Feasibility of Inhaled Nitrous Oxide Versus Intravenous Ketamine in TRD With Suicidal Ideation: A Pilot RCT

Suicidal ideation is highly prevalent among individuals with treatment-resistant depression (TRD), with approximately 30% of TRD patients attempting suicide at least once during their lifetime. The evidence supporting efficacy of antidepressants for suicidal ideation in TRD is sparse, and new treatment options with rapid-acting anti-suicidal effects are urgently needed. Intravenous ketamine (IVK) has been shown to exert acute anti-suicidal effects that were sustainable up to 7 days after a single infusion of IVK, repeated dose IVK administrations have also demonstrated anti-suicidal effects. However, IVK could have potential cognitive adverse effects, high potential for misuse and abuse, and reported increases in suicidal ideation post-administration suggest that IVK might not be the most suitable treatment option for those with acute suicidality. An emerging alternative for suicidal ideation is inhaled nitrous oxide (N2O), which shares similar mechanisms with IVK but is easier to administer, is safer, and is more cost-effective. The tolerability, side effects, feasibility, and preliminary efficacy of N2O compared to IVK for the treatment of suicidal ideation in TRD are yet to be evaluated, and the current trial aims to examine this. Over 2 years, we will conduct a pilot randomized trial with 30 TRD participants with suicidal ideation (age 18 to 65) who will be randomized to either 50% N2O to inhale over 60 mins or 0.5 mg/kg IVK over 40 mins, twice weekly for 4 weeks. We will compare the effect of IVK and N2O for acutely suicidal TRD individuals with respect to feasibility, tolerability and safety of both treatment interventions as primary outcomes, and quantitative metrics of suicidal ideation and depressive symptoms as secondary outcomes. This project is led by an early career investigator and involves an interdisciplinary team of knowledge users and senior investigators who have experience in anesthesia, psychiatry, clinical trials with IVK and N2O for depression, and biostatistics. This trial will provide the critical pilot data to refine the sample size estimate and plan a large multi-site trial to definitively compare N2O to IVK as a treatment option for TRD with suicidal ideation and form the foundation to enable further development of glutamatergic treatments for suicidality.