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

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

The purpose of the study aims to determine whether different concentrations of nitrous oxide (N2O) have different antidepressant effects for adults with treatment-resistant major depression.

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

1. Adults 18-75 years of age;
2. Current diagnosis of unipolar major depressive disorder (MDD) without psychosis as confirmed by structured clinical interview for DSM-IV disorders;
3. A score of >= 9 on the Montgomery-Åsberg Depression Rating Scale (MADRS);
4. 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;
5. Good command of the English language.

Exclusion Criteria

1. Meets criteria for any DSM-IV diagnosis for schizophrenia, bipolar, schizoaffective, obsessive-compulsive, personality, or panic disorders;

2. Any recent (within past 12 months) history of substance dependence or abuse (except tobacco), determined by reported history or urine drug screen;

3. Ability to become pregnant and not using effective contraception;

4. Contraindication against the use of nitrous oxide:

   1. Pneumothorax
   2. Bowel obstruction
   3. Middle ear occlusion
   4. Elevated intracranial pressure
   5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
   6. Pregnant patients
   7. Breastfeeding women

5. Inability to provide informed consent;

6. Any other factor that in the investigators' judgment may affect patient safety or compliance