N2O for Acute Suicidality and Depression in the ED

Study Overview
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Brief Summary
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Investigators are conducting this double-blind, randomized control trial (RCT), to compare inhaled N2O+ treatment as usual (TAU) versus inhaled placebo+TAU; demonstrating the feasibility and tolerability of the intervention in an emergency department (ED) setting on an acutely suicidal population.

Detailed Description
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Past studies have shown that a single dose of ketamine, an NMDA- receptor antagonist has fast and long lasting anti-depressant effect. Although a promising antidepressant and potential anti-suicidal agent, ketamine has very significant side effects including: dissociation, hallucinations, delusional thinking, cognitive impairment, and significant sympathetic nervous system activation. Nitrous Oxide (N2O) is an NMDA-receptor antagonist with a well-known safety profile used as an analgesic. In a proof-of-concept pilot study, this study's investigator recently demonstrated that N2O also has rapid and marked antidepressant effects in patients with severe treatment-resistant depression (TRD); further sub-analyses showed N2O significantly reduced suicidal ideation (SI). While N2O administration may lead to a reduction in SI, it remains unknown whether severely suicidal patients requiring hospitalization on inpatient psychiatric units would benefit. Investigators hypothesize that N2O will rapidly and safely dampen suicidal thinking with minimal side effects in this population. Participants will be randomized to receive either N2O or placebo. The study intervention is in tandem with prescribed treatment-as-usual (TAU) by emergency department physicians relating to diagnosis (depression, anxiety, suicidal ideation); which typically involves anxiolytic medications and/or brief psychotherapy administered by care team psychiatry providers. Study intervention response will be assessed using a self-administered psychiatric diagnostic tool (Computerized Adaptive Testing Mental Health [CAT-MH] scores relating to suicide, depression, and anxiety; to determine whether a single 45-minute inhalation of nitrous oxide vs placebo reduces symptoms.

Official Title
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Inhaled Nitrous Oxide for Acute Suicidality and Depression in the Emergency Department

Conditions
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Suicidal Ideation, Major Depressive Disorder, Treatment Resistant Depression

Intervention / Treatment
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* Drug: Nitrous oxide gas for inhalation
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18-65 years of age, acutely suicidal, presenting to the adult emergency department with documented history of non-psychotic major depressive disorder. Exclusion Criteria: Current psychotic or catatonic symptoms as determined by the hospital care team. Unable or unwilling to give consent for study participation (ability to provide consent will be established by treating physician) Lifetime DSM-V (medical history) diagnoses of schizophrenia, schizoaffective disorders, bipolar disorder, obsessive-compulsive disorder, and panic disorders. Meets current DSM-V substance use disorder of greater than mild severity (other than nicotine or marijuana) Significant pulmonary disease and/or requiring supplemental oxygen. Administration of other NMDA-receptor antagonist treatment (e.g., ketamine) within two weeks of entry into study. Contraindications for N2O (pneumothorax, bowel obstruction, middle ear occlusion, elevated intracranial pressure) Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12. Women who are pregnant or breastfeeding Any other factor that in the investigators' judgment may affect patient safety or compliance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: Participants are randomly assigned to one of two treatment arms (nitrous vs placebo). Dosing includes a single inhalation session of either 50% Nitrous oxide in oxygen mixture (FiO2 0.5) vs placebo (oxygen-air mixture FiO2 ≈0.3).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment; Nitrous Oxide 50%<br>A single 45-minute session of inhaled 50% nitrous oxide. | Drug: Nitrous oxide gas for inhalation<br>* Administration of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.<br>* Other names: Laughing Gas;|
| Placebo Comparator: Control; Oxygen-air mixture<br>A single 45-minute session of inhaled Oxygen-air mixture | Drug: Placebo<br>* Administration of the placebo (oxygen-air mixture [FiO2 ≈0.3]), will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.<br>* Other names: Sham;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response Based on Changes in Computerized Adaptive Testing Scores | Monitor changes in Computerized Adaptive Testing Mental Health (CAT-MH) scores relating to suicide, depression, and anxiety; to determine whether a single 45-minute inhalation of nitrous oxide vs placebo reduces symptoms. The CAT-MH is a validated self-reporting electronic diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide', 'depression', and 'anxiety'. Generated scores include severity and liklihood percentile: suicide = (%) low, intermediate, high depression = (%) normal, mild, moderate, severe anxiety = (%) normal, mild, moderate, severe | Up to 24-hours from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Compliance | Evaluate compliance of an acutely suicidal population in an Emergency Department (ED) setting, to complete a single 45-minute inhalation of nitrous oxide vs placebo. Determined by 'ability', 'inability', or 'refusal' to complete the entire 45-minute inhalation session (nitrous oxide vs placebo). | Intervention completion, 45-minutes | 
| Treatment Response Correlation to Lifetime Predictors Associated with Suicide | Evaluate if lifetime predictors (e.g., personal/family history of suicide attempts or suicide, history of alcohol dependence, and worst lifetime suicidal ideation) of eventual suicide correlate with the acute reduction in symptom severity following treatment. Lifetime predictors will be determined by medical and social history, and family history related to mental health. Symptom reduction is determined by changes in CAT-MH scores, over 24-hours from baseline. The CAT-MH is a validated self-reporting electronic diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide', 'depression', and 'anxiety'. Generated scores include severity and liklihood percentile: suicide = (%) low, intermediate, high depression = (%) normal, mild, moderate, severe anxiety = (%) normal, mild, moderate, severe | Up to 24-hours from baseline | 
| Rapid Treatment Response | Evaluate any acute reduction in symptoms. Based on changes in CAT-MH scores (suicide, depression, anxiety) at 30-minutes to 1-hour following treatment. Study patients ability to complete self-administered CAT-MH following inhalation may impact time-point. The CAT-MH is a validated self-reporting electronic diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide', 'depression', and 'anxiety'. Generated scores include severity and liklihood percentile: suicide = (%) low, intermediate, high depression = (%) normal, mild, moderate, severe anxiety = (%) normal, mild, moderate, severe | At 30-minutes to 1-hour from intervention conclusion | 
| Sustained Treatment Response | Evaluation of sustained response based on changes in CAT-MH scores at several time-points or until the patient is transferred or discharged from the ED. The CAT-MH is a validated self-reporting electronic diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide', 'depression', and 'anxiety'. Generated scores include severity and liklihood percentile: suicide = (%) low, intermediate, high depression = (%) normal, mild, moderate, severe anxiety = (%) normal, mild, moderate, severe | Up to 24-hours from intervention conclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Suicidal, Depression, Nitrous, Antidepressant, MDD, TRD