Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies

Most clinical major depression responds to standard treatments (medication and psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond to these treatments and are referred to as treatment-resistant major depression (TRMD). New treatments for TRMD are needed, and one promising line of research are drugs known as N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, our group demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD.

All patients will receive 3 randomized, one hour nitrous oxide inhalations to placebo (0% N2O), low dose (25% N2O), and high dose (50% N2O). Inhalation sessions will be at least 4 weeks apart. Mood will be assessed at baseline, 2 and 24 hours, and 1, 2, and 4 weeks post-inhalation for each dose.

Inclusion criteria

• Adults 18-75 years of age;
• Current diagnosis of unipolar major depressive disorder (MDD) without psychosis as confirmed by structured clinical interview for DSM-IV disorders;
• A score of >= 9 on the Montgomery-Åsberg Depression Rating Scale (MADRS);
• Documented (i.e., chart review) lifetime failure to respond to >=3 adequate dose/duration antidepressant treatment trials, ≥1 medication failure in the current depressive episode;
• Good command of the English language.

Exclusion criteria

• Meets criteria for any DSM-IV diagnosis for schizophrenia, bipolar, schizoaffective, obsessive-compulsive, personality, or panic disorders;
• Any recent (within past 12 months) history of substance dependence or abuse (except tobacco), determined by reported history or urine drug screen;
• Ability to become pregnant and not using effective contraception;
• Contraindication against the use of nitrous oxide:

• Pneumothorax
• Bowel obstruction
• Middle ear occlusion
• Elevated intracranial pressure
• Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
• Pregnant patients
• Breastfeeding women
• Inability to provide informed consent;
• Any other factor that in the investigators' judgment may affect patient safety or compliance