post-drug administration ]
  15. Height [ Time Frame: Assessed an average of 3 days after baseline ]
  16. Endothelial Function assessed via RH-PAT using the EndoPAT. [ Time Frame: Assessed an average of 3 days after baseline and lasts approximately 30 minutes ]
    Will be assessed via RH-PAT using the EndoPAT.

  17. Frontal Perfusion assessed using an MRI scan [ Time Frame: Assessed approximately 5 days after baseline and post-drug administration ]
    Will be assessed using an MRI scan.

  18. Biomarkers (B12 and nitric oxide (NO)) [ Time Frame: Assessed an average of 3 days after baseline ]
    B12 and nitric oxide (NO) will be examined as predictors of response owing to known associations with the mechanism of action of N2O.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02351869


Locations
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Canada, Ontario
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Investigators
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Principal Investigator: Benjamin I Goldstein, MD Sunnybrook Health Sciences Centre
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Responsible Party: Dr. Benjamin Goldstein, Associate Professor, University of Toronto, Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT02351869    
Other Study ID Numbers: 435-2013
First Posted: January 30, 2015    Key Record Dates
Last Update Posted: June 24, 2020
Last Verified: June 2020
Additional relevant MeSH terms:
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Bipolar Disorder
Bipolar and Related Disorders
Mental Disorders
Midazolam
Nitrous Oxide
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anesthetics, Inhalation
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents