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

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:

5. Pneumothorax

6. Bowel obstruction

7. Middle ear occlusion

8. Elevated intracranial pressure

9. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12

10. Pregnant patients

11. Breastfeeding women

12. Inability to provide informed consent;

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